# projects

application_id: 8589705
project_number: 1R21AI107978-01
project_title: Farnesylated effectors of Legionella
administering_ic: NIAID
award_notice_date: 2013-05-24
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: AI
serial_number: 107978
program_official: KORPELA, JUKKA K
project_start_date: 2013-05-24
project_end_date: 2015-04-30
study_section: Special Emphasis Panel[ZRG1 IDM-A (80)]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant) Bacterial pathogens utilize type III-VII translocation systems to inject a large cadre of protein effectors into the host cell leading to modulation of cellular processes and manifestation of disease. Although many injected bacterial effectors are targeted into host cellular membranes to attain biological function the mechanisms of membrane targeting of injected bacterial effectors are not well understood. We have recently described a novel mechanism for anchoring an injected bacterial effector into host membranes through host-mediated farnesylation which covalently links a protein to a 15-carbon "farnesyl" lipid moiety. Farnesylation of proteins is a conserved eukaryotic post-translational lipidation of  conserved cysteine residue within the C-terminal teterapeptide "CaaX" motif of a protein. Farnesylation of hydrophilic proteins such as Ras enable the lipidated protein to be anchored into the lipid bi-layer of membranes to exhibit biological function.   
       Within amoeba and human cells the Legionnaires' disease bacterium Legionella pneumophila (Lp) resides and proliferate within an ER-remodeled Legionella-containing vacuole (LCV) which evades lysosomal fusion. Remodeling the LCV within amoeba and human cells is dependent on the Dot/Icm type IV secretion system which injects ~300 effectors into the host cell. We have shown that the Ankyrin B (AnkB) Dot/Icm-injected effector of Lp is anchored to the LCV membrane through host-mediated farnesylation of its "CaaX" motif which is indispensable for Lp intracellular proliferation.    
       Our preliminary data show that the host farnesylation enzymes are recruited to the cytosolic side of the LCV membrane which is novel among intra-vacuolar pathogens. The cytosolic side of the LCV membrane is highly enriched with other farnesylated proteins in addition to AnkB. In silico genomic analyses of Lp genomes have identified 6 Lp genes encoding novel proteins that harbor a C-terminal CaaX motif. The 6 encoded novel proteins are translocated into the host cell by the Dot/Icm system and have been designated as prenylated effectors of Legionella (Pel). When the Pels are ectopically expressed in human cells evidence suggests that the effectors associate with cellular membranes but this membrane localization is perturbed upon: 1) inhibition of host farnesylation; or 2) substitution of the conserved cysteine residue (pel C-A) within the CaaX motif of the Pels. Importantly a pelB null mutant and a pelB 502C-A substitution mutant exhibit similar severe defects in intracellular proliferation in macrophages. Therefore our hypothesis is: The injected novel Pel effectors are farnesylated by the host cell farnesylation machinery that targets them to specific cellular membranes to exhibit their functions required for intracellular proliferation of Lp. To test the hypothesis our
specific aims are to determine: I) Host mediated farnesylation and membrane-anchoring of the Pel effectors; and 2) Role of the pel effectors and their farnesylation in the intracellular infection by Lp.    
       The Significance of our studies: 1) Lp is a major cause of pneumonia; 2) The proposed studies will enhance our knowledge of Lp-host interaction through deciphering the role of novel translocated effectors in the intracellular infection; 3) Since our in silico genomic analyses show
prevalence of the C-terminal CaaX motif in effectors of other pathogens with type III-VII translocated systems our studies will stimulate investigations into a new paradigm in other pathogens; and 4) Our findings will contribute to our understanding the role of farnesylation in various human diseases such as Ras-mediated malignancies.   
       Innovation of the proposed studies come from: 1) the hypothesis; 2) hijacking the host farnesylation machinery by the pathogen-containing vacuole which is highly enriched with farnesylated proteins; 3) Novelty of the 6 Pels Dot/Icm-translocated effectors indicating novel functions in cellular modulations; 4) Our multidisciplinary approach of deciphering role of host-mediated lipidation of the Pel effectors combined with their biological functions in the intracellular infection by Lp; and 5) The major role for PelB and its C-terminal CaaX motif in the intracellular infection of human macrophages.

project_terms:
Abbreviations;Amoeba genus;Ankyrins;Bacteria;Biological Process;C-terminal;Carbon;Cell physiology;Cells;Cellular Membrane;Co-Immunoprecipitations;Computer Simulation;Cysteine;Data;Defect;Disease;Enzymes;Exhibits;Genes;Genome;Genomics;Human;Infection;Investigation;Knowledge;Legionella;Legionella pneumophila;Legionnaires' Disease;Link;Lipids;Malignant Neoplasms;Mediating;Membrane;Pneumonia;Prevalence;Proliferating;Protein Farnesylation;Proteins;Recruitment Activity;Role;Side;System;Testing;Transferase;Type IV Secretion System Pathway;Vacuole;farnesylation;human disease;innovation;interdisciplinary approach;macrophage;mutant;novel;pathogen;protein farnesyltransferase;public health relevance

public_health_relevance:
To proliferate within cells intracellular bacterial pathogens inject protein effectors into the host cell that interact with specific host targets to remodel the
host cell into a niche permissive for bacterial proliferation. Some of the injected bacterial effectors are anchored into host membranes but the mechanisms involved in this membrane anchoring are not known. Host-mediated lipidation of the injected effector is a potential mechanism of membrane anchoring. Our proposed studies on Legionella pneumophila explore 6 injected bacterial effectors that have the potential to be lapidated by the host. We will deciphe the role of the 6 effectors and their lipidation and membrane anchoring in their biological function in intracellular bacterial proliferation.


application_id: 8589434
project_number: 2R44AA018226-03A1
project_title: Selection-driven plant metabolites for treatment of CNS diseases
administering_ic: NIAAA
award_notice_date: 2013-09-09
opportunity_number: PA-11-335
application_type: 2
activity_code: R44
ic: AA
serial_number: 018226
suffix: A1
program_official: EGLI, MARK
project_start_date: 2010-08-20
project_end_date: 2015-08-31
study_section: Special Emphasis Panel[ZRG1 ETTN-M (11)]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This project aims to demonstrate that the evolution of plant biosynthetic pathways can be accelerated and driven to favor the synthesis of ligands which interact with a specific human target protein. This is achieved by subjecting mutant plant cells to selection pressures favoring the survival of mutants with the phenotype of interest. As an example this approach will be used to optimize pharmacological activity in Lobelia cardinalis which inhibits the human dopamine transporter (hDAT) putatively by its ability to synthesize the complex alkaloid lobinaline. A stable transgenic line of L. cardinalis plant cells expressing the hDAT has been established. These cells show increased sensitivity to toxins transported into the cell by the hDAT including the neurotoxin MPP+. A large genetically diverse population of gain-of-function mutants expressing the hDAT has now been generated and selected on medium containing 100uM MPP+ which kills the vast majority of the transgenic mutants. However individual mutants that are over-producing inhibitors of the hDAT have a survival advantage so that the MPP+-resistant population is greatly "enriched" in clones with this bioactivity. Preliminary GC/MS analysis of individual MPP+-resistant mutants with increased hDAT inhibitory activity indicates that many of these are overproducing lobinaline but the rest are generating other metabolites some of which are not detectable in the wild-type plant. Phase II is designed to demonstrate that this biotechnology can be used to (a) generate novel natural products with a specific valuable pharmacology (b) provide a biosynthetic production system for these compounds in mutant plants. The process should be of particular value when a plant-derived lead compound such as lobinaline is too complex for chemical synthesis. The first specific aim is to analyze the remaining MPP+-resistant population to determine those individuals in which lobinaline content cannot explain increased hDAT inhibitory activity. Separation (assay-guided preparative HPLC) and tentative identification (GC/MS) of active compounds will be followed by pharmacological evaluation in vitro in comparison with lobinaline and a synthetic inhibitor of the hDAT. The most active compounds will then be tested for functional effects on the DAT in rat brain in vivo using electrochemistry. In parallel studies the
mutant clonal cultures which are overproducing active metabolites to the greatest extent will be regenerated to intact mutant plants and extracts analyzed to establish whether the pharmacological /chemical phenotype is retained. The ultimate aim is to commercialize the technology as a platform for discovering and producing novel plant-derived natural products targeted on specific human CNS proteins.

project_terms:
1-Methyl-4-phenylpyridinium;Agonist;Alkaloids;Amphetamines;Antioxidants;Award;Biological Assay;Biological Factors;Biotechnology;Brain;Cell Culture Techniques;Cell Line;Cells;Central Nervous System Diseases;Chemicals;Complex;Computer Simulation;Corpus striatum structure;Development;Drug Addiction;Drug Industry;Electrochemistry;Evaluation;Evolution;Free Radical Scavenging;Guanine + Cytosine Composition;High Pressure Liquid Chromatography;Hormonal;Human;In Vitro;Individual;Killings;Lead;Ligands;Lobelia;Medicine;Methods;Mitochondria;Modification;National Institute on Alcohol Abuse and Alcoholism;Natural regeneration;Neurodegenerative Disorders;Neurotoxins;Nicotine;Nicotinic Receptors;Norepinephrine;Nucleus Accumbens;Pathway interactions;Pharmaceutical Preparations;Pharmacology;Phase;Phenotype;Plant Extracts;Plants;Population;Population Heterogeneity;Predisposition;Preparation;Process;Production;Proteins;Rattus;Resistance;Rest;Serotonin;Small Business Innovation Research Grant;Small Business Technology Transfer Research;Source;Structure;System;Techniques;Technology;Testing;Therapeutic Uses;Toxin;Transgenic Organisms;United States National Institutes of Health;base;chemical synthesis;design;directed evolution;dopamine transporter;gain of function;gain of function mutation;high throughput screening;improved;in vivo;inhibitor/antagonist;interest;mutant;novel;pre-clinical;pressure;programs;public health relevance;radioligand;uptake

public_health_relevance:
Plants are a major source of existing medicines but the pharmaceutical industry has now almost abandoned this source in favor of synthetic chemicals. One reason is that plant metabolites are often too complex for synthetic methods to be used for their modification or production. The technology being developed by Naprogenix uses the plants own biosynthetic capacity to modify the active chemicals contained in the plant. It is also capable of increasing the amounts of the active chemicals that are present. The "directed evolution" of a plant species using this technology is capable of generating novel compounds that may be of value in many CNS diseases for example the targets in this project are important in drug dependence and neurodegenerative disease.


application_id: 8589227
project_number: 1R43EY023122-01A1
project_title: A Novel Adherence Technology for Ophthalmic Medications
administering_ic: NEI
award_notice_date: 2013-09-11
opportunity_number: PA-12-088
application_type: 1
activity_code: R43
ic: EY
serial_number: 023122
suffix: A1
program_official: WUJEK, JEROME R
project_start_date: 2013-09-30
project_end_date: 2015-03-29
study_section: Special Emphasis Panel[ZRG1 RPHB-C (10)]
contact_pi_person_id: 8872445
contact_pi: BAILEY, MICHAEL
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
budget_start_date: 2013-09-30
project_abstract:
ABSTRACTTechnological aids supporting medication management for chronically ill patients are proliferating offered inelectronic telehealth devices. Pill organizers reminders monitors and usage communicators have enabled anarray of home health aids to support users and caregivers in pill management and monitoring. Beyond bulkpills additional medication forms such as topicals are gaining popularity in unique drug delivery systems.However topical medications have limited electronic monitoring means for promoting and tracking adherenceeven though the consequences of nonadherence are just as alarming as with oral meds. For example glaucomais a leading cause of blindness worldwide yet patient compliance with topical medication regimens issuboptimal at best. Ophthalmic drug adherence is daunting due to several unique barriers: 1) complexity-- theapplication of eye drops can be highly complicated involving multiple drugs taken several times daily 2)administration-- visually impaired patients often cannot correctly identify medication and read labels 3)lability-- many drugs react adversely to extreme conditions and 4) lack of patient options-- no multi-drugcontainer exists with feature-rich reminding monitoring and intervention functions. Moreover a primarybarrier to administration of eye drops is the problematic issue of actually administering drops properly. Thisproject will leverage our world-class medication adherence system and our team's exceptional skill sets andexperience in developing an ophthalmic medication dispensing system that will instruct remind monitorcommunicate and report in a highly affordable practical and user-sensitive model. It includes a dropdispensing device that assures only one drop is properly applied to the eye in sterile safe and correctapplication with infrared monitoring.

project_terms:
Address;Adherence (attribute);Back;Blindness;Caregivers;Caring;Chronic Disease;Chronically Ill;Comorbidity;Companions;Complex;Compliance behavior;Computer software;Data;Development;Devices;Disease;Dose;Drops;Drug Containers;Drug Delivery Systems;Drug Stability;Drug usage;Electronics;Elements;Engineering;Ensure;Evaluation;Event;Eye;Eyedrops;Focus Groups;Funding;Funding Category;Generations;Glaucoma;Health;Health Care Costs;Heating;Home environment;Housing;Injectable;Intellectual Property;Intervention;Label;Leadership;Light;Liquid substance;Medication Management;Mind;Mission;Modeling;Monitor;Names;Ointments;Optic Nerve;Oral;Outcome;Participant;Patients;Pharmaceutical Preparations;Phase;Physiologic Intraocular Pressure;Proliferating;Protocols documentation;Reading;Refrigeration;Regimen;Reporting;Research Personnel;Self-Administered;Self-Help Devices;Small Business Innovation Research Grant;Solutions;Sterility;Suspension substance;Suspensions;System;Technology;Telephone;Testing;Therapeutic;Time;United States National Institutes of Health;Vial device;Vision;Visual impairment;Visually Impaired Persons;base;combat;effectiveness measure;experience;improved;innovation;medication compliance;novel;ophthalmic drug;pill (pharmacologic);point of care;prevent;prototype;public health medicine (field);public health relevance;satisfaction;skills;telehealth;usability;web site

public_health_relevance:
PROJECT NARRATIVEA critical public health concern is mismanagement of medications which all-too-oftenexacerbates diseases and multiplies comorbidities. It is part of NIH's mission to promoteinnovation in combating diseases. We propose a novel multi-drug medication reminder/monitorsystem that serves to improve adherence to drugs in liquid and ointment form for which there isno technological aid currently.


application_id: 8588787
project_number: 5R01CA035635-27
project_title: Specificity of Intercalation Reactions
administering_ic: NCI
award_notice_date: 2013-11-15
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 035635
program_official: FU, YALI
project_start_date: 1984-03-01
project_end_date: 2015-12-31
study_section: Macromolecular Structure and Function B Study Section[MSFB]
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): DNA is an underrepresented target for small molecule therapeutic agents. One reason for the dearth of DNA targeted drugs is that the fundamental molecular mechanisms that govern sequence- and structural-selective ligands to DNA remain poorly understood. In order to develop design principles for targeting specific DNA sites a thorough understanding of the binding mechanisms of existing compounds that bind to DNA with unique types of selectivity is needed. The long-range goal of this project is to understand the mechanism of DNA intercalation reactions with particular emphasis on the energetic basis of sequence- and structural-selective binding. Renewal is sought for a successful and highly productive basic science program that has produced several promising avenues for DNA-targeted drug development. Four-stranded G-quadruplex DNA structures have emerged as important functional elements within the genome and represent important new targets for therapeutic drugs. G-quadruplexes are functional elements that are important in telomere biology and are emerging as important control elements in the expression of many genes particularly oncogenes. Research in the next funding period will focus on biophysical studies of G-quadruplex structure folding and stability and on their selective interactions specific quadruplex structures with drug-like molecules. Specific aims include: 1. Determination of the structure of the 200 nt single-stranded DNA overhang that is a conserved feature of human telomeres. 2. Determination of the thermodynamic stability of higher-order quadruplex structures and the kinetics of the folding. 3. Determination of the thermodynamics and kinetics of drug binding to specific quadruplex structures including the higher-order structures in telomeric DNA and the G-quadruplex "silencer" element found in the c-myc promoter. The results of these proposed studies will deepen our understanding of the structure and stability of functionally important G-quadruplexes and will provide fundamental mechanistic information of use in the rational design of new small molecules to selectively target functionally important quadruplex structures.

project_terms:
Base Sequence;Basic Science;Beryllium;Binding (Molecular Function);Binding Proteins;Biology;Calorimetry;Cell Cycle;Computing Methodologies;Coupled;Crystallography;DNA;DNA Intercalation;DNA Structure;Diffusion;Drug Kinetics;Drug Stability;Drug Targeting;Elements;Fluorescence;Foundations;Funding;G-Quartets;Gene Expression;Genes;Genome;Goals;Higher Order Chromatin Structure;Human;Human Genome;In Vitro;Indium;Kinetics;Ligand Binding;Ligands;Methods;Molecular;New Agents;Oncogenes;Pharmaceutical Preparations;Process;Promotor (Genetics);Property;Proteins;Radial;Reaction;Refractory;Regulatory Element;Research;Research Design;Resolution;Sedimentation process;Single-Stranded DNA;Site;Specificity;Structural Models;Structure;Telomerase;Testing;Therapeutic Agents;Thermodynamics;Time;Transcriptional Silencer Elements;base;biophysical properties;biophysical techniques;c-myc Genes;design;dimer;driving force;drug development;innovation;intercalation;light scattering;molecular dynamics;new therapeutic target;programs;public health relevance;sedimentation velocity;small molecule;telomere

public_health_relevance:
G-quadruplexes are four-stranded DNA structures that are thought to be functionally import elements in the human genome. Quadruplexes have emerged as potential drug targets. The proposed project will use computational and biophysical methods to study the structure stability and drug binding of functionally significant quadruplex structures. The results will be of fundamental use for guiding the design of new drugs targeted toward quadruplexes.


application_id: 8586142
project_number: 1R43CA179911-01
project_title: Virtual Fly-Over Colonoscopy System for Clinical Test-SBIR Phase 1
administering_ic: NCI
award_notice_date: 2013-09-17
opportunity_number: PA-12-088
application_type: 1
activity_code: R43
ic: CA
serial_number: 179911
program_official: NARAYANAN, DEEPA
project_start_date: 2013-09-17
project_end_date: 2015-08-31
study_section: Special Emphasis Panel[ZRG1 SBIB-T (10)]
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 OC
and 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;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:
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: 8585935
project_number: 5P30NS051220-09
project_title: MOLECULAR MECHANISMS
administering_ic: NINDS
award_notice_date: 2013-12-06
opportunity_number: PAR-08-116
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
subproject_number: 7623
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD 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: 2013-12-01
budget_end_date: 2014-11-30
project_abstract:
CORE E. Molecular Mechanisms Core Plans: This core represents an expansion of the role of the previous Pharmacokinetics & Biomarker Core into what we now will call a Molecular Mechanisms Core in order to better meet the needs of the SCoBIRC faculty and other neuroscience investigators who use the SCoBIRC Core Facilities. In its former role the core managed by Core Director Dr. Edward D. Hall and Assistant Core Director and Supervisor Dr. Jeff Bosken primarily employed GC-MS and HPLC technologies
for bioanalytical measurements of drugs and potential injury-related biomarker compounds in biofluids (e.g blood urine cerebrospinal fluid). However the core's scope was expanded very eariy during the current funding period to include equipment (LiCor Odyssey Infrared Image Analyzer) and expertise for highly sensitive analysis of immunoblots using infrared-emitting secondary anfibodies. This technology has been heavily employed by several SCoBIRC and other BBSRB neuroscience investigators. More recently the
core has added an Applied Biosystem StepOnePlus quantitative RT-PCR capability for gene expression analysis studies which is growing in use. However going forward we intend to add another functional component to the Core to support the large number of SCoBIRC and other neuroscience faculty who are studying changes in mitochondrial bioenergetics in in vitro and in vivo models of acute and chronic neurodegenerative disease models. The growing interest in mitochondrial functional studies across several
funded and pilot projects has made it desirable to centralize this capability into the core to insure methodological consistency and quality control and comparability of data across laboratories. We plan to provide this centralized capability by first of all shifting existing equipment used for mitochondrial preparation and bioenergetic analyses of ex vivo mitochondrial isolates into the core and secondly to add new Seahorse technology for highly sensitive imaging of mitochondrial bioenergetics and dysfunction and
whole cells in culture models.
Requested Molecular Mechanisms Core Equipment and Supplies: We are specifically requesting funding for purchase of the following. Note: all equipment quotes are listed in Appendix I
 Seahorse Bioscience XF96 Dual Analyte Extracellular Analyzer- Justification: This state of art technology is capable of detecting real time changes in up to 3 analytes of cellular metabolism in a non-destructive manner in both energy producing pathways. $171636
Molecular Mechanisms Core Usage: The following SCoBIRC and other neuroscience invesfigators who have and will continue to use the core include: Cambi Geddes Gerhardt Gash Guttman Hall Rabchevsky Saatman Smith Snow Springer Sullivan Zhang and Zhu.
Molecular Mechanisms Core Staffing: The Center Core Grant PI Dr. Edward D. Hall (5% effort) will confinue to serve as Core Director for the Molecular Mechanisms Core. Dr. Jeff Bosken (100% effort) will also continue to serve as Core Supervisor. He will also be specifically responsible for conduct and training in regards to the bioanalytical instrumentation (GC-MS HPLC) functional component. Dr. Indrapal Singh
(25% effort) a Research Assistant Professor who is highly expert in mitochondrial bioenergetic studies will be responsible for the mitochondrial bioenergetics component of the core in regards to equipment maintenance training and pilot study conduct. . He will be responsible for maintenance pilot studies and training of laboratory personnel in regards to the immunoblotting (western slot infra-red imaging) and quantitative RT-PCR gene expression functions of the core.

project_terms:
Acute;Bioenergetics;Biological Markers;Blood;Cells;Center Core Grants;Cerebrospinal Fluid;Chronic;Core Facility;Data;Disease model;Drug Kinetics;Energy Metabolism;Equipment;Equipment and Supplies;Faculty;Functional disorder;Funding;Gases;Gene Expression;Gene Expression Profiling;Genus Hippocampus;High Pressure Liquid Chromatography;Image;Immunoblot Analysis;In Vitro;Injury;Laboratories;Laboratory Personnel;Life;Liquid substance;Maintenance;Measurement;Metabolism;Mitochondria;Modeling;Molecular;Neurodegenerative Disorders;Neurosciences;Pathway interactions;Performance;Pharmaceutical Preparations;Pilot Projects;Preparation;Quality Control;Research;Research Personnel;Reverse Transcriptase Polymerase Chain Reaction;Role;Snow;Technology;Testing;Time;Training;Urine;Western Blotting;extracellular;in vivo Model;instrumentation;interest;meetings;method development;professor;spinal cord and brain injury


application_id: 8585933
project_number: 5P30NS051220-09
project_title: MICROSCOPY CORE
administering_ic: NINDS
award_notice_date: 2013-12-06
opportunity_number: PAR-08-116
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
subproject_number: 7622
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
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: 2013-12-01
budget_end_date: 2014-11-30
project_abstract:
The Microscopy Image Analysis and Stereology Core located on the BBSRB fourth floor provides advanced instrumentation required for neurotrauma and other neuroscience research including two Olympus Provis AX70 Fluorescence Microscopes (Image Pro interfaced via MagnaFire Digital Camera) an Olympus BX 41 with Video Camera an Olympus BX 50 Epifluorescent Microscope (Bioquant Stereology package + 3D topographer interfaced with MagnaFire Digital Camera and Optronics Video Camera) a Zeiss Axiovert 200 M microscope and a Nikon E400 teaching microscope with DAGE Video Camera. In addition to this existing equipment SCoBIRC recently invested in three new specialized microscopes with funding from the NIH. The first an Olympus FluoViewTM 300 point-scanning point-detection confocal laser scanning microscope designed for biology research applications has excellent resolution efficiency of excitation and an intuitive user-friendly interface including preset parameters for individual users. The FluoViewTM 300 is also capable of 3D rendering and time-lapse observation and TTL I/O signals can be generated to coordinate experiments timed with external instrumentation. Additionally two high-sensitivity photomultiplier tubes (PMTs) are located directly within the FV300 confocal fluorescence emission light path for high sensitivity detection of the fluorescence signal. The second stereology microscope is an inverted Olympus IX 81 outfitted with motorized stage encoders and the BioQuant Nova Prime software particulariy well suited for quantification using modern stereological tools. The core is staffed by a Core Director Patrick Sullivan Ph.D. SCoBIRC Associate Director and Associate Professor of Anatomy & Neurobiology and an Assistant Director Alexander Rabchevsky Ph.D. Associate Professor of Physiology both of whom are well versed in the use of multiple image analysis endpoint measures and confocal imaging as endpoints in theirresearch. Both have expertise in developing protocols used to assess tissue sparing and cell loss in neurotrauma research.

project_terms:
Anatomy;Biology;Cell Count;Cells;Center Core Grants;Computer software;Computers and Advanced Instrumentation;Detection;Doctor of Philosophy;Educational process of instructing;Electrons;Equipment;Floor;Fluorescence;Funding;Housing;Human Resources;Image;Image Analysis;Individual;Lasers;Light;Measurement;Measures;Microscope;Microscopic;Microscopy;Neurobiology;Neurosciences Research;Physiology;Protocols documentation;Research;Resolution;Scanning;Signal Transduction;Staging;Time;Tissues;Tube;United States National Institutes of Health;design;digital;digital imaging;fluorescence microscope;instrumentation;light emission;method development;photomultiplier;professor;research study;spinal cord and brain injury;tool;transmission process;user-friendly


application_id: 8585931
project_number: 5P30NS051220-09
project_title: BEHAVIORAL TESTING
administering_ic: NINDS
award_notice_date: 2013-12-06
opportunity_number: PAR-08-116
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
subproject_number: 7621
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2013-12-01
budget_end_date: 2014-11-30
project_abstract:
The Behavioral Testing Core is housed within two rooms in the basement of BBSRB. B028 is a dedicated room for behavioral assessment of rats in which the Core has the capability of performing a) cognitive testing of learning and memory using a Morris water maze system b) sensory testing using a whisker nuisance task c) nociceptive testing using a Hargreaves plantar device and d) locomotor function testing using the Basso Beattie Bresnahan (BBB) scale and the foot misplacement apparatus (horizontal ladder). B030 is a dedicated room for behavioral assessment of mice in which the Core has the capability of performing cognitive testing of learning and memory using a white Morris water maze (for black mice) or a black maze (for white mice) in conjunction with an updated digital tracking system. Mice can also be evaluated for sensorimotor function using a corner turn test vestibulomotor ability using the rotarod apparatus and simple and complex motor function using the composite neuroscore neurological severity score. Basso mouse scale (BMS) grip strength meter and string test. Specific instruments purchased with P30 funds include 2 AccuScan Instruments EzVideoDV Automated Tracking System Digital Systems a Columbus Instruments Rotamex-5 and Foot Misplacement Apparatus 2 analgesia meters and a wading pool for open field locomotor assessment. Kathryn Saatman Ph.D. directs the Behavioral Testing Core along with Assistant Core Director Alexander Rabchevsky. Stephen Onifer Ph.D provide day-to-day management of core operations and overseeing training data storage and dissemination and core usage. Two senior technicians who are trained in behavioral testing in rodent TBI models (Ms. Jennifer Pleasant 25% effort) and SCI models (Mr. Travis Lyttle 25% effort) assist and instruct new core users with the behavioral assessments.

project_terms:
Absence of pain sensation;Behavior assessment;Center Core Grants;Cognitive;Complex;Data Storage and Retrieval;Devices;Doctor of Philosophy;Equipment;Evaluation Methodology;Funding;Housing;Learning;Memory;Modeling;Motor;Mus;Neurologic;Nociception;Rattus;Research;Rodent;Sensorimotor functions;Sensory;Severities;System;Testing;Training;Update;Vibrissae;behavior test;digital;foot;grasp;improved;instrument;meter;morris water maze;operation;ranpirnase;spinal cord and brain injury


application_id: 8585928
project_number: 5P30NS051220-09
project_title: ANIMAL MODELING
administering_ic: NINDS
award_notice_date: 2013-12-06
opportunity_number: PAR-08-116
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
subproject_number: 7620
contact_pi_person_id: 1884283
contact_pi: SCHEFF, STEPHEN W
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2013-12-01
budget_end_date: 2014-11-30
project_abstract:
CORE B. Animal Modeling Core Plans: This core previously named the Animal Surgery & TBI/SCI Model Core will be renamed Animal Modeling Core to reflect the expansion of the capabilities of this widely used facility beyond its previous use as an animal surgery and neurotrauma modeling resource. While these functions will continue to constitute the central component of the core which will be the Surgery and In Vivo Models Component we request funding to add physiological (blood pressure heart rate arterial oxygenation body temperature and electrophysiological (e.g. somatosensory evoked potentials magnetically-evoled inter-enlargement recordings) monitoring capability during the acute recovery period after experimental neurotrauma. In addition we request support to establish a Viral Vectors Component and a Genetically-Modified Mice Component. These latter two capabilities currently exist within individual SCoBIRC laboratories (Dr. George Smith's lab in the former instance and Dr. Geddes' in the latter case). However the increasing need for the application of these across multiple laboratories has made it sensible to now expand and incorporate them under the umbrella of our Animal Modeling Core in order to improve access to them and to insure technical standardization across user laboratories.

project_terms:
Acute;Animal Model;Animals;Blood Pressure;Body Temperature;Breeding;Center Core Grants;Funding;Genes;Genotype;Heart Rate;Improve Access;Individual;Knock-out;Laboratories;Microinjections;Modeling;Monitor;Mus;Names;Operative Surgical Procedures;Physiologic Monitoring;Physiological;Recovery;Research;Resources;Rodent;Somatosensory Evoked Potentials;Standardization;Transgenic Organisms;Viral Vector;in vivo;in vivo Model;spinal cord and brain injury


application_id: 8585926
project_number: 5P30NS051220-09
project_title: ADMINISTRATIVE & BIOINFORMATICS
administering_ic: NINDS
award_notice_date: 2013-12-06
opportunity_number: PAR-08-116
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
subproject_number: 7619
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD 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: 2013-12-01
budget_end_date: 2014-11-30
project_abstract:
The core which is located in SCoBIRC-controlled space on the 4th floor ofthe BBSRB will continue to provide an administrative and organizafional framework to support monitor and coordinate the usage of each of the research cores and related activities and achieve increased collaboration among investigators. Ongoing scheduling of the research cores is done and monitored via our existing OfficeTracker system. Administrative functions will also include financial oversight (including maintenance contracts) and core facility staff management. In addition the core will continue to maintain a secure server to store and archive scientific data from each of the cores and and individual investigators. The core will also continue to maintain and further develop the existing Spinal Cord Injury-
Related Gene Database or SCIgenes database which is accessible via the internet
(httD://scigenes.ukv.edu). The goal of the database is to serve the spinal cord injury research community by compiling information at a single site about genes and gene products relevant to spinal cord injury such that gene sequence can be linked with protein function so that data mining algorithms will be able to determine patterns in the gene products affected by spinal cord injury. These patterns help predict relationships
between proteins and therefore biochemical pathways affected by spinal cord injury.

project_terms:
Accounting;Affect;Algorithms;Archives;Biochemical Pathway;Bioinformatics;Budgets;Center Core Grants;Collaborations;Communities;Computers;Contracts;Core Facility;Data;Data Storage and Retrieval;Databases;Equipment;Floor;Funding;Genes;Goals;Grant;Human Resources;Individual;Internet;Link;Maintenance;Monitor;Pattern;Printing;Proteins;Research;Research Personnel;Schedule;Secure;Site;Spinal cord injury;System;data mining;posters;protein function;spinal cord and brain injury


application_id: 8585370
project_number: 7R01NS065842-05
project_title: Perlecan Domain V is a Novel Promoter of Brain Repair after Stroke
administering_ic: NINDS
award_notice_date: 2012-12-03
opportunity_number: PA-08-099
application_type: 7
activity_code: R01
ic: NS
serial_number: 065842
program_official: BOSETTI, FRANCESCA
project_start_date: 2010-04-01
project_end_date: 2015-03-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7568819
contact_pi: BIX, GREGORY JAYE
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL 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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Stroke is the third leading cause of death and the leading cause of serious long-term disability in the U.S. However while advances have been made in acute stroke treatment our understanding of the mechanisms underlying brain self-repair after stroke remains poor. Therefore the problem of brain repair and stroke rehabilitation is an emerging research priority with the underlying goal of identifying and improving brain reparative processes.  Brain repair reportedly occurs in a close temporal-spatial neurovascular niche of revascularization (angiogenesis) and neuronal repopulation (neurogenesis). We hypothesize that the post-stroke brain stimulates angiogenesis and neurovascular niche formation in part by generating a bioactive fragment of the extracellular matrix (ECM) perlecan. Our hypothesis is based on several key observations including our preliminary data: Stroke results in proteolytic generation of bioactive fragments of perlecan the most protease-sensitive ECM component studied and perlecan is required for both angiogenesis and neurogenesis. Our preliminary studies indicate that the C-terminal fragment of perlecan domain V (DV) a previously identified modifier of angiogenesis 1) is upregulated in the brain after stroke 2) enhances brain angiogenesis in vitro and in vivo 3) increases brain endothelial cell secretion of brain derived neurotrophic factor (BDNF) an important pro-angiogenic neuroprotective and migration promoting factor in the neurovascular niche and 4) may exert these effects through the pro-angiogenic (5(1 integrin. Empowered by this new knowledge we now plan to 1) Determine the role of DV in brain angiogenesis and neurovascular niche formation 2) Determine the integrin-related signaling pathway by which DV affects brain angiogenesis and neurovascular niche formation and 3) Determine the importance and therapeutic potential of DV to post-stroke brain repair. Specifically we plan to demonstrate that DV stimulates brain angiogenesis and neurovascular niche formation via interaction with the (5(1 integrin and subsequent release of BDNF and demonstrate that DV enhances post-stroke brain repair. The proposed studies are significant in that they investigates differences between brain and nonbrain angiogenesis seek to establish a novel mechanism of post-stroke brain self-repair for therapeutic exploitation and suggests a significantly longer therapeutic window than currently employed stroke therapies. Our investigation is innovative because it suggests that ECM fragments generated by brain injury could possess beneficial effects and identifies a novel cause of brain endothelial cell BDNF release. Our long term goal is to develop DV as a human stroke therapy.    PUBLIC HEALTH RELEVANCE: Stroke is the third leading cause of death and the leading cause of serious long-term disability in the U.S. However while advances have been made in trying to minimize brain injury after stroke little is known about how to stimulate repair of injured brain tissue. Therefore we propose to study the potential benefits of a stroke-generated protein fragment in a stroke animal model with the goal of developing a new type of human stroke therapy.

public_health_relevance:
Project NarrativeStroke is the third leading cause of death and the leading cause of serious long-termdisability in the U.S. However while advances have been made in trying to minimizebrain injury after stroke little is known about how to stimulate repair of injured braintissue. Therefore we propose to study the potential benefits of a stroke-generatedprotein fragment in a stroke animal model with the goal of developing a new type ofhuman stroke therapy.


application_id: 8583981
project_number: 1R21DE023207-01A1
project_title: Blocking of IL-6 function to prevent Pg mediated Th17 response
administering_ic: NIDCR
award_notice_date: 2013-07-08
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: DE
serial_number: 023207
suffix: A1
program_official: MELILLO, AMANDA A
project_start_date: 2013-07-09
project_end_date: 2015-06-30
study_section: Special Emphasis Panel[ZRG1 MOSS-B (02)]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN S
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Th17 cells are emerging as critical players in many chronic inflammatory diseases including chronic periodontitis. Periodontal disease besides being the most prevalent form of bone pathology in humans is a risk factor for life-threatening conditions such as cardiovascular diseases and diabetes. Attempts to describe the pathogenesis of periodontal disease within the conceptual framework of Th1/ Th2 model have been inconclusive. Several human studies in CP have shown elevated levels of IL-17 signature cytokine of Th17 cells and presence of Th17 cells in the inflamed gingiva. However underlying mechanism of Th17 differentiation and their role in the pathogenesis of CP is not known. In this regard pro-inflammatory pleotropic cytokine IL-6 plays a critical role in differentiation of Th17
cells and inhibition of regulatory T cells. Due to this role of IL-6 blocking of IL-6 function ha become an attractive target for treatment of chronic inflammatory and autoimmune diseases. Many clinical trials involving blocking of IL-6 signaling molecules are currently ongoing. In line with this CP although is initiated by microbes which include P. gingivalis disease pathogenesis and progression is immune mediated with high levels of IL-6. P. gingivalis implicated in CP relies on multiple virulence factors like fimbriae LPS and cysteine proteinases ginipains (RgpA and RgPB) which use different signaling receptors to exert their influence. While fimbriae FimA/ Pg LPS targets TLR2 gingipains (RgpA RgpB) signal through PAR-2. Both the receptors are expressed by human dendritic cells. In view of this information major hypothesis of the proposal is that Pg PAMP's adhesins and gingipains which use different PRR's have distinct immune-modulatory roles in TH17 differentiation and blocking of IL-6 signaling molecules represents an important therapeutic target to prevent Pg initiated Th17 differentiation. The major objective of this proposal is to identify molecular therapeutic targets o inhibit Pg and its PAMP's mediated Th17 differentiation and bone loss. To address this we will focus on two approaches first we will investigate the potential of Pg and it PAMP's in induction of IL-6 regulation of IL-6 signaling molecules and in Th17 differentiation by in-vitro cultured monocyte derived dendritic cells (MoDCs).Second we will target IL-6 signaling molecules: a) IL-6 receptor (IL-6R) with anti- IL-6R antibodies b) signal transducing protein gp130Fc and c) Jak2 inhibitor which have been proven to be effective in many chronic inflammatory and autoimmune diseases. The Long term goal of this study is to develop immune-modulatory intervention strategies for fine- tuning the host response to maximize the protective response and minimize the destructive aspects of the periodontal host response. Positive findings will establish the regulation of human Th17 cells by P. gingivalis adhesins and gingipains. Results of the present investigation will be useful in design of novel therapeutic targets.

project_terms:
Address;Alveolar Bone Loss;Animal Model;Antigens;Arginine;Autoimmune Diseases;Bacterial Adhesins;CD4 Positive T Lymphocytes;Cardiovascular Diseases;Cells;Chronic;Clinical Trials;Cysteine Protease;Degenerative polyarthritis;Dendritic Cells;Development;Diabetes Mellitus;Disease;Fc Receptor;Genes;Genetic Polymorphism;Gingiva;Gingival Crevicular Fluid;Goals;Gram-Negative Anaerobic Bacteria;Human;Immune;Immune response;In Vitro;Inflammatory;Interleukin 6 Receptor;Interleukin-1;Interleukin-12;Interleukin-17;Interleukin-6;Intervention;Investigation;Lead;Life;Maintenance;Mediating;Microbe;Modeling;Molecular;Mus;Myocardial Infarction;Oral;Oral mucous membrane structure;PAR-2 Receptor;Pathogenesis;Pathology;Patients;Pattern;Periodontal Diseases;Periodontitis;Phase;Physiologic pulse;Plasma;Play;Porphyromonas gingivalis;Process;Production;Proteins;Receptor Signaling;Regulation;Regulatory T-Lymphocyte;Reporting;Rheumatoid Arthritis;Risk Factors;Role;Signal Transduction;Signaling Molecule;Symptoms;T-Lymphocyte;TNFSF11 gene;Therapeutic Agents;Toll-Like Receptor 2;Tooth Loss;Virulence Factors;base;bone;bone loss;cardiovascular disorder risk;cost;cytokine;design;fimbria;gingipain;human disease;inhibitor/antagonist;interleukin-21;interleukin-23;microbial;monocyte;new therapeutic target;novel therapeutics;oral bacteria;pathogen;prevent;public health relevance;receptor;response;therapeutic target

public_health_relevance:
Periodontitis is a chronic inflammatory disease that can lead to not only tooth loss at a cost estimated to be $70 billion but also are associated with risk of
cardiovascular disease and myocardial infarction. Periodontitis is initiated by oral bacteria present in the gums and symptoms of disease are a result overproduced immune response. Thus identifying and blocking critical bacterial and host responses involved in the disease process is the key to cure the gum disease.


application_id: 8583505
project_number: 1R21AI097608-01A1
project_title: Identification of host factors required for Yersinia pestis macrophage infection
administering_ic: NIAID
award_notice_date: 2013-05-28
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: AI
serial_number: 097608
suffix: A1
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2013-06-01
project_end_date: 2015-05-31
study_section: Special Emphasis Panel[ZRG1 IDM-A (80)]
contact_pi_person_id: 8061232
contact_pi: LAWRENZ, MATTHEW B
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Plague is an acute infection caused by Yersinia pestis a Gram-negative facultative intracellular bacterium that infects and survives in macrophages. Growing evidence suggests that intracellular growth is important for mammalian colonization by Y. pestis. Upon entry into macrophages Y. pestis remains in a membrane-bound compartment called the Yersinia-containing vacuole (YCV) but it is not killed by the macrophage. Furthermore the bacterium actively inhibits acidification of the YCV. We hypothesize that Y. pestis interacts with specific host factors in order to alter YCV maturation and acidification. While bacterial factors important for intracellular survival have been identifie the molecular mechanisms used by the bacterium to survive within macrophages have not been defined. To identify these factors/pathways we have built a novel Y. pestis bioreporter to monitor Y. pestis survival in macrophages. Using this bioreporter we have developed an inhibitory RNA-based assay to specifically identify host factors that alter Y. pestis intracellular
survival. With this assay we will perform a genome wide screen to identify host factors/pathways required for Y. pestis survival in macrophages (Aim 1). Using a combination of in silico and microscopy analysis we will also specifically identify host factors identified in our screen that alter phagosome maturation to the benefit of Y. pestis (Aim 2). These studies will be the first to target the host cell to understand the mechanisms used by Y. pestis to survive in host cells.

project_terms:
Acute;Antibiotic Resistance;Antibiotics;Bacteria;Binding (Molecular Function);Biological;Biological Assay;Cell Communication;Cell Survival;Cells;Computer Simulation;Confocal Microscopy;Data;Dendritic Cells;Development;Disease;Federal Government;Future;Growth;Human;Immune;Immune system;Infection;Integration Host Factors;Killings;Membrane;Microscopy;Molecular;Monitor;Mus;Nature;Pathway interactions;Phagocytosis;Phagosomes;Pharmaceutical Preparations;Plague;Plague Vaccine;Process;RNA;RNA Interference;Reagent;Small Interfering RNA;Specificity;Staging;Testing;Vacuole;Virulence;Work;Yersinia;Yersinia pestis;base;cell killing;combat;design;genome wide association study;genome-wide;human disease;innovation;insight;macrophage;novel;novel therapeutic intervention;novel therapeutics;novel vaccines;pathogen;public health relevance;resistant strain;screening;tool;weapons

public_health_relevance:
Yersinia pestis is the causative agent of plague an acute human disease and potential bioweapon. The work proposed here will identify host targets required by Y. pestis to infect cells of the innate immune system. Understanding the interactions between Y. pestis and the host immune system will allow us to design new vaccine and therapeutic approaches to combat plague infections.


application_id: 8583142
project_number: 3R01AR061578-02S1
project_title: BISPHOSPHONATE USE AND BONE QUALITY
administering_ic: NIAMS
award_notice_date: 2013-07-12
opportunity_number: RFA-AR-13-003
application_type: 3
activity_code: R01
ic: AR
serial_number: 061578
suffix: S1
program_official: LESTER, GAYLE E
project_start_date: 2012-07-01
project_end_date: 2014-06-30
study_section: Special Emphasis Panel[ZAR1 KM (M1)]
contact_pi_person_id: 7875292
contact_pi: MALLUCHE, HARTMUT H
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Bisphosphonates (BPs) halt bone loss and prevent osteoporosis-related fractures in the more than 4 million Americans currently using these drugs but long-term BP use may be linked to clinically relevant loss of load-bearing mechanical strength. This remains a significant unanswered challenge to the medical community.  The broad long-term objective of the proposed study is to provide new information regarding the time- dependent effects of BP on bone stiffness and strength and thus to improve the confidence of physicians and patients regarding use of BPs for treating the world's more than 200 million osteoporotic patients.  The goal of this study is to use an advanced conceptual approach and data obtained from the parent study to quantify bones load-bearing mechanical competence as a function of long-term BP treatment.  The proposal tests the central hypothesis that long-term BP treatment is characterized by time- dependent favorable and unfavorable changes in bone quality.  The specific aims are to: 1) build a new interdisciplinary research team that contributes needed expertise in finite element (FEA) and advanced regression analyses 2) use micro-CT imaging to construct 3D models of bone incorporate parent-study derived structure and material data into these models evaluate these models by using FEA calculate functionally relevant bone stiffness and strength parameters and 3) analyze the BP treatment time-dependent changes in these parameters using advanced regression methods.  These aims will be accomplished by adding new interdisciplinary investigators to the team to provide the needed technical expertise. Research methods to be used in this blinded cross-sectional study of 60 human bone samples identified in the parent study include micro-CT imaging and finite element analyses. Advanced nonlinear regression analyses will be used to evaluate the relationships between BP treatment duration and bone stiffness and strength.  The results of the proposed study are expected to indicate when the maximum benefit of BP treatment is attained the duration of this benefit the time at which this benefit begins to decline and the time at whih this benefit might return to baseline or dip below. These findings should remove the prevailing uncertainty regarding the safety of BP treatment and thereby providing major health and economic benefits.  The anticipated findings of the proposed study are of great relevance to the NIAMS mission. They will change the current therapeutic paradigm for osteoporosis treatment and provide increased confidence to physicians and patients regarding BP use. Sustained benefits will accrue due to the efforts of the newly created interdisciplinary team and their continuing application of their collective expertise to address other metabolic bone diseases.

project_terms:
Address;Affect;American;Archives;Biomechanics;Blinded;Clinical;Collaborations;Communities;Competence;Cross-Sectional Studies;Data;Drug usage;Economics;Elements;Finite Element Analysis;Fracture;Goals;Healthcare;Human;Image;Interdisciplinary Study;Kentucky;Link;Measurement;Measures;Mechanics;Medical;Metabolic Bone Diseases;Methods;Metric;Mission;Modeling;Musculoskeletal Diseases;National Institute of Arthritis and Musculoskeletal and Skin Diseases;Osteoporosis;Outcomes Research;Parents;Patients;Physicians;Problem Solving;Regression Analysis;Research;Research Methodology;Research Personnel;Research Support;Safety;Sampling;Structure;Technical Expertise;Testing;Therapeutic;Time;Uncertainty;Universities;Weight-Bearing state;Withholding Treatment;X-Ray Computed Tomography;base;bisphosphonate;bone;bone health;bone imaging;bone loss;bone quality;clinically relevant;health economics;improved;interdisciplinary collaboration;mathematical model;parent grant;prevent;public health relevance;three-dimensional modeling;treatment duration

public_health_relevance:
A new interdisciplinary research team is being created to elevate bone quality assessment capabilities of the parent grant team by adding expertise in mathematical modeling of computerized tomography (CT) images of bone from the University of Kentucky bone archive consisting of more than 8000 bone samples the majority of whom are from patients with osteoporosis. Two clinically relevant measurements of bone quality i.e. stiffness and strength will be measured in bone samples from osteoporotic patients treated with various durations of bisphosphonates and compared to untreated osteoporotic patients. Expected economic benefits for healthcare payers and clinical benefits for the more than 200 million people worldwide affected by osteoporosis are: 1) an enhanced ability to identify bisphosphonate treatment-related bone quality changes over time 2) determination of optimal duration of treatment and time at which the benefit may decline and 3) an enduring team collaboration that will continue solving problems associated with osteoporosis and related bone health problems.


application_id: 8582901
project_number: 3R01AR060701-04S1
project_title: The role of satellite cells in adult skeletal muscle growth and maintenance
administering_ic: NIAMS
award_notice_date: 2013-08-23
opportunity_number: RFA-AR-13-003
application_type: 3
activity_code: R01
ic: AR
serial_number: 060701
suffix: S1
program_official: BOYCE, AMANDA T
project_start_date: 2010-09-17
project_end_date: 2014-08-31
study_section: Special Emphasis Panel[ZAR1 KM (M1)]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: MCCARTHY, JOHN JOSEPH
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The purpose of this revision is to expand the scope of the parent grant to determine the role of muscle stem cells (satellite cells) in revascularization f muscle tissue during critical limb ischemia. Through initial discussions among members of the interdisciplinary research team we originally hypothesized that satellite cells are required for muscle to recover from ischemia-induced muscle injury. Support for this hypothesis came from a recent study by Drs. McClung and Kontos demonstrating that differential activation of myogenic gene expression in different inbred strains of mice is a key component of the genetic regulation of the muscle response to ischemia. To test this novel hypothesis we utilized our interdisciplinary expertise in both skeletal muscle and vascular biology to perform a preliminary study to directly assess the role of satellite cells in the response of skeletal muscle to hind lim ischemia (HLI) using the standard model of femoral artery ligation and excision. Using the Pax7-DTA mouse which enables inducible satellite cell ablation in response to tamoxifen (developed in the parental grant) we compared the ischemic response of muscle that contained satellite cells (vehicle group) to muscle depleted (>90%) of satellite cells (tamoxifen group). One week after HLI performed by Dr. McClung the level of damage observed in muscle of the vehicle group (n=4) was consistent with that previously reported by Kontos and McClung in wild-type C57BL/6 mice. In contrast in the tamoxifen group in which satellite cells had been genetically ablated a cohort of mice appeared to be almost completely protected from necrosis completely contrary to our original hypothesis. Although some of the tamoxifen-treated mice showed muscle injury similar to that of the vehicle-treated group Pax7 immunohistochemistry revealed that the these mice significantly recovered PAX7+ cell number during ischemia and appear to have had either incomplete deletion of Pax7+ cells or recovery of Pax7-expressing cells. Post-surgical flow measurements post harvest anatomic verification of complete arterial resection and limb necrosis in a known "poor responder" BALB/c parental strain (positive control) cohort performed in concert with these surgeries confirmed surgical ischemia ruling out surgical variation as an explanation for this stunning observation. Finally the mice that were protected against ischemia-induced damage showed a trend towards a greater number of CD31 immunostained capillaries compared to vehicle-treated mice. These results suggest the intriguing possibility that satellite cells have an unanticipated and novel role in the skeletal muscle response to ischemia that may include the regulation of the muscle vascular response. Thus the specific aim of this revision is to perform a detailed characterization of this response n a larger cohort of mice so that a definitive conclusion can be reached regarding the role of satellite cells in the muscle vascular and regenerative response to critical limb ischemia.

project_terms:
A Mouse;Ablation;Adult;Affect;American;Anatomy;Architecture;Area;Arteries;Biology;Blood Vessels;Blood capillaries;Blood flow;C57BL/6 Mouse;Cell Count;Cells;Contralateral;Data;Diphtheria Toxin;Excision;Fiber;Future;Gene Expression;Genetic;Grant;Harvest;Immunohistochemistry;Inbred BALB C Mice;Inbred Strains Mice;Injury;Interdisciplinary Study;Investigation;Ischemia;Ligation;Limb structure;Magnetic Resonance Imaging;Maintenance;Measurement;Mediating;Modeling;Morphology;Mouse Strains;Mus;Muscle;Muscle satellite cell;Myogenic Regulatory Factors;Myopathy;Natural regeneration;Necrosis;Operative Surgical Procedures;Outcome;PAX7 gene;PECAM1 gene;Patients;Perfusion;Peripheral arterial disease;Play;Postoperative Period;Process;Recovery;Regulation;Reporting;Role;Skeletal muscle structure;Smooth Muscle Actin Staining Method;Tamoxifen;Testing;Time;Variant;Vascular remodeling;Weight;capillary;cohort;density;femoral artery;indexing;insight;male;member;muscle metabolism;novel;parent grant;protective effect;public health relevance;regenerative;response;satellite cell;skeletal muscle growth;trend

public_health_relevance:
Peripheral artery disease affects 8-12 million Americans and results in limb ischemia that produces a skeletal muscle myopathy. The purpose of this revision is to determine if skeletal muscle stem cells (satellite cells) have a role in muscle and vascular remodeling in response to ischemia.


application_id: 8582550
project_number: 5R01DK090460-04
project_title: Maternal Exercise Protects Offspring from Obesity and Insulin Resistance
administering_ic: NIDDK
award_notice_date: 2013-12-12
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: DK
serial_number: 090460
program_official: SILVA, CORINNE M
project_start_date: 2011-01-01
project_end_date: 2015-12-31
study_section: Integrative Physiology of Obesity and Diabetes Study Section[IPOD]
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
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_abstract:
DESCRIPTION (provided by applicant):  The intrauterine environment affects the development of the growing embryo and an unsuitable environment can lead to termination of pregnancy. However emerging research has shown that more subtle factors can potentially influence long-term health in the offspring. For instance malnourished pregnant mothers produce smaller offspring that have a higher incidence of obesity diabetes and heart disease during adulthood. To this point most published studies have focused on negative changes in offspring caused by detrimental diets or stressful behavior. However in the Western world maternal obesity is an ever-increasing problem and epidemiology studies are now pointing to metabolic derangements in their offspring. In an attempt to be pro-active maternal voluntary exercise during pregnancy was chosen as a potential short-term intervention to improve health outcomes in offspring. Fasting circulating glucose and insulin levels were lower in offspring born to exercised dams compared to those born to non-exercised dams and glucose disposal and insulin sensitivity were significantly improved. As a result our hypothesis for this proposal is that maternal voluntary exercise during pregnancy and nursing will improve glucose regulation and decrease obesity and hypertension in offspring. The first aim is designed to determine whether maternal voluntary exercise can improve insulin sensitivity in offspring fed a normal standard diet and protect against obesity insulin resistance and hypertension progression in high calorie diet-fed offspring. The second aim hopes to elucidate the mechanism for long-lasting insulin sensitivity in offspring born to exercised dams which is likely through enhanced insulin signaling. The third aim will determine whether maternal exercise can be used as an intervention to improve pathology outcomes in offspring resulting from maternal consumption of a high calorie diet or gestational diabetes mellitus. To explore these aims female mice will be placed into sedentary or voluntary exercise groups. The exercise dams will have 24 hour access to running wheels before mating and throughout pregnancy and nursing. The maturing offspring will not have access to running wheels for any portion of the study. Obesity glucose and insulin tolerance and hypertension will be monitored in the offspring fed either standard or high calorie diet. These studies will provide important information on the potential positive impact maternal exercise can have on offspring health. Obesity diabetes and cardiovascular disease are at epidemic levels and interventions targeting gestation might be an efficient way to stem the tide.

project_terms:
Acetylation;Adult;Adult Children;Affect;Age;Behavior;Biological Assay;Blood Pressure;Body Composition;Cardiovascular Diseases;Commit;Consumption;CpG Islands;Development;Diabetes Mellitus;Diet;Discipline of Nursing;Disease;Embryo;Environment;Epidemic;Epigenetic Process;Exercise;Fasting;Female;Genes;Gestational Diabetes;Glucokinase;Glucose;Glucose Transporter;Health;Heart Diseases;Histone Acetylation;Home environment;Hour;Human;Hypertension;Incidence;Injection of therapeutic agent;Insulin;Insulin Receptor;Insulin Resistance;Insulin Signaling Pathway;Intervention;Laboratories;Lead;Liver;Longevity;Measures;Metabolic;Methylation;Modeling;Monitor;Mothers;Motor;Mus;Obese Mice;Obesity;Outcome;Parents;Partner in relationship;Pathology;Pathway interactions;Performance;Phenotype;Phosphorylation;Pilot Projects;Population;Pregnancy;Probability;Promoter Regions (Genetics);Proteins;Publishing;Research;Role;Running;Skeletal muscle structure;Termination of pregnancy;Testing;Tissues;Ursidae Family;Very Light Exercise;Western World;blood glucose regulation;design;epidemiology study;fasting glucose;feeding;glucose disposal;glucose tolerance;glucose-6-phosphatase;improved;insulin sensitivity;insulin signaling;insulin tolerance;leptin receptor;next generation;novel;offspring;pregnant;programs;protein expression;public health relevance;response;sedentary;stem;trend;unborn child

public_health_relevance:
Exercise is currently used as a treatment for gestational diabetes but the long-term influence of this intervention on offspring health has been ignored. The proposed studies will provide novel information on whether maternal exercise can be used as an intervention to decrease obesity diabetes and hypertension development in offspring. Maternal exercise during pregnancy is a very realistic intervention that may provide a lifetime of benefits for the next generation.


application_id: 8582361
project_number: 3R01AR061939-02S1
project_title: Beta Catenin Regulation of Skeletal Muscle Hypertrophy
administering_ic: NIAMS
award_notice_date: 2013-07-11
opportunity_number: PA-11-260
application_type: 3
activity_code: R01
ic: AR
serial_number: 061939
suffix: S1
program_official: BOYCE, AMANDA T
project_start_date: 2012-07-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZAR1 KM (M1)]
contact_pi_person_id: 8263548
contact_pi: ESSER, KARYN A
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This is a revised application to our parent grant "Beta-catenin regulation of skeletal muscle hypertrophy" being submitted in response to RFA-AR-13-003 NIAMS Building Interdisciplinary Research Team (BIRT) Revision Awards. We have established an interdisciplinary research team with Dr. Dasarathy a transplant hepatologist with a joint appointment in the Department of Pathobiology at the Lerner Research Institute in the Cleveland Clinic. In addition to his clinical duties Dr. Dasarathy heads an active research program investigating the molecular and metabolic mechanisms underlying skeletal muscle sarcopenia induced by cirrhosis. This work has found that hyperammonemia caused by cirrhosis leads to sarcopenia as the result of increased myostatin expression and decreased protein synthesis. Preliminary data in C2C12 myotubes showed that over- expression of -catenin was able to block the increase in myostatin expression in response to ammonium. Based on this preliminary data we propose in this revision to test the hypothesis that over-expression of -catenin will prevent the deleterious effects (decreased protein synthesis loss of muscle mass) caused by hyperammonemia-induced myostatin expression. To test this hypothesis the following aim will be pursued: Determine if over-expression of -catenin is able to protect skeletal muscle against hyperammonemia. Both in vitro and in vivo experiments will be performed to determine if over-expression of -catenin is capable of mitigating the deleterious effects of myostatin expression induced by ammonium. The proposed in vitro and in vivo studies are expected to demonstrate that over-expression of -catenin is capable of rescuing the sarcopenic phenotype by repressing myostatin expression. These proposed experiments extend the scope of the original proposal beyond the regulation of ribosome biogenesis by -catenin to examine the ability of -catenin to prevent cirrhosis-induced sarcopenia. The notion that -catenin may provide a mechanism for rescuing the loss of muscle mass associated with cirrhosis has significant clinical implication given the recent identification
of small molecules capable of activating -catenin signaling. In addition the data generated under this award are expected to serve as the basis for an R01 grant application in response to PA-12-208 "Functions of Skeletal Muscle beyond Contractions" which seeks to promote research that "leads to novel strategies to protect or treat common diseases and conditions".

project_terms:
Adult;Affect;Ammonium;Applications Grants;Appointment;Area;Award;Biochemical;Biogenesis;Caliber;Characteristics;Cirrhosis;Clinic;Clinical;Complication;DNA;Data;Deterioration;Dietary Intervention;Disease;Down-Regulation;Environment;Exons;Exposure to;Functional disorder;Genetic Recombination;Head;Hindlimb;Hormonal;Hyperammonemia;In Vitro;Interdisciplinary Study;Joints;Laboratories;Lithium;Malnutrition;Measures;Mediating;Metabolic;Modeling;Molecular;Morbidity - disease rate;Morphology;Mortality Vital Statistics;Muscle;Muscle Fibers;Muscle Proteins;National Institute of Arthritis and Musculoskeletal and Skin Diseases;Outcome;Patients;Phenotype;Promotor (Genetics);Protein Biosynthesis;Proteins;Puromycin;Quality of life;RNA;Rattus;Regulation;Reporting;Research;Research Institute;Ribosomes;Sampling;Signal Transduction;Skeletal muscle structure;Tamoxifen;Testing;Time;Transplantation;Weight;Western Blotting;Work;adverse outcome;ammonium acetate;base;beta catenin;gain of function;in vivo;inhibitor/antagonist;liver transplantation;muscle form;muscle hypertrophy;mutant;myostatin;novel strategies;parent grant;prevent;programs;public health relevance;research study;response;restoration;sarcopenia;small molecule;success

public_health_relevance:
The loss of skeletal muscle mass (sarcopenia) associated with cirrhosis has an adverse affect on the survival quality of life and outcome success following liver transplantation. The purpose of this revision is to test the hypothesis that over-expression of -catenin can prevent cirrhotic sarcopenia.


application_id: 8581491
project_number: 1K25AG043546-01A1
project_title: Statistical Genetics Methods for Mixed Pathologies
administering_ic: NIA
award_notice_date: 2013-08-12
opportunity_number: PA-11-196
application_type: 1
activity_code: K25
ic: AG
serial_number: 043546
suffix: A1
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
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;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: 8580803
project_number: 1K01DA031961-01A1
project_title: Glutamate Receptor Modulation of Calcium Signaling in Neuropathic Pain
administering_ic: NIDA
award_notice_date: 2014-01-17
opportunity_number: PA-11-190
application_type: 1
activity_code: K01
ic: DA
serial_number: 031961
suffix: A1
program_official: RAPAKA, RAO
project_start_date: 2014-02-01
project_end_date: 2019-01-31
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
project_terms:
AMPA Receptors;Address;Adult;Adverse effects;Amyloid beta-Protein;Analgesics;Award;Behavior;Behavioral;CTOP;Calcium;Calcium Signaling;Cell Fractionation;Cell surface;Cells;Chemosensitization;Data;Electrophysiology (science);Endogenous Opiates;Fiber;Glutamate Receptor;Glutamates;Goals;Health;Healthcare;Hyperalgesia;Image;Inflammation;Inflammatory;Injury;Lead;Masks;Mediating;Membrane;Mentors;Mission;Modeling;Mus;N-Methyl-D-Aspartate Receptors;NMDA receptor antagonist;Naltrexone;Neurons;Opioid;Opioid Receptor;Pain;Pain management;Peripheral;Permeability;Phosphorylation;Receptor Activation;Receptor Signaling;Receptors Opioid mu;Research;Research Technics;Resolution;Sensory;Signal Transduction;Slice;Spinal Cord;Techniques;Testing;Western Blotting;base;career;central sensitization;chronic pain;clinically relevant;dorsal horn;inflammatory pain;innovation;nerve injury;neuronal excitability;painful neuropathy;postsynaptic;receptor function;research study;response;spinal nerve posterior root;therapeutic target;trafficking


application_id: 8580477
project_number: 1R01AG045833-01
project_title: Circadian rhythms and melatonin signaling in the aging gastrointestinal system
administering_ic: NIA
award_notice_date: 2013-08-14
opportunity_number: RFA-AG-13-007
application_type: 1
activity_code: R01
ic: AG
serial_number: 045833
program_official: MACCHIARINI, FRANCESCA
project_start_date: 2013-08-15
project_end_date: 2017-05-31
study_section: Special Emphasis Panel[ZAG1 ZIJ-5 (M2)]
contact_pi_person_id: 1862567
contact_pi: CASSONE, VINCENT M
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_abstract:
DESCRIPTION (provided by applicant):  Biological circadian clocks are fundamental properties of all living organisms studied in any detail. In animals clocks regulate the timing of
sleep: wake cycles as well as the coordination of internal body functions such as temporal variations in temperature hormone levels aspects of disease and gastrointestinal physiology. The molecular bases for biological rhythms are at least in part regulated by the expression of "clock genes" a group of genes whose complex interactions govern 24-hour rhythms. Work in our lab has demonstrated that clock genes are important in the regulation of colonic motility: the mouse colon possesses a functional circadian clock that regulates rhythms of a wide array of genes as well as intestinal motility. Further we have shown that the colonic clock regulates multiple downstream processes associated with normal intestinal motility absorption cell proliferation and cell signaling as well as potential pathological processes.  In addition in mammals there is a hierarchical organization in which a central pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) coordinates multiple peripheral processes as well as entrains the entire system to the light: dark cycle (LD) through specialized photic pathways. Our general hypothesis is that the global regulation of gastrointestinal circadian rhythms involves the complex bi-directional interaction of central SCN clockworks and intestinal clocks themselves and that disruption of any of these predisposes us to disease.  The overall objective of this proposal is to determine the underlying mechanism through which colonic motility varies with the time of day under normal circumstances and to determine the consequences of aging on circadian patterns of colonic motility. Our hypothesis is that one factor mediating changes in intestinal function during aging is the circadian secretion of the hormone melatonin by the pineal gland and by intestinal tissues themselves. We will therefore ask what aspects of gastrointestinal rhythms are affected by normal aging (Specific Aim 1). We will then ask whether pineal melatonin influences gastrointestinal rhythmicity in young vs aged mice at several levels of biological organization. Finally we will ask whether interference in the production of melatonin affects aging aspects of gastrointestinal rhythmicity by comparing melatonin deficient strains of mice (C57/Bl6) with strains of mice capable of producing melatonin cycles (C3H) and whether these processes are dependent the known melatonin receptor molecules by comparing wild-type with MT1 receptor MT2 Receptor and MT2/MT2 receptor knockout mice.

project_terms:
Acetylcholine;Address;Affect;Age;Aging;Aging-Related Process;Animals;Biological;Biological Rhythm;Cell Proliferation;Circadian Rhythms;Colon;Complex;Data;Disease;Exhibits;Future;Gastrointestinal Physiology;Gene Expression;Gene Expression Profile;Genes;Harvest;Health;Hormones;Hour;Hypothalamic structure;In Vitro;Intestinal Motility;Intestines;Knock-out;Knockout Mice;Life;Light;Mammals;Measures;Mediating;Melatonin;Melatonin Receptors;Molecular;Mouse Strains;Mus;Muscle;Organism;Pacemakers;Pathologic Processes;Pathway interactions;Pattern;Periodicity;Peripheral;Phase;Physiological;Pineal gland;Process;Production;Property;Publishing;RNA;Receptor Melatonin MT1;Receptor Melatonin MT2;Regulation;Reporter;Role;Signal Transduction;Sleep Wake Cycle;Symptoms;System;Temperature;Testing;Time;Tissues;Variant;Wild Type Mouse;Work;absorption;aged;base;cell motility;circadian pacemaker;design;gastrointestinal;gastrointestinal function;gastrointestinal system;in vivo;interest;nano-string;normal aging;pressure;receptor;research study;response;suprachiasmatic nucleus

public_health_relevance:
Disruption of circadian clocks has deleterious effects on the health of most people especially among the aged and many of these issues are reflected in deteriorating gastrointestinal health. Further there is evidence that the pineal hormone melatonin may ameliorate symptoms associated with both sleep: wake cycles and gastrointestinal health in young and old people. This study will determine the mechanisms of circadian patterns of gastrointestinal gene expression and motility in young and old mice and will determine whether decreased melatonin signaling contributes to declining gastrointestinal health. The data may point to future treatments for normal but discomforting gastrointestinal health during aging.   
   
DISCLAIMER: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation based upon the group's discussion there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore the critiques may not fully reflect the final opinions of the
individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.


application_id: 8580441
project_number: 1UH2TR000875-01
project_title: Fruit exosome-like particles for therapeutic delivery of extracellular miRNAs
administering_ic: NCATS
award_notice_date: 2013-07-31
opportunity_number: RFA-RM-12-014
application_type: 1
activity_code: UH2
ic: TR
serial_number: 000875
program_official: TAGLE, DANILO A
project_start_date: 2013-08-01
project_end_date: 2015-07-31
study_section: Special Emphasis Panel[ZRG1 OBT-Z (50)]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: GUO, PEIXUAN
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop exosome-like nanoparticles as a delivery vehicle for targetable delivery of extracellular RNA (exRNA) primarily focusing on miRNAs which modulate gene expression and induce immune responses upon delivery in mouse tumor models. Development of exRNA-based therapeutics must overcome challenges including issues of delivery potential off-target effects safety toxicity the cost of large scale production elimination of potential biohazards to the environmen and tissue specificity. Unlike the situation with artificially synthesized nanoparticles or liposomes naturally derived nanoparticle-size exosomes are released from many different types of cells. miRNAs and RNAs can be encapsulated in naturally derived exosomes and the RNAs are stable and a number of miRNAs can be naturally encapsulated simultaneously in these exosomes. Recently data published by ours and other groups have demonstrated that mammalian exosomes can deliver poorly soluble agents chemotherapeutic drugs and siRNA in vivo. A limitation of this mode is the need for large-scale production of exosomes and potential biosafety. Our preliminary data show that exosome-like nanoparticles can be isolated in large quantities from the tissue of edible plants including grapes. We have demonstrated that exosome-like nanoparticles from grapes are composed of small RNAs proteins and lipids. An edible plant-derived nano-vector (EPNV) assembled from grape exosome-like derived lipids is capable of encapsulating siRNAs. Co-delivery of folic acid with the chemotherapy drug paclitaxel by EPNVs results in an increased efficiency in tumor tissue targeting. Reducing the size of EPNVs by passing them through an appropriate pore size filter significantly enhances EPNV translocation to the brain and oral administration of the EPNVs results in their migration to the liver. Based on these preliminary data and the current literature we propose to: (1) Determine whether an EPNV can deliver therapeutic miR17 via oral administration to target metastatic colon tumor in the liver subsequently inducing NK cell activation to kill metastatic tumor cells; (2) Determine whether miR155 encapsulated in EPNV promotes differentiation of myeloid derived suppressor cells (MDSCs) into mature dendritic cells in mouse breast/brain tumor models; (3) Determine whether a therapeutic dose of miRNA17 or miRNA155 delivered by EPNV induces no side-effects in mouse tumor models; and (4) Determine whether EPNV can be produced in large scale amounts economically for use in clinical settings. Demonstration of using a EPNV-based delivery system loaded with a desired therapeutic extracellular RNA (exRNA) including microRNA to target to inflammatory cells and tumor cells in vivo would not only be a significant step forward in the treatment of cancer but also provide a powerful tool for
identifying the role and effects of each small RNA encapsulated in resident or circulating microvesicles on the recipient cells. We will accomplish this in our study by knock-out and knock-in strategies.

project_terms:
Adverse effects;Animals;Antibodies;Biohazardous Substance;Biological Assay;Brain;Brain Neoplasms;Breast;Cells;Clinic;Clinical;Colon Carcinoma;Colonic Neoplasms;Curcumin;DNA;Data;Dendritic Cells;Development;Disease;Dose;Down-Regulation;Edible Plants;Encapsulated;Environment;Evaluation;Folic Acid;Fruit;Gene Expression;Goals;Grapefruit (food);Grapes;Human;Immune response;Immunotherapy;In Vitro;Inflammatory;Intranasal Administration;Killings;Knock-in Mouse;Knock-out;Laboratories;Light;Lipids;Liposomes;Literature;Liver;MHC Class I Genes;Malignant Neoplasms;Mammalian Cell;Metastatic Neoplasm to the Liver;MicroRNAs;Modeling;Mus;Myelogenous;Myeloid Cells;NK Cell Activation;Neoplasm Metastasis;Non-Viral Vector;Nucleic Acids;Oral Administration;Paclitaxel;Pharmaceutical Preparations;Phenotype;Play;Prevention;Production;Proteins;Protocols documentation;Publishing;RNA;Research Personnel;Role;Safety;Science;Signal Transduction;Small Interfering RNA;Small RNA;Specificity;Suppressor-Effector T-Lymphocytes;System;Testing;Therapeutic;Therapeutic Agents;Tissues;Tomatoes;Toxic effect;Tumor Tissue;Viral Vector;aqueous;base;cancer cell;cancer therapy;cell type;chemotherapeutic agent;chemotherapy;cost;expression vector;extracellular;in vivo;intravenous administration;large scale production;migration;mouse model;nanoparticle;nanosized;nanovector;neoplastic cell;overexpression;particle;prevent;public health relevance;receptor;targeted delivery;tool;trafficking;tumor;vector-induced

public_health_relevance:
The concept that extracellular RNA (exRNA) may alter target cell phenotypes by way of intercellular signaling is becoming universally accepted in science. Whether exRNA can be used as a therapeutic agent is not known. The overall goal of this study is to develop grape lipid derived nano vectors for the delivery of exRNAs as therapeutic agents to target tumor cells as well as inflammatory cells in animal tumor models. Additionally we will assess the therapeutic potential of exRNA used in a clinical setting.


application_id: 8580175
project_number: 2R44CA136017-04
project_title: SapC-DOPS Nanovesicles for Treating Glioblastoma Multiforme
administering_ic: NCI
award_notice_date: 2013-09-19
opportunity_number: RFA-CA-12-023
application_type: 2
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: Special Emphasis Panel[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:
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 with
aggressive brain tumors.


application_id: 8578836
project_number: 7R01DA026837-04
project_title: Rural and Urban African American Cocaine Users' Perceived Need for Care
administering_ic: NIDA
award_notice_date: 2012-12-12
opportunity_number: PA-12-270
application_type: 7
activity_code: R01
ic: DA
serial_number: 026837
program_official: JONES, DIONNE
project_start_date: 2012-11-06
project_end_date: 2014-06-30
study_section: Community Influences on Health Behavior Study Section[CIHB]
contact_pi_person_id: 8423409
contact_pi: BORDERS, TYRONE FINLEY
other_pis: Not Applicable
congressional_district: 06
department: ADMINISTRATION
primary_duns: 939017877
primary_uei: 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): We seek to study the factors associated with rural/urban differences in perceived need for both drug abuse treatment and HIV testing because these are complementary services which could be integrated within formal drug abuse treatment programs or other locations to better meet the needs of African American cocaine users. We focus on perceived need among African American cocaine users because of their low rates of drug abuse treatment and HIV testing nationally as well as their demonstrated low perceived need for drug abuse treatment high rates of risky sexual behaviors and aversion to seeking HIV testing at local health departments in our prior research. Given that our prior natural history research did not include any urban areas we do not know whether the low rates of drug abuse treatment and HIV testing among rural Arkansans are specific to rural residents (e.g. whether there is a disparity in access for rural African Americans) or whether urban African American cocaine users differ in other critical factors. To address these issues we plan to conduct a community-based mixed methods study of African American cocaine users residing in rural and urban areas of Arkansas. Specifically we propose a sequential mixed-method design with qualitative key informant interviews conducted first (30 rural 30 urban) followed by larger-scale structured interviews (200 rural 200 urban) using standardized instruments pertinent measures from our prior rural health services and HIV research and newly developed questions based on our initial qualitative work. Respondent-Driven Sampling (RDS) a variant of snowball sampling will be used to identify and recruit participants. The primary aims of the study are: 1) Using qualitative methods to describe rural/urban differences in pathways to drug use and drug use cultures perceptions of access to drug abuse treatment and HIV testing awareness and perceptions of what constitutes drug abuse treatment and HIV testing and preferences for formal or informal drug abuse treatment and the site or location of HIV testing; 2) Using quantitative and qualitative methods to compare and contrast rural and urban cocaine users' perceived need for drug abuse treatment and HIV testing and key predisposing enabling health and other factors which could impede or facilitate perceived need; and 3) Using quantitative methods to investigate whether rural/urban differences in perceived need for drug abuse treatment and HIV testing are mediated by key predisposing enabling and health factors as well as treatment and testing awareness and preferences. The knowledge gained from this project will enable health policy makers treatment program managers and providers to make more informed decisions about how to encourage and facilitate the utilization of drug abuse treatment and HIV testing among African American cocaine users in the Southern U.S. an underserved and high risk population.    PUBLIC HEALTH RELEVANCE: Of public health concern are the low rates of drug abuse treatment and high rates of HIV among African American cocaine users especially in the Southern U.S. The knowledge gained from the proposed research would enable managers of public and behavioral health systems to make more informed decisions about how to target and tailor culturally sensitive messages aimed at increasing awareness of the benefits of drug abuse treatment and HIV testing. The proposed research would also provide new insight into whether HIV testing should be integrated within drug abuse treatment facilities to better meet the needs of rural as well as urban African American cocaine users.

public_health_relevance:
PROJECT NARRATIVEOf public health concern are the low rates of drug abuse treatment and high rates of HIV among AfricanAmerican cocaine users especially in the Southern U.S. The knowledge gained from the proposed researchwould enable managers of public and behavioral health systems to make more informed decisions about how totarget and tailor culturally sensitive messages aimed at increasing awareness of the benefits of drug abusetreatment and HIV testing. The proposed research would also provide new insight into whether HIV testingshould be integrated within drug abuse treatment facilities to better meet the needs of rural as well as urbanAfrican American cocaine users.


application_id: 8577254
project_number: 2R01CA125454-06
project_title: Regulation of Snail in breast cancer progression and metastasis
administering_ic: NCI
award_notice_date: 2013-07-08
opportunity_number: PA-11-260
application_type: 2
activity_code: R01
ic: CA
serial_number: 125454
program_official: WOODHOUSE, ELIZABETH
project_start_date: 2007-09-13
project_end_date: 2018-04-30
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Affect;BRCA1 gene;Binding Proteins;Boxing;Brain;Breast;Breast Cancer Cell;CCL2 gene;Caenorhabditis elegans;Cancer cell line;Cancer stem cell;Cells;Cellular Stress;Characteristics;Chromatin;Clinical;Complex;Data;Development;Disease;Distant Metastasis;Down-Regulation;E-Cadherin;Endoplasmic Reticulum;Environment;Enzymes;Epithelial;Exhibits;Fostering;Gene Silencing;Goals;Growth Factor;Homeostasis;Human;IL8 gene;Immune;Infiltration;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Interleukin-6;Intervention;Intestines;Intrinsic factor;Knowledge;Leukocytes;Location;Lung;Lymphocyte;Malignant Neoplasms;Mammary Neoplasms;Mediating;Medical Oncologist;Mesenchymal;Molecular;Mus;Mutation;Neoplasm Metastasis;Outcome;Pathologist;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Play;Promotor (Genetics);Proteins;Reagent;Recording of previous events;Recruitment Activity;Recurrence;Regulation;Repression;Research;Role;Sampling;Signal Pathway;Signal Transduction;Site;Snails;Stromal Neoplasm;Testing;Therapeutic Intervention;Tissues;Up-Regulation (Physiology);cancer therapy;cell injury;chemokine;chromatin modification;coping;cytokine;endoplasmic reticulum stress;epithelial to mesenchymal transition;gene repression;genome wide association study;in vivo;inhibitor/antagonist;innovation;insight;macrophage;malignant breast neoplasm;multidisciplinary;neoplastic cell;novel;novel therapeutics;outcome forecast;paracrine;prevent;programs;public health medicine (field);public health relevance;research study;response;success;trait;tumor;tumor microenvironment;tumor progression;ubiquitin isopeptidase;ubiquitin-protein ligase;wound;young woman

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


application_id: 8576714
project_number: 1R01CA172379-01A1
project_title: Novel resveratrol analogs and colorectal cancer treatment
administering_ic: NCI
award_notice_date: 2013-08-06
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: CA
serial_number: 172379
suffix: A1
program_official: EMENAKER, NANCY J
project_start_date: 2013-08-06
project_end_date: 2018-05-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7013090
contact_pi: LIU, CHUNMING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States and accounts for more than 50000 deaths per year. CRC is initiated by mutations of adenomatous polyposis coli (APC) and b-catenin genes which result in abnormal activation of the Wnt signaling pathway. Inhibition Wnt signaling is essential for CRC prevention and treatment; however prior efforts along these lines were not successful because of the side effects displayed by these inhibitors. We hypothesize that natural products and their analogs are ideal therapeutic agents if they target key pathways in CRC and possess minimal toxicity. Recently we reported that resveratrol which is found in the skin of red grapes significantly inhibits Wnt signaling. Resveratrol is reported to have anti-cancer activity and not toxic at concentration (1 gram/day) effective for CRC treatment but resveratrol has a half-life in vivo that limits its utility as a therapeutic agent. Supported by an
R21 grant (RCA139359) we designed and synthesized resveratrol analogs called FlDAS agents that are more potent than resveratrol in cell based assays and possess significantly greater half-lives than reservatrol. One particular compound FlDAS-4r inhibits growth of human CRC xenografts in nude mice and is well tolerated in mice. Using a biotinylated biologically active form of FIDAS-4r we identified methionine adenosyltransferase 2A (MAT2A) as the direct target for resveratrol analogs. Our central hypothesis is that resveratrol and its analogs inhibit MAT2A and regulate the levels and metabolism of S-adenosylmethionine (SAM) thus inhibiting Wnt signaling and the proliferation of CRC cells. To further define the molecular mechanism of these anti- cancer agents and to develop these agents for CRC treatment and chemoprevention we will pursue the following three Specific Aims: 1) To define the mechanisms regulating inhibition of MAT2A by FIDAS agents; 2) To delineate the mechanisms of how FIDAS agents inhibit CRC cell growth; and 3) To characterize novel FIDAS agents using in vivo mouse models.

project_terms:
APC gene;Accounting;Adenomatous Polyposis Coli;Adverse effects;Affect;Anabolism;Animal Model;Antineoplastic Agents;Binding (Molecular Function);Biological;Biological Assay;Biological Factors;Biological Process;CTNNB1 gene;Cancer Cell Growth;Cancer Etiology;Cell Proliferation;Cell model;Cells;Cessation of life;Chemoprevention;Chemopreventive Agent;Colorectal Cancer;Development;Disclosure;Drug Targeting;Epigenetic Process;Event;Family;Funding;Future;Generations;Genes;Genetic Transcription;Genetically Engineered Mouse;Goals;Grant;Grapes;Growth;Half-Life;Histones;Human;Hypermethylation;In Vitro;Lead;Legal patent;Malignant Neoplasms;Malignant neoplasm of liver;Mediating;Metabolism;Methionine;Methylation;Modeling;Molecular;Molecular Target;Mortality Vital Statistics;Mus;Mutation;Neoplasms;Nude Mice;Organoids;Pathway interactions;Patients;Polyamines;Promotor (Genetics);Publications;Reporting;Resveratrol;Role;S-Adenosylmethionine;Signal Pathway;Signal Transduction;Skin;Testing;Therapeutic;Therapeutic Agents;Toxic effect;United States;Xenograft procedure;analog;base;cancer cell;cancer prevention;cancer therapy;colon carcinogenesis;colorectal cancer prevention;design;drug candidate;efficacy testing;in vivo;inhibitor/antagonist;methionine adenosyltransferase;mouse model;novel;public health relevance;research study;trans-resveratrol;tumor metabolism;tumor progression

public_health_relevance:
Colorectal cancer is the second leading cause of cancer death in the United States. Resveratrol and its novel analogs are promising agents for colorectal cancer prevention and treatment. This project will explore novel mechanisms of action of resveratrol analogs using cell and animal models of colorectal cancer in order to develop better chemopreventive and therapeutic agents in the future.


application_id: 8576243
project_number: 1R01GM104123-01A1
project_title: Functional analysis of programmed genome rearrangement
administering_ic: NIGMS
award_notice_date: 2013-08-23
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: GM
serial_number: 104123
suffix: A1
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
project_abstract:
DESCRIPTION (provided by applicant):    
This proposal stems from our recent discovery that the sea lamprey (unlike other vertebrates) undergoes large- scale genome rearrangements during the normal course of its embryonic development. Programmed genome rearrangement (PGR) results in the highly reproducible elimination of ~20% of the lamprey's genome during the establishment of somatic cell lineages in the early embryo. Recent work has revealed that: 1) hundreds of gene-coding fragments are eliminated 2) human homologs of lost genes generally possess "pluripotency" functions 3) computational analysis of "next-gen" sequence datasets identify predicted recombination sites that mediate deletion events which have been validated experimentally indicating that PGR is mediated in part by recombination and 4) proteins expressed in the early embryo show sequence-specific binding to validated recombination sites. With the advent of extensive sequence resources for lamprey and methods for gene knockdown and transcript replacement lamprey will continue to provide unique insights into the rearrangement biology of vertebrate genomes and the genetics of somatic vs. germline cell fate. As such this research is broadly relevant to NIGMS research programs in genetics and developmental biology particularly towards understanding the biology of genomes chromosomes and epigenetics vertebrate developmental genetics stem cell biology genetic mechanisms of DNA recombination/repair and oncogenesis. The specific aims of this proposal will seek to further characterize lamprey PGR at the genetic level in order to deduce its molecular mechanisms and use this information to guide functional studies of the biological causes and consequences of genome rearrangement. Specific Aim 1 will allow us to further refine our functional models of PGR by developing a meiotic map for the lamprey genome and integrating this with existing somatic and germline genome assemblies. Analyses of this map will shed critical light on the scale distribution biological function and likely mechanisms of deletion. Specific Aim 2 dissects the biological function of genes that are deleted through PGR. Experiments performed under this aim will use morpholino mediated gene knockdowns and transcript replacement to elucidate the function of somatically deleted genes and their human homologs. Specific Aim 3 identifies genes that mediate PGR and characterizes their molecular function. Experiments performed under this aim will use morpholino-mediated knockdown to elucidate the function of genes that bind recombination sites during PGR then use transcript replacement to test whether human homologs can partly or completely replace these functions. This will provide a direct assay for the capacity of identified human homologs to participate in somatic recombination. Critically these approaches do not rely on pre-existing knowledge regarding the function of human genes and therefore hold great potential for the discovery of new gene functions. These studies are expected to provide unique insight into vertebrate genome biology and yield information that might not be achievable outside of the context of PGR.

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:
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.


application_id: 8574955
project_number: 1R01AA021722-01A1
project_title: Behavioral Dysregulation and Alcohol Sensitivity in Risky Drivers
administering_ic: NIAAA
award_notice_date: 2013-08-05
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: AA
serial_number: 021722
suffix: A1
program_official: BLOSS, GREGORY
project_start_date: 2013-08-05
project_end_date: 2017-07-31
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Acute;Address;Alcohol dependence;Alcohols;Attention deficit hyperactivity disorder;Automobile Driving;Awareness;Behavior;Behavioral;Behavioral Mechanisms;Blood;Blood alcohol level measurement;Characteristics;Cognitive;Cognitive deficits;Counseling;Data;Disinhibition;Dose;Environment;Environmental Risk Factor;Funding Opportunities;Impaired cognition;Impairment;Impulsivity;Incentives;Incidence;Informal Social Control;Injury;Intervention;Laboratories;Legal;Licensing;Link;Neurocognitive;Patient Self-Report;Performance;Personality inventories;Phase;Phenotype;Prevention;Regulation;Reporting;Research;Rewards;Risk;Risk-Taking;Speed (motion);Techniques;Testing;United States;United States National Institutes of Health;Vehicle crash;Wit;addiction;alcohol effect;alcohol response;alcohol sensitivity;distraction;drinking;driving behavior;driving under influence;high risk;impaired driving performance;improved;innovation;offender;programs;public health medicine (field);public health relevance;recidivism;response;success;theories;trafficking;trait;treatment program;willingness

public_health_relevance:
One in every 127 licensed drivers is arrested for driving under the influence (DUI) and recidivism rates are high with over one-third of DUI offenders re-offending within three years. The proposed project examines DUI drivers from a cognitive dysfunction perspective that targets deficits in specific mechanisms of behavioral regulation. Identification of specific cognitive deficits in DUI offenders is critical for guiding new interventions that will move treatment beyond general addiction counseling. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page


application_id: 8574316
project_number: 1R15HD072713-01A1
project_title: Accents & Syntactic Attachment: Exploring how pitch accents affect the resolution
administering_ic: NICHD
award_notice_date: 2013-07-01
opportunity_number: PA-12-006
application_type: 1
activity_code: R15
ic: HD
serial_number: 072713
suffix: A1
program_official: ALVAREZ, RUBEN PAUL
project_start_date: 2013-07-01
project_end_date: 2017-06-30
study_section: Language and Communication Study Section[LCOM]
contact_pi_person_id: 2219344
contact_pi: CARLSON, KATHRYN A
other_pis: Not Applicable
congressional_district: 05
department: MISCELLANEOUS
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): This project aims to contribute to a better understanding of the effects of linguistic prosody (as opposed to affective or emotional prosody) on sentence processing. In particular it explores the effects of pitch accents on syntactically ambiguous sentences. It is well-known that prosodic boundaries one of the two major prosodic units in English can affect the attachment of ambiguous phrases. Pitch accents on the other hand are usually thought to influence only semantic and discourse representations of a sentence by marking given vs. new vs. contrastive information. This research explores the hypothesis that pitch accents can attract attachment especially in the presence of a prosodic boundary after the nearest attachment site. A series of auditory experiments will explore accent effects on attachment in three different syntactic structures with and without supportive prosodic boundaries. Following experiments will place the sentences in contexts to examine whether the focus conveyed by a preceding question can also attract attachment and whether accents remain informative for attachment when they clearly contrast with prior context.

project_terms:
Accent;Adult;Affect;Affective;Aphasia;Auditory;Brain Injuries;Child;Comprehension;Diagnosis;Disease;Elements;Emotional;Goals;Health;Hearing;Kentucky;Language;Left;Linguistics;Patients;Pattern;Positioning Attribute;Process;Psychology;Recruitment Activity;Research;Research Project Grants;Resolution;Semantics;Series;Site;Structure;Students;Testing;experience;phrases;programs;public health relevance;research study;right hemisphere brain damage;syntax;undergraduate research;undergraduate student

public_health_relevance:
This project will contribute to a fuller understanding of how prosody or the tune and rhythm of language affects sentence processing. It explores how pitch accents an aspect of linguistic prosody (rather than affective or emotional prosody) can modify the syntactic structure and meaning of a sentence. The better we understand the use of linguistic prosody and its sub-units in language comprehension for unimpaired adults the better we will be able to analyze what uses are disordered vs. spared in patients with aphasia or other types of brain damage or children with hearing difficulties and the better we can plan to treat these problems.


application_id: 8574307
project_number: 1R15GM107820-01
project_title: Mechanistic Elucidation of RNA Modifying Enzymes
administering_ic: NIGMS
award_notice_date: 2013-08-07
opportunity_number: PA-12-006
application_type: 1
activity_code: R15
ic: GM
serial_number: 107820
program_official: GERRATANA, BARBARA
project_start_date: 2013-08-07
project_end_date: 2017-07-31
study_section: Macromolecular Structure and Function E Study Section[MSFE]
contact_pi_person_id: 1925871
contact_pi: MUELLER, EUGENE G
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): All organisms modify their RNA after transcription yet both the physiological importance of particular modified nucleosides and the mechanisms by which they are generated remain unknown. The mechanistic elucidation of the generation of two such modified nucleosides will be undertaken: pseudouridine (the most common) and 4-thiouridine (which protects bacteria against exposure to UV light). Pseudouridine synthases convert uridine residues in RNA into pseudouridine the C-glycoside isomer. There are many such enzymes in all organisms and they fall into six families. Mutation or deletion of one human pseudouridine synthase dyskerin leads to the disease dyskeratosis congenita and the widespread occurrence and conservation of pseudouridine residues in RNA attests to their physiological importance. The new investigations extend our success towards the elucidation of the chemical mechanism followed by the pseudouridine synthases and ThiI the enzyme responsible for 4-thiouridine generation. Knowledge of the mechanisms is valuable in its own right as a chemical precedent and because it may allow the more efficient development of pharmaceuticals that specifically targets these enzymes in pathogenic bacteria. In particular recent results strongly disfavor one of the two mechanisms that had dominated thought on how pseudouridine is formed and simultaneously suggest a previously unrecognized possibility. This new alternative will be tested using kinetic isotope effect studies. The preference of the pseudouridine synthase RluA for its various substrates will also be investigated to probe the mode of molecular recognition that allows this enzyme to distinguish substrate from non-substrate RNA. A novel mechanism for 4-thiouridine generation involving a disulfide-linked adduct between ThiI and RNA will be tested by fully characterizing a species that match its properties in preliminary experiments. The identity of new mechanistically important amino acid residues of ThiI will also be sought. These projects will be undertaken by graduate students and by undergraduate researchers to expose them to cutting-edge research methods and thought.

project_terms:
5 fluorouridine;Active Sites;Address;Age;Amino Acids;Aminoacylation;Anabolism;Anticodon;Aspartic Acid;Bacteria;Base Sequence;Biological;C-glycoside;C-terminal;Chemicals;Competence;Defect;Deuterium;Development;Disease;Disulfides;Dyskeratosis Congenita;Eating;Enzymes;Event;Excision;Exposure to;Family;Generations;Genetic Transcription;Human;In Vitro;Investigation;Iron;Isomerism;Isotopes;Kinetics;Knowledge;Label;Left;Link;Mammals;Methylation;Modification;Mutation;Names;Nucleosides;Organism;Pharmacologic Substance;Physiological;Physiological Processes;Polyadenylation;Principal Investigator;Property;Protons;Pseudouridine;RNA;RNA Splicing;Research Methodology;Research Personnel;Role;Route;Sequence Analysis;Site;Site-Directed Mutagenesis;Sulfides;Sulfur;System;Testing;Thiamine;Thiosulfate Sulfurtransferase;Thiouridine;Transfer RNA;Ultraviolet Rays;United States National Institutes of Health;Uracil;Uridine;Ursidae Family;Work;adduct;disulfide bond;falls;graduate student;in vivo;interest;molecular recognition;novel;operation;pathogen;pathogenic bacteria;persulfides;preference;programs;public health relevance;research study;stem;success

public_health_relevance:
All organisms chemically alter their RNA after it is made but this important physiological process remains incompletely understood in terms of both the particular purpose of each modification and the mechanism by which it is achieved. The new investigations extend our success in characterizing the enzymes responsible for the generation of 4-thiouridine which is a bacterial photo protectant and pseudouridine the most common modification. Both have been proposed to operate by novel mechanisms which will be elucidated. Knowledge of the mechanism followed by these enzymes is interesting as a chemical precedent and because it may allow the more efficient development of pharmaceuticals that target these enzymes in pathogenic bacteria while leaving human enzymes unaffected.


application_id: 8574075
project_number: 1R15HL115556-01A1
project_title: Magnetic Cellular Assembly and Microfluidic Conditioning for Generation of Functi
administering_ic: NHLBI
award_notice_date: 2013-08-12
opportunity_number: PA-12-006
application_type: 1
activity_code: R15
ic: HL
serial_number: 115556
suffix: A1
program_official: BALDWIN, TIM
project_start_date: 2013-08-13
project_end_date: 2017-07-31
study_section: Special Emphasis Panel[ZRG1 BST-F (90)]
contact_pi_person_id: 8765816
contact_pi: GIRIDHARAN, GURUPRASAD A
other_pis: Not Applicable
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Cardiovascular diseases affect 70 million Americans resulting in an economic burden of $300 billion and accounting for nearly 40% of all deaths in the US. Conventional treatments of myocardial injury do not achieve myocardial regeneration. Therefore stem cell and tissue engineering based approaches for cardiac tissue regeneration have been actively pursued. Existing scaffold based 3D tissue engineering approaches accomplish tissue regeneration in non-biomimetic environments and with limited control over 3D architecture. Mimicking the 3D cellular organization and replicating mechanical loading patterns seen in vivo will address shortcomings associated with conventional techniques and significantly enhance functionality of tissues generated in vitro. In this proposal we will enable a platform technology for magnetic cellular assembly of multiple cell types encapsulated in magnetic hydrogels (M-Gels) that mimic the tissue-level cell densities to form 3D cardiac tissue structures. Microscale perfusion networks will be integrated into the 3D constructs to ensure delivery of nutrients and meet the high metabolic needs of cardiac cells. Patterned constructs will be cultured within a microfluidic Cardiac Cell Culture Model (CCCM) that accurately replicates pressure and stretch loading seen in the left ventricle. Our prior work clearly demonstrates our ability to pattern complex architectures in both 2D and 3D and accomplish cell culture within the CCCM under realistic mechanical stresses that promote cyclic stretch cell alignment and spontaneous synchronous contractions. Specifically we will: (A) accomplish assembly of cardiac cells encapsulated in magnetic hydrogels (M-gels) around a sacrificial porogen network to attain in vivo like tissue-level cell densities and architecture (B) utilize th CCCM to culture magnetically assembled cardiac tissue constructs in a cell culture environment that mimics the pressure-volume changes seen in the left ventricle and enable extraction of intact tissue following culture and (C) accomplish characterization of morphological and functional properties of magnetically assembled and microfluidically conditioned tissue constructs in vitro and determine the role of 3D patterning integration of microscale perfusion networks and culture under loading regimens of pressure and stretch on in vitro cardiogenesis and the ability to generate functional myocardial tissue that can potentially be used to repair myocardial infarctions. Though chick embryonic cardiac cell populations will be used to demonstrate the feasibility of proposed activities the developed techniques will be compatible with cardiac stem and progenitor cell populations for generation of functional cardiac patches.

project_terms:
Accounting;Address;Adult;Affect;American;Architecture;Behavior;Biomechanics;Biomedical Research;Cardiac;Cardiac Myocytes;Cardiovascular Diseases;Cardiovascular system;Cell Culture Techniques;Cell Density;Cell Survival;Cells;Cessation of life;Complex;Cultured Cells;Defect;Dimensions;Economic Burden;Embryo;Encapsulated;Endothelial Cells;Engineering;Ensure;Environment;Exposure to;Fibroblasts;Gel;Gene Expression;Generations;Goals;Heart;Hydrogels;In Vitro;Injury;Lead;Left ventricular structure;Magnetism;Mechanical Stress;Mechanics;Membrane;Metabolic;Microcirculation;Microfluidics;Modeling;Morphology;Myocardial;Myocardial Infarction;Myocardial tissue;Natural regeneration;Nutrient;Pattern;Perfusion;Physiological;Population;Property;Recreation;Regenerative Medicine;Regimen;Role;Seeds;Site;Stem cells;Stretching;Structure;Techniques;Technology;Thick;Tissue Engineering;Tissue Grafts;Tissues;Work;base;cardiogenesis;cell type;cellular engineering;clinically relevant;conditioning;conventional therapy;density;design;experience;flexibility;in vivo;magnetic field;meetings;monolayer;nanoparticle;pressure;protein expression;repaired;scaffold;stem;tissue regeneration

public_health_relevance:
PROJECT NARRATIVEThe goal of this proposal is to design a strategy to generate functional cardiac tissue in vitro which can besurgically placed to repair myocardial infarctions in the heart. Using new and unique technologies toaccomplish 3D magnetic assembly of cardiac cells integrate microscale vasculature and culture cells underpressure-volume changes in the heart we will attempt to mimic the structural and functional details of the invivo environment.


application_id: 8574068
project_number: 1R15HL120068-01
project_title: Fibrin Clot Architecture Regulated by Factor XIII
administering_ic: NHLBI
award_notice_date: 2013-08-05
opportunity_number: PA-12-006
application_type: 1
activity_code: R15
ic: HL
serial_number: 120068
program_official: WARREN, RONALD Q
project_start_date: 2013-08-05
project_end_date: 2016-07-31
study_section: Special Emphasis Panel[ZRG1 VH-C (90)]
contact_pi_person_id: 1912066
contact_pi: MAURER, MURIEL C.
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In blood coagulation thrombin cleaves fibrinogen (AaBbg)2 sites for fibrin polymerization are revealed and fibrin clot formation begins. Thrombin-activated Factor XIII is responsible for catalyzing the formation of covalent cross-links between fibrin molecules and in fibrin-enzyme complexes. The main objective of the research project is to examine how fibrin clot architecture can be regulated by FXIII. Intermolecular cross-links involving the fibrinogen aC region help secure lateral fibrin aggregation and lead to production of a more robust fibrin clot. Clot character can also be altered by influencing thrombin's ability to cleave the FXIII activation peptide segment. The roles of individual aC and FXIII amino acid regions in clot formation will be assessed. A greater understanding of these molecular details can be translated into new strategies to positively impact medical conditions. The vital biomaterial fibrin can be manipulated to create a stronger or weaker blood clot. FXIII and the resultant fibrin network are already known to play crucial roles in stemming blood loss in wound healing and in cardiovascular disease. For the development of new therapeutics to regulate blood clot structure critical gaps in our knowledge must be resolved. More information is needed on 1) the kinetic and structural features of fibrinogen aC a key substrate for FXIII and
2) the use of FXIII A2 mutants to fine tune FXIII activation and its subsequent functional effects.
The proposed research for this application will thus address two hypotheses: 1) FXIII is hypothesized to take advantage of specific reactive glutamines within the C (233-425) segment along with local and more distant C residues to promote formation of fibrin - cross-links. Such covalent cross-links enhance intermolecular fibrin chain contacts clot strength and protection from degradation and 2) FXIII A2 V34X mutants are hypothesized to possess different abilities to be activated and the extent of tranglutaminase function can be used to alter fibrin clot character. The FXIII A2 mutants will include the common polymorphism L34 and the aromatic substitutions F34 W34 and Y34. The biochemical methods required to address these aims include mass spectrometry solution NMR kinetic assays and measurements of fibrin clot formation and architecture. The knowledge gained from these studies will be used to improve the utilization of a biomaterials-based network for therapeutic purposes.

project_terms:
Active Sites;Address;Amino Acids;Anticoagulants;Architecture;Binding (Molecular Function);Biochemical;Biocompatible Materials;Biological Assay;Blood Clot;Blood coagulation;Cardiovascular Diseases;Cleaved cell;Coagulation Process;Complement;Cytolysis;Development;Distant;Environment;Enzymes;Factor XIII;Factor XIIIa;Fibrin;Fibrinogen;Fibrinopeptide A;Fibrinopeptide B;Genetic Polymorphism;Glutamine;Health;Hemorrhage;High Pressure Liquid Chromatography;Individual;Kinetics;Knowledge;Label;Lateral;Lead;MALDI-TOF Mass Spectrometry;Mass Spectrum Analysis;Measurement;Medical;Methods;Molecular;Multienzyme Complexes;Mutation;Network-based;P-2;Peptides;Physiological;Play;Positioning Attribute;Predisposition;Production;Property;Proteins;Research;Research Project Grants;Role;Secure;Site;Solutions;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Structure;Study models;TOCSY;Therapeutic;Thrombelastography;Thrombin;Time;Translating;Work;Wound Healing;base;crosslink;design;improved;mutant;novel therapeutics;polymerization;programs;public health relevance;stem

public_health_relevance:
The strength and architecture of a fibrin clot network can be regulated by Factor XIII. More information is needed on how to control activation of Factor XIII and how the resultant enzyme introduces rigid cross-links into this vital biomaterials-based network. Stronger or weaker clots may be designed to handle particular medical conditions. Studies may lead to novel therapeutic strategies for dealing with blood loss wound healing and/or the onset of cardiovascular disease.


application_id: 8573350
project_number: 2R01CA091901-11
project_title: Novel aureolic acid type antitumor agents
administering_ic: NCI
award_notice_date: 2013-08-01
opportunity_number: PA-11-260
application_type: 2
activity_code: R01
ic: CA
serial_number: 091901
program_official: FU, YALI
project_start_date: 2001-06-01
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1 BCMB-B (02)]
contact_pi_person_id: 2257319
contact_pi: ROHR, JURGEN T
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): Aureolic acid-type anticancer agents such as mithramycin (MTM) chromomycin (CMM) and durhamycin (DHM) are potent anticancer and anti-HIV drugs with a unique mode-of-action. They inhibit the growth of cancer cells by cross-linking GC-rich DNA thereby shutting down specificity-protein (Sp)-dependent pathways toward various proto-oncogenes including c-myc and c-src the latter being associated with the unique hypocalcemic activity found for these drugs. Particularly MTM is important and has become a popular biochemical tool to study Sp-dependent signal transduction pathways but -due to its toxic side effects- is rarely used as anticancer agent except for the treatment of tumor hypercalcemia refractory to other chemotherapy. However MTM was identified in 2011 by the NCI as the only lead from a screen of 50000 compounds that inhibits the EWS-FLI1 transcription factor responsible for the highly malignant phenotype of Ewing sarcomas which often affect children and were untreatable for the past 40 years. In addition another NCI group found in June 2012 that MTM represses cigarette smoke induced ABCG2 efflux pumps responsible for the drug resistance of lung and esophageal cancers and inhibited multiple stem-cell related pathways relevant for tumorigenicity and proliferation of such cancers. A few years ago MTM was identified as a potential lead drug against neurological diseases arthritis and for the treatment of hematologic disorders. All these new applications require only very small less toxic concentrations of the drug although the mode-of-action in these contexts remains obscure particularly the mode affecting the EWS-FLI1 transcription factor. MTM's biosynthesis has been studied intensely during the previous funding periods of this research project and consequently pursued combinatorial biosynthetic efforts revealed various biosynthetic intermediates and many new MTM-analogues which allowed deducing important structure-activity-relationships. Two regions are of special interest: First a modification of the 3-side chain first exemplified in the superior analogues MTM SK and MTM SDK led to much better anticancer activity profiles with a greatly improved therapeutic index compared to MTM itself. Second exchange of the D-mycarose sugar in E-position of MTM's trisaccharide chain by D-digitoxose led to superior analogues with greatly reduced toxic side effects. This now allows for new strategies to further concentrate on these regions of the molecule for further drug optimization.  During the previous biosynthetic studies biosynthetic intriguing and interesting key
enzymes were discovered which need to be further investigated particularly the co-dependent enzymes MtmGIV/MtmC (bifunctional glycosyltransferase/methyltransferase-ketoreductase) MtmOIV/MtmW (C-C-bond cleaving oxygenase/ketoreductase) which play key roles for the 3-side chain and the trisaccharide chain formation. Furthermore the PKS release remains unclear and it is hypothesized that another co-dependent enzyme pair namely oxygenase MtmOII and cyclase MtmX play an important role for this process. The goal here is to gain a deeper understanding of the biosynthetic roles mechanisms and interactions of these key enzymes of the MTM pathway to pave the way for the optimization and re-engineering of these enzymes that are crucial for novel further improved MTM derivatives. It is planned to (a) further investigate unclear biosynthetic steps and mechanisms of the MTM and other aureolic acid pathways (b) to further develop strategies for the selective generation of new improved MTM analogues including selective 3-side chain and sugar exchange/glycorandomization strategies (c) to analyze intriguing enzymes particularly recently discovered co- dependent enzyme pairs. New resulting MTM analogues will be submitted to the NCI DTP (developmental therapeutics program) for further mechanistic investigations.

project_terms:
ABCG2 gene;Address;Adverse effects;Affect;Anabolism;Anti-HIV Agents;Antineoplastic Agents;Arthritis;Biochemical;Biological Factors;Cancer Cell Growth;Child;Chromomycins;Cleaved cell;DNA;Developmental Therapeutics Program;Disease;Drug resistance;EWS-FLI1 fusion protein;Engineering;Enzymatic Biochemistry;Enzymes;Ewings sarcoma;Funding;Generations;Goals;Hypercalcemia;Investigation;Lead;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Methods;Methyltransferase;Modification;Oxygenases;Pathway interactions;Pattern;Pharmaceutical Preparations;Play;Plicamycin;Positioning Attribute;Process;Production;Proteins;Proto-Oncogenes;Reaction;Refractory;Research;Research Project Grants;Role;SRC gene;Side;Signal Transduction Pathway;Specificity;Stem cells;Structure-Activity Relationship;Techniques;Therapeutic Index;Toxic effect;Trisaccharides;Tumorigenicity;Work;analog;anticancer activity;antitumor agent;base;c-myc Genes;chemotherapy;chromomycin;cigarette smoke-induced;combinatorial;crosslink;design;digitoxose;drug modification;efflux pump;glycosylation;glycosyltransferase;improved;interest;malignant phenotype;mycarose;nervous system disorder;novel;protein structure;public health relevance;sugar;tool;transcription factor;tumor

public_health_relevance:
The proposed work aims to develop and refine a new generation of aureolic acid type natural product analogues with significantly diminished toxicity that will be useful as anticancer drugs and/or as drugs to treat neurological diseases arthritis and hematologic disorders. To enable the production of these fine-tuned drugs through combinatorial biosynthesis or chemo-enzymatic engineering in-depth research of the biosynthetic machinery of three aureolic acid pathways will be explored including key enzymes followed by enzyme re- engineering. In addition based on so far achieved structure-activity-relationship studies chemoenzymatic approaches for drug derivatization glycosylation exchange methods and chemoenzymatic glycorandomization techniques will be applied to selectively alter crucial structural features.


application_id: 8573255
project_number: 271201000010I-0-27100003-1
project_title: Pharmaceutical Formulation of Lead Drug Candidates
administering_ic: NIA
project_start_date: 2012-09-20
project_end_date: 2016-12-31
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:
Task Order 3 Purpose: Preparation of Intravenous formulations of (RR)-4'-Methoxy-1- Naphthylfenoterol (MNF)

project_terms:
Blood - brain barrier anatomy;Drug Formulations;Intravenous;Lead;Pharmaceutical Preparations;Pharmacologic Substance;Preparation;Toxic effect;drug candidate


application_id: 8573020
project_number: 5R01ES020870-03
project_title: Cell survival and arsenic carcinogenesis
administering_ic: NIEHS
award_notice_date: 2013-11-06
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: ES
serial_number: 020870
program_official: THOMPSON, CLAUDIA L
project_start_date: 2012-01-15
project_end_date: 2016-10-31
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;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: 8570618
project_number: 1R21DE023633-01
project_title: SGK1 is a Central Regulator of P. gingivalis-Induced Inflammation
administering_ic: NIDCR
award_notice_date: 2013-05-27
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: DE
serial_number: 023633
program_official: MELILLO, AMANDA A
project_start_date: 2013-07-01
project_end_date: 2015-06-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 16064057
contact_pi: WANG, HUIZHI
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Porphyromonas gingivalis (P. gingivalis) is a Gram-negative anaerobic bacterium and a causative agent of periodontitis.  Studies assessing the host inflammatory response to P. gingivalis have demonstrated that Toll-like receptor (TLR)-2 is the predominant TLR involved in the recognition of LPS and various other microbe-associated molecular patterns of P. gingivalis.  However the underlying cell-signaling pathways especially the intracellular regulatory molecules regulating the P. gingivalis (TLR2)-mediated inflammatory response are not fully understood. Using  siRNA  and  Cre/loxP  system  we have  for the first time  identified  that  serum-  and glucocorticoid-inducible kinase 1 (SGK1) suppresses P. gingivalis-mediated inflammatory responses in innate immune cells.  SGK1 is a ubiquitous serine/theronine kinase belonging to AGC kinase family (Protein kinase A -G and -C family) and can be activated by PI3 kinase.  Whereas the PI3K-Akt-GSK3- pathway has been demonstrated to play a critical regulatory role in TLR-mediated inflammatory responses the functional role of SGK1 in TLR-mediated immune responses is entirely unknown.  Therefore the studies proposed here are intend to identify and characterize how SGK1 regulates P. gingvalis induced inflammatory mediators as well as to delineate how the TLRs are involved in the phosphorylation and activation of SGK1. We hypothesize SGK1 is a critical kinase that controls inflammation of innate immune cells upon stimulation with P. gingivalis by regulating activation of Forkhead box protein O1 (FoxO1) and its downstream CCAAT/enhancer-binding protein beta (C/EBP-). This hypothesis is further substantiated by (i) the prediction of phosphorylation sites (by the software NetworKIN) identified FoxO1 as the optimum substrate of SGK1; (ii) our preliminary data showing that P. gingivalis stimulation phospho-activates SGK1 and abolishes the binding of FoxO1 to the promoter of C/EBP- in BMDC; and (iii) our recent publication demonstrating that PDK2 inhibition mediates FoxO1 nuclear sequestration and enhances TLR4 mediated inflammatory responses in innate immune cells (15). These observations provide a strong rationale for SGK1 in modulating P. gingivalis mediated inflammatory response via the TLR2-SGK1-FoxO1-C/EBP- axis.  The specific aims will establish the role for SGK1 as an endogenous inhibitor of the P. gingivalis-mediated inflammatory response and delineate how SGK1 is activated in response to P. gingivalis stimulation as well as determine if SGK1 negatively regulates P. gingivalis induced pro-inflammatory cytokines production via modification of the activity of FoxO1 and its downstream C/EBP- . Successful completion of this project will result in the isolation a novel and potentiall critical signaling pathway (TLR2-PI3K-SGK1-FoxO1-C/EBP- ) and greatly aid in the understanding of how the host inflammatory response is being regulated which will pave the way for the development of immunoregulatory therapeutics that should have relevance well beyond the oral cavity.

project_terms:
Affect;Atherosclerosis;Back;Binding (Molecular Function);Boxing;CCAAT-Enhancer-Binding Protein-beta;CCAAT-Enhancer-Binding Proteins;Cells;Chronic;Computer software;Cyclic AMP-Dependent Protein Kinases;Data;Development;Diabetes Mellitus;Disease;Exploratory/Developmental Grant for Diagnostic Cancer Imaging;Family;Figs - dietary;Genes;Glucocorticoids;Gram-Negative Anaerobic Bacteria;Immune;Immune response;Immune system;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Low Birth Weight Infant;Mediating;Microbe;Modification;Molecular;Nature;Nuclear;Oral cavity;Outcome;Pathway interactions;Pattern;Periodontitis;Periodontium;Phosphatidylinositols;Phosphorylation;Phosphorylation Site;Phosphotransferases;Play;Porphyromonas gingivalis;Predisposition;Process;Production;Promotor (Genetics);Protein-Serine-Threonine Kinases;Proteins;Publications;Receptor Signaling;Regulation;Role;Septic Shock;Serine;Serum;Signal Pathway;Signal Transduction;Small Interfering RNA;System;Systemic disease;TLR2 gene;TLR4 gene;Therapeutic;Time;Toll-Like Receptor 2;Toll-like receptors;Tretinoin;Work;base;cytokine;high reward;in vivo;inhibitor/antagonist;innovation;microbial;novel;nucleotide receptor;public health relevance;receptor;research study;response;success;therapeutic target

public_health_relevance:
Periodontitis is a chronic inflammatory disease and Porphyromonas gingivalis (P. gingivalis) is considered as a major causative agent. The host's immune response to P. gingivalis has been shown to play a fundamental role in the disease process by controlling the inflammatory response. Thus identifying the intracellular molecule that controls the host inflammatory response and elucidating the related mechanisms are critical for developing potential therapeutic targets to control periodontitis.


application_id: 8565231
project_number: 261201000031C-8-0-4
project_title: Patterns of Care (POC) Quality of Care Dx Yr 2011
administering_ic: NCI
project_start_date: 2012-09-30
project_end_date: 2013-09-29
contact_pi_person_id: 11520348
contact_pi: TUCKER, THOMAS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
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 with metastatic melanoma mesothelioma astocytoma/oligodendroglioma ovarian cancers and neuroblastoma

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


application_id: 8564315
project_number: 275201200010C-0-0-1
project_title: Novel Pharmacotherapies for Alcoholism
administering_ic: NIAAA
project_start_date: 2012-09-24
project_end_date: 2013-03-23
contact_pi_person_id: 11597791
contact_pi: LITTLETON, JOHN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
Alcoholism is a complex condition in which there are many potential molecular and therapeutic targets for pharmacotherapy. This "fast track" SBIR contract aims to investigate compounds targeted on the glutamate/NMDA receptor (NMDAR) and the nicotinic receptor for acetylcholine (nicAChR). These targets have direct relevance to several of the major therapeutic targets including detoxification of acute withdrawal neurotoxicity relapse organ damage co-morbid neuropathic pain and co-morbid drug abuse (including smoking). Naprogenix first identifies synthetic drugs or plant metabolites by high throughput pharmacological screening prioritizing lead compounds which have valuable multifunctionality. Leads are then tested in whole animal screens and models reflecting different specific aspects of alcoholism and the most promising are optimized by synthetic modification or by a novel plant genomic approach. Phase 1 of this "fast track" proposal is to complete preliminary studies at the molecular level on the 4 current best therapeutic candidates (2 synthetics and 2 natural products) and to prepare sufficient quantities of these for cellular studies and whole animal evaluation in phase 2. Also during phase 2 the company with the National Institute on Alcohol Abuse and Alcoholism (NIAAA) will contact major pharmaceutical and nutritional companies to explore the further development of these compounds as medications or nutraceuticals.

project_terms:
Acute;Address;Alcoholism;Animal Model;Animals;Biological Factors;Complex;Contracts;Development;Drug Metabolic Detoxication;Drug abuse;Evaluation;Genomics;Glutamates;Investigation;Lead;Modeling;Modification;Molecular;Molecular Target;N-Methyl-D-Aspartate Receptors;National Institute on Alcohol Abuse and Alcoholism;Nicotinic Receptors;Nutraceutical;Nutritional;Organ;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Phase;Plants;Relapse;Screening procedure;Small Business Innovation Research Grant;Smoking;Staging;Testing;Therapeutic;Withdrawal;alcoholism pharmacotherapy;neurotoxicity;novel;painful neuropathy;preclinical evaluation;programs;therapeutic target


application_id: 8554909
project_number: 275200800006C-9-0-1
project_title: NATIONAL CHILDREN'S STUDY
administering_ic: NICHD
project_start_date: 2008-09-26
project_end_date: 2013-09-25
contact_pi_person_id: 11597758
contact_pi: TOLLERUD, DAVID
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
funding_mechanism: R and D Contracts
project_abstract:
The National Children's Study (NCS) is prospective longitudinal cohort study of the individual and combined effects of environmental exposures and gene environmental interactions on child health and development in a representative sample of approximately 100000 children born in the United States. The children will be followed from before birth until age 21. The importance and timeliness of this study are based on many factors including past experiences demonstrating profound effects of environmental exposures such as exposures to alcohol during pregnancy and to lead in early childhood on child health and development; the special vulnerabilities of children to environmental exposures compared to adults; known ongoing exposures such as prevalent levels of non-persistent pesticides or hours of media exposure per day in young children; and evidence for environmental contributions or causes to such high-impact conditions as autism developmental delay and developmental disability asthma and obesity. The primary aim of the NCS is to investigate the separate and combined effects of environmental exposures (chemical biological physical psychosocial) as well as gene-environment interactions on pregnancy outcomes child health and development and precursors of adult disease. Unique features of the study include its focus on environmental exposures at the earliest stages of pregnancy (as well as thereafter) and the breadth of planned exposure and outcome measurements. The NCS responds to the Congressional mandate of the Children's Health Act of 2000 that the NICHD and a consortium of federal agencies plan and conduct a longitudinal study of the impacts of environmental exposures on children. The NCS will employ a national probability sampling approach to select locations and participants for conduct of the study. The sampling design utilizes a multistage clustered approach. In the first stage 105 locations (generally corresponding to single counties) were randomly selected from all U.S. counties. Seven of the locations serve as the initial or Vanguard Locations participating in the pilot phase of the NCS. Because the focus of the study includes assessment of the impact of exposures that occur early in pregnancy both pregnant women and their partners and women of childbearing age comprise the initial target population for enrollment. Data will be collected in combinations of face-to-face contacts and remote collection methods e.g. telephone computer or mail-in questionnaires. The expected frequency of contact (face-to-face or remote) is approximately every three months through age one every six months through age five years and annually thereafter. For a sample of children enrolled in the study visits will also be made to child care and school settings for collection of environmental samples and observational data. Anticipated biologic specimens include blood urine hair and nail clippings from mothers and children; blood urine and hair from fathers; cord blood umbilical cord and placental tissues and meconium collected at/around the time of delivery; vaginal swabs and breast milk from mothers. Anticipated environmental samples include air dust soil food and water.

project_terms:
21 year old;Address;Adolescent;Adult;Age;Air;Asses;Biological;Birth;Blood;Chemical Exposure;Child;Child Care;Child Development;Child health care;Clip;Cohort Studies;Collection;Computers;County;Data;Databases;Disease;Dust;Enrollment;Environment;Environmental Exposure;Environmental Risk Factor;Fathers;Female of child bearing age;Food;Frequencies (time pattern);Future;Genes;Hair;Health;Hour;Human Milk;Individual;Infant;Lead;Location;Longitudinal Studies;Mails;Measurement;Meconium;Methods;Mothers;Nail plate;National Children's Study;National Institute of Child Health and Human Development;Other Genetics;Outcome;Participant;Pesticides;Phase;Pregnancy;Pregnancy Outcome;Pregnant Women;Probability Samples;Questionnaires;Resources;Sampling;Schools;Severities;Soil;Specimen;Staging;Swab;Target Populations;Telephone;Time;Tissues;Umbilical Cord Blood;United States;Urine;Vagina;Variation (Genetics);Visit;Water;alcohol exposure;base;design;early childhood;environmental chemical exposure;experience;gene environment interaction;prospective;psychosocial;repository;social;young adult


application_id: 8551729
project_number: 5R01NR014189-02
project_title: Early Detection and Prevention of Mild Cognitive Impairment due to cerebrovascula
administering_ic: NINR
award_notice_date: 2013-06-03
opportunity_number: RFA-NR-12-010
application_type: 5
activity_code: R01
ic: NR
serial_number: 014189
program_official: TULLY, LOIS
project_start_date: 2012-09-26
project_end_date: 2017-06-30
study_section: ZNR1-REV-T(13)
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: MOSER, DEBRA KAY
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): There is a great unmet need to distinguish clinically between the different causes of cognitive impairment in elderly individuals for the sake of early diagnosis and therapeutic intervention designed to improve outcomes for patients. The University of Kentucky Alzheimer's Disease Center (UK-ADC) has been at the forefront of studying the most prevalent causes of Non-AD MCI demonstrating that over two-thirds of elderly patients have non-AD brain conditions that deleteriously affect cognition. We have chosen to focus on MCI due to cerebrovascular disease (MCI-CVD). This application focuses on defining the pathological underpinnings and relationships of specific risk factors to MCI-CVD developing clinical diagnostic criteria for MCI-CVD using imaging serum and CSF biomarkers that will also allow longitudinal evaluation and assessment of therapeutic interventions in MCI-CVD. As such the current application represents a comprehensive bench-to-bedside translational program designed to directly increase our understanding of and impact the major cause of cognitive decline in the elderly population today. The multidisciplinary team represents leaders in the field with proven track histories of scientific accomplishments and collaborative enterprise in the area of MCI. Successful completion of project aims will allow an integrated understanding of MCI-CVD with the potential for tremendous impact on one of the major healthcare crises facing the nation today.

project_terms:
Affect;Age-Years;Alzheimer's Disease;Area;Autopsy;Biological;Biological Markers;Blood;Brain;Brain Diseases;Brain Pathology;Cardiovascular Diseases;Cerebrospinal Fluid;Cerebrovascular Disorders;Clinical;Clinical Trials;Cognition;Cognitive;Data;Dementia;Diagnostic;Diagnostic Imaging;Disease;Doctor of Philosophy;Early Diagnosis;Elderly;Ensure;Etiology;Evaluation;Healthcare;Image;Impaired cognition;Individual;Intervention;Kentucky;Medical;Modification;Natural History;Neuropsychological Tests;Outcome;Pathology;Patients;Persons;Placebo Control;Population;Prevalence;Prevention;Randomized;Recording of previous events;Research Personnel;Risk Factors;Scientific Advances and Accomplishments;Serum;Staging;Statistical Models;Testing;Therapeutic Intervention;Universities;bench to bedside;cohort;design;digital;disorder risk;improved;mild cognitive impairment;multidisciplinary;older patient;programs;public health relevance;standard of care;success;therapy design

public_health_relevance:
Mild cognitive impairment (MCI) is often conflated with early Alzheimer's disease (AD) although a large proportion of individuals with MCI lack AD pathology. Especially among individuals beyond 85 years of age the prevalence of non-AD brain diseases such as cerebrovascular disease (CVD) surpasses that of advanced AD. We have chosen to focus on MCI due to cerebrovascular disease (MCI-CVD). The current application represents a comprehensive bench-to-bedside translational program designed to directly increase our understanding of and impact the major cause of cognitive decline in the elderly population today. The multidisciplinary team represents leaders in the field with proven track histories of scientific accomplishments and collaborative enterprise in the area of MCI. Successful completion of project aims will allow an integrated understanding of MCI-CVD with the potential for tremendous impact on one of the major healthcare crises facing the nation today.


application_id: 8550807
project_number: 5U01ES022564-02
project_title: Countermeasures for chlorine-induced airway fibrosis
administering_ic: NIEHS
award_notice_date: 2013-08-01
opportunity_number: PAR-11-155
application_type: 5
activity_code: U01
ic: ES
serial_number: 022564
program_official: NADADUR, SRIKANTH
project_start_date: 2012-09-25
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1-MDCN-J(50)R]
contact_pi_person_id: 2736750
contact_pi: HOYLE, GARY W.
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent because of the possibility that it could be released in industrial accidents or terrorist attacks. Acute effects of chlorine inhalation include dyspnea hypoxemia pneumonitis and pulmonary edema. Longer term consequences of chlorine inhalation include pulmonary function impairment and airway structural changes that have been observed in some exposed individuals. We have developed a mouse chlorine inhalation model in which animals develop pulmonary edema inflammation airway obstruction and airway hyperreactivity within one day after exposure. In new studies related to the current application we have characterized injury and repair of the lung at longer times after chlorine inhalation. We have observed that airways with a partial loss of epithelium are repaired quickly by the proliferation and differentiation of epithelial cells that survive chlorine exposure. In contrast portions of airways with few surviving epithelial cells are repaired inefficiently and fibroproliferative lesions develop at such sites within a week after chlorine exposure. This development of airway fibrosis is associated with impaired lung function including increased respiratory system resistance and airway hyperreactivity to inhaled methacholine. In the current application we propose to develop countermeasures that can be administered following a chemical attack or accidental release to prevent chlorine-induced airway disease. The hypothesis to be tested in the proposed studies is that inefficient repair of airway epithelium following chlorine lung injury leads to airway fibrosis and impaired lung function; agents that mimic anti-fibrotic effects of airway epithelium or stimulate airway repair will ameliorate chlorin- induced airway disease. Specific Aim 1 will characterize airway epithelial repair airway fibrosis
and lung function impairment following chlorine exposure in mice. Specific Aims 2-5 will evaluate the efficacy of the following potential countermeasures for the treatment of chlorine-induced airway disease: the prostanoid receptor agonists butaprost and iloprost; the long-lasting ss-agonist formoterol and the type 4 phosphodiesterase inhibitor rolipram; stimulation of plasminogen activation with urokinase-type plasminogen activator or the plasminogen activator inhibitor-1 inhibitor tiplaxtinin; and manipulation of Wnt/ss-catenin signaling with lithium chlorie or pyrvinium. Specific Aim 6 will involve development of a ferret model of chlorine-induced airway disease and testing of countermeasures in this non-rodent species. The proposed studies are expected to identify a countermeasure for prevention of chronic airway disease that develops as a result of an acute high level exposure to chlorine.

project_terms:
Acute;Adrenergic Agonists;Affect;Agonist;Airway Obstruction;Animals;Breathing;Cell Proliferation;Chemical Warfare;Chemicals;Chlorine;Chronic;Cyclic AMP;Development;Disease;Dyspnea;Epithelial;Epithelial Cells;Epithelium;Exposure to;Ferrets;Fibrosis;Goals;Human;Hypoxemia;Iloprost;Impairment;Individual;Industrial Accidents;Inflammation;Irritants;Kinetics;Lesion;Lithium;Lithium Chloride;Lung;Measurement;Modeling;Mus;Non-Rodent Model;Phosphodiesterase Inhibitors;Plasminogen;Plasminogen Activator;Plasminogen Activator Inhibitor 1;Pneumonia;Poisons;Prevention;Production;Prostaglandins;Pulmonary Edema;Recording of previous events;Research;Resistance;Resolution;Respiratory System;Respiratory physiology;Rodent;Rolipram;Signal Pathway;Signal Transduction;Site;Structure;Structure of respiratory epithelium;Symptoms;Testing;Time;Toxic effect;Unconscious State;United States;Urokinase;airway epithelium;airway hyperresponsiveness;animal rule;butaprost;chlorin;chlorine gas;efficacy testing;formoterol;inhibitor/antagonist;injury and repair;lung development;lung injury;methacholine;novel;phosphoric diester hydrolase;prevent;prostaglandin EP2 receptor;public health relevance;pulmonary function;receptor;repaired;research study;respiratory;restoration

public_health_relevance:
The goal of the proposed experiments is to develop novel ways to treat chronic airway disease caused by acute high level exposure to chlorine gas. This type of research is important because of concerns that U.S. civilians could be adversely affected by the accidental or intentional release of highly toxic chemicals such as chlorine.


application_id: 8550180
project_number: 2R56NS061933-05A1
project_title: MiR-15/107 microRNAs are important genetic regulators in Alzheimer disease
administering_ic: NINDS
award_notice_date: 2012-09-25
opportunity_number: PA-11-260
application_type: 2
activity_code: R56
ic: NS
serial_number: 061933
suffix: A1
program_official: CORRIVEAU, RODERICK A
project_start_date: 2008-04-01
project_end_date: 2014-06-30
study_section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
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): The miR-15/107 miRNA group are paralogous microRNAs (miRNAs) with overlapping gene regulatory impact that are downregulated in Alzheimer's disease (AD) brains. Our underlying hypothesis is that miR- 15/107 gene augmentation (up-regulation) will help to reduce brain cellular expression of BACE1 and tau kinases (PKA and CDK5-regulating proteins). We have strong preliminary evidence in support of this hypothesis. The overall goal of the present research proposal is to obtain information necessary to develop future miRNA-based brain therapies and to increase our knowledge about miRNAs' role in AD. Therapeutic strategies must involve either stimulating endogenous miRNA production or alternatively a "gene therapy" approach with exogenously introduced RNA or viral vectors. The key challenges before developing brain therapies related to miR-15/107 genes are 1> to understand upstream stimuli that alter miR-15/107 expression in human brains and 2> define downstream genes regulated by these miRNAs including an assessment of the potential for manipulating the "off-target effects" of miR-15/107-related miRNAs. We thus propose novel experiments in human brain and in primary rat brain-derived cultured cells. Specific Aims for this research project: Specific Aim #1: Define the specific AD-relevant signaling pathways that modulate miR-15/107 gene expression. Aim 1A: Perform hypothesis-based studies in cultured rat primary brain cells anchored in our preliminary results finding that glucose levels and discrete neuroinflammatory stimuli specifically alter miR-15/107 gene expression which may suggest strategies for miRNA-based therapies. Aim 1B: Perform comprehensive miR-15/107 expression profiling in human brain to understand how parameters linked with AD risk correlate with altered miR-15/107 gene expression because miRNA neurochemical studies need to be anchored in human brain data. Specific Aim #2: Define the exact "downstream" mRNA targets regulated by miR-15/107 genes in primary cultured rat brain cells. Preliminary data indicate that miR-15/107 genes may be a key mechanistic link between metabolic changes and increased tau phosphorylation in human brains. Using methods that were developed and optimized in our laboratory we will perform comprehensive analyses of miR-15/107 miRNA targets in primary cultured rat brain cells. Specific Aim #3: Manipulate and minimize "off-target" effects of miRNAs using RNA sequence modifications in primary cultured brain cells. Cultured neurons will be transduced with lentivirus vectors harboring altered sequences related to miR-15/107 genes. We have already generated miRNA expressing lentivirus and transduced primary cultured neurons to help optimize the potential impact of miRNA-based therapies in the brain. The overall goal is to produce reagents with optimal "on-target" and minimal "off-target" impact in order to maximize the potential value of small RNA- based therapeutics.

project_terms:
Address;Aging;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease risk;Astrocytes;Base of the Brain;Biochemistry;Brain;CDK5 gene;Cancer cell line;Cultured Cells;Cyclic AMP-Dependent Protein Kinases;Data;Funding;Future;Gene Expression;Gene Expression Regulation;Genes;Genetic;Glucose;Goals;Grant;Human;Inflammatory;Knowledge;Laboratories;Lead;Lentivirus Vector;Link;Messenger RNA;Metabolic;Metabolic Diseases;Metabolic Pathway;Methods;MicroRNAs;Microglia;Modification;Molecular Profiling;Mus;Neurons;Organism;Overlapping Genes;Pathogenesis;Pathway interactions;Patients;Production;Proteins;RNA;RNA Sequences;Rattus;Reagent;Research Project Grants;Research Proposals;Role;Signal Pathway;Small Interfering RNA;Small RNA;Stimulus;Subfamily lentivirinae;Therapeutic;Therapeutic Agents;Transcript;Up-Regulation (Physiology);Viral Vector;Work;base;beta-site APP cleaving enzyme 1;brain cell;cofilin;design;gene therapy;innovation;neurochemistry;novel;research study;tau phosphorylation;tau-protein kinase;tool

public_health_relevance:
The objective of this project is to better understand the causes of Alzheimer's disease and the linkages between this disease and the metabolic changes seen in aging.  We will characterize in human brains (and in primary cultured rat brain cells) a newly-discovered high impact level of gene regulation which are called microRNAs focusing on a key group of genes we defined as the "miR-15/107 group" of miRNAs.  Based on our preliminary data we think that we can produce information that directly or indirectly contributes to therapeutics for Alzheimer's disease patients.


application_id: 8550125
project_number: 5R03HD071291-02
project_title: The Role Of CCL20 In Ovulation: A Novel Mediator Of Ovarian Leukocyte Recruitment
administering_ic: NICHD
award_notice_date: 2013-06-24
opportunity_number: PA-10-064
application_type: 5
activity_code: R03
ic: HD
serial_number: 071291
program_official: TAYMANS, SUSAN
project_start_date: 2012-09-24
project_end_date: 2015-06-30
study_section: Reproduction, Andrology, and Gynecology Study Section[CHHD-R]
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
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_abstract:
DESCRIPTION (provided by applicant):  The preovulatory LH surge sets in motion a chain of events that culminate in breakdown of the ovarian follicle wall and release of the egg in a process known as ovulation. Ovulation involves an inflammatory process that is characterized by a massive influx of white blood cells known as leukocytes to the ovary. This influx of leukocytes is critical for fertility as removal of leukocytes in experimental models blocks oocyte release. However the factor(s) underlying the recruitment of leukocytes to the ovary are unknown. The present proposal will examine a newly identified candidate chemokine ligand 20 (CCL20). Our preliminary data shows that mRNA for CCL20 is massively induced in the human during the early and late preovulatory stage in the granulosa and theca cells from the ovarian follicle. Yet other than our preliminary data nothing is known as to temporal patterns of expression the regulation or function of CCL20 and its receptor CCR6 in the ovary. The present proposal builds on these provocative findings and will test the overall hypothesis that the LH surge stimulates an increase in CCL20 and the increase in this chemokine results in recruitment of leukocytes that impact events necessary for ovulation. This hypothesis will be addressed using a unique model where the granulosa and theca from human periovulatory follicles will be collected prior to and at three designated times after hCG to induce ovulation (early late and postovulatory). These human samples will be compared and contrasted to changes in CCL20 and CCR6 in the rat ovary using a well characterized rodent model for ovulation. This will be accomplished by the following three Aims. Aim 1 will determine the changes in the expression of the CCL20 and CCR6 system in both the human and rat ovary. This Aim will also determine how CCL20 and CCR6 expression is regulated via the major ovulatory pathways induced by LH. Aim 2 will explore the role of CCL20 in leukocyte recruitment into the ovary using well-characterized migration and invasion models. Due to the potential role of CCL20 to regulate cellular differentiation Aim 3 will investigate the role of CCL20 on ovarian cell function specifically the ability of granulosa cells to survive differentiate and make sterid hormones. Additionally the impact of CCL20 on ovarian cells will be assessed using microarray technology. The major strengths of the current proposal lie in the use of well characterized human preovulatory follicles as a foundation to understand the cellular expression regulation and the impact of CCL20 on the events associated with ovulation in the human and our integrated comparative approach across species to elucidate the role that this chemokine plays in the ovulatory process. Nothing is known about CCL20 and its receptor in the ovary. As such the proposed studies are extremely timely to elucidate the role that this chemokine system plays in the coordinated processes of follicular rupture and oocyte release which are fundamental aspects of normal human ovarian physiology.

project_terms:
Address;Animals;Apoptosis;Biological Assay;CCR6 gene;Cell Cycle Kinetics;Cell physiology;Cells;Contraceptive Agents;Data;Epidermal Growth Factor;Event;Excision;Experimental Models;Fertility;Figs - dietary;Foundations;Genes;Hormones;Human;Human Chorionic Gonadotropin;In Vitro;Inflammatory;Inflammatory Response;Leukocytes;Ligands;Matrix Metalloproteinases;Mediator of activation protein;Messenger RNA;Microarray Analysis;Modeling;Motion;Oocytes;Ovarian;Ovarian Follicle;Ovarian Tissue;Ovary;Ovulation;Pathway interactions;Pattern;Physiology;Play;Process;Progesterone;Prostaglandins;Proteins;Rattus;Reaction;Recruitment Activity;Regulation;Reporting;Rodent;Rodent Model;Role;Rupture;Sampling;Signal Pathway;Signal Transduction;Staging;Steroid biosynthesis;Stimulus;System;Testing;Time;Tissues;chemokine;comparative;egg;granulosa cell;migration;novel;receptor;research study;theca cell

public_health_relevance:
The proposed studies will investigate the underlying mechanism involved in human ovulation which is a process where the egg is released from the follicle in the ovary. These studies will focus on a protein chemokine ligand 20 (CCL20) that we believe serves to attract white blood cells into the ovary to help breakdown the wall of the ovarian follicle to allow the egg to be released. Only by fully understanding such basic tenets of ovarian function will we be able to promote or inhibit the events associated with the ovulatory process thereby facilitating and increasing fertility or acting in a contraceptive manner to decrease fertility.


application_id: 8550085
project_number: 5R44GM093411-03
project_title: Enhancing mammalian glycoprotein production in the baculovirus expression vector
administering_ic: NIGMS
award_notice_date: 2013-08-20
opportunity_number: PA-12-088
application_type: 5
activity_code: R44
ic: GM
serial_number: 093411
program_official: MARINO, PAMELA
project_start_date: 2010-05-01
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1-IMST-J(15)B]
contact_pi_person_id: 9710810
contact_pi: FATH-GOODIN, ANGELIKA
other_pis: GEISLER, CHRISTOPH
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The baculovirus expression vector system (BEVS) is a proven powerful and versatile method of eukaryotic protein expression. It is used to produce vaccines diagnostics and biologically active proteins for a multitude of research projects. Like all expression systems however BEVS has its disadvantages. One is the fact that expression is short-lived due to virus-induced cell death and lysis. ParaTechs has already commercialized a product that addresses this shortcoming. Cell lines that express a viral ankyrin gene show delayed death and lysis of baculovirus-infected cells thereby significantly enhancing recombinant protein production. This activity referred to as vankyrin-enhanced BEVS (VE-BEVSTM) boosts target protein expression up to 22-fold. A second limitation of baculovirus expression is that insect cells lack the ability to produce terminally sialylated complex N-glycans which limits the usefulness of BEVS for the expression of human therapeutic proteins. GlycoBac LLC has developed a transgenic insect cell line (SfSWT4) that expresses six mammalian glycosylation enzymes allowing synthesis of terminally sialyated proteins. This Phase II proposal combines ParaTechs' VE technology with GlycoBac's cell line to optimize expression of "humanized" N-glycans. In Phase I the transgenic cell line SfSWT4 was transformed with several vankyrin genes under the control of different promoters. Polyclonal cells were screened for enhanced glycoprotein expression. Data demonstrating that infected cells lived longer and produced more authentically sialylated protein confirmed our hypothesis. Phase II will extend these studies by (1) cloning and characterization of VE-SWTTM cells according to FDA guidelines for cells used to produce vaccines and biological; (2) examining synergistic effects between VE virus vectors and VE-SWT cell lines to provide greater levels of enhancement; and (3) demonstrating enhanced expression of medically relevant glycoproteins in VE-SWTTM cells. These Phase II studies will significantly expand the applications of ParaTechs' VE-BEVS technology and GlycoBac's glycoengineered cell lines. Personnel at both companies have experience with the techniques to be used. Preliminary studies indicate that this technology has a significant chance of performing as envisioned. Furthermore prior marketing experience with transformed cell lines previously released from the two companies suggests a significant demand for the expanded technology. This new technology should be relatively easy to commercialize based on the established reputations of ParaTechs Inc. and GlycoBac LLC and the growing demand for improved cell lines to express recombinant humanized glycoproteins.

project_terms:
Address;Alteplase;Ankyrins;Baculovirus Expression System;Baculoviruses;Biological;Cell Death;Cell Line;Cells;Cessation of life;Cloning;Complex;Cytolysis;Data;Development;Diagnostic;Disadvantaged;Engineering;Enzymes;Funding;Genes;Glycoproteins;Goals;Guidelines;Human;Human Resources;Individual;Influenza Virus Hemagglutinin Glycoproteins;Insecta;Integral Membrane Protein;Life;Marketing;Methods;Modeling;Pharmacologic Substance;Phase;Polysaccharides;Positioning Attribute;Process;Production;Promotor (Genetics);Property;Proteins;Recombinant Proteins;Recombinants;Research Personnel;Research Project Grants;Serum-Free Culture Media;Site;Structure;System;Techniques;Technology;Testing;Transformed Cell Line;Transgenic Organisms;United States National Institutes of Health;Vaccines;Viral;Virus;alpha 1-Antitrypsin;base;efficacy testing;experience;expression vector;glycosylation;improved;new technology;phase 2 study;protein expression;therapeutic protein;vector

public_health_relevance:
The inability of insect cells to produce terminally sialylated complex N-glycans limits the usefulness of the baculovirus expression system for the production of human therapeutic proteins. This proposal addresses that deficiency and aims to develop new cell lines that produce authentic "humanized" N-glycans in the context of ParaTechs' vankyrin-enhanced baculovirus technology. Successful completion of these objectives will produce cells that provide the highest levels of accurately processed secreted and transmembrane proteins and will be marketed to individual researchers and pharmaceutical companies engaged in structure-function studies of the human secretome and development of protein therapeutics.


application_id: 8549257
project_number: 5R21EY022871-02
project_title: Tectal influences on visual thalamic activity: an optogenetic approach
administering_ic: NEI
award_notice_date: 2013-08-14
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: EY
serial_number: 022871
program_official: STEINMETZ, MICHAEL A
project_start_date: 2012-09-30
project_end_date: 2015-09-29
study_section: Special Emphasis Panel[ZRG1-IFCN-L(02)M]
contact_pi_person_id: 1864719
contact_pi: GUIDO, WILLIAM
other_pis: KRAHE, THOMAS E
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Much is known about how inputs from sources other than the retina affect the thalamic relay of retinal signals in route to the visual cortex. They arse from a variety of subcortical and cortical sources comprise the bulk of synapses onto thalamic relay cells and act as modulators to affect the gain of retinogeniculate signal transmission. The superior collliculus (SC) a primary retino-recipient structure also sends a prominent projection to the dorsal lateral geniculate nucleus (dLGN) the first order nucleus that conveys retinal signals to visual cortex. However whether SC input acts as a driver to help shape the receptive field structure of dLGN relay neurons or as a modulator to dampen or amplify the flow of thalamic information remains untested. To understand how information arising from the SC influences dLGN function and how particular SC cell types contribute to this we shall make use of mouse transgenics to visualize or target cell types and projections of the tectogeniculate pathway optogenetics to photo-activate SC inputs to evoke postsynaptic activity in dLGN cells and in vitro and in vivo recording techniques to assess whether SC inputs behave as drivers or modulators of dLGN activity. These combined approaches will allow us to selectively control the neuronal activity of the tecto-geniculate pathway and shed light on how interactions between two retino- recipient subcortical structures affect the processing and transfer of visual information.

project_terms:
Action Potentials;Acute;Address;Affect;Area;Behavior;Cations;Cell Nucleus;Cells;Chimera organism;Chloride Ion;Chlorides;Data;Depressed mood;Dorsal;Electric Stimulation;Electrodes;Eye;Fiber;Fiber Optics;Glutamates;Halorhodopsins;Head Movements;Imagery;In Vitro;Lateral Geniculate Body;Lead;Light;Location;Mammals;Mus;Mutation;Neurons;Optic tract structure;Pathway interactions;Pattern;Peripheral;Physiologic pulse;Process;Property;Pump;Reporter;Retina;Retinal;Retinal Ganglion Cells;Route;Sense Organs;Sensory;Shapes;Signal Transduction;Slice;Source;Space Perception;Structure;Synapses;Techniques;Tectum Mesencephali;Thalamic structure;Transgenic Mice;Variant;Viral Vector;Visual;Visual Cortex;Whole-Cell Recordings;adeno-associated viral vector;biocytin;cell type;extracellular;image processing;in vivo;information processing;insight;loss of function;nerve supply;nervous system disorder;object recognition;optogenetics;polypeptide;postsynaptic;receptive field;recombinase;red fluorescent protein;research study;response;retinogeniculate;retinotectal;superior colliculus Corpora quadrigemina;tool;transmission process;vector;visual information;visual stimulus

public_health_relevance:
These studies will provide valuable information about how first-order sensory nuclei of the thalamus receive and process information from peripheral sense organs. They shall also reveal how afferent input from central structures can modulate the flow of thalamic information in route to sensory cortical areas. Understanding the functional and structural organization of thalamic circuitry with optogenetic tools may offer further insight intothe study and treatment of neurological disorders that result from the formation of abnormal patterns of connectivity.


application_id: 8549153
project_number: 5U01CA151648-05
project_title: RNA Nanotechnology in Cancer Therapy
administering_ic: NCI
award_notice_date: 2013-07-24
opportunity_number: RFA-CA-09-013
application_type: 5
activity_code: U01
ic: CA
serial_number: 151648
program_official: MORRIS, STEPHANIE A
project_start_date: 2010-08-25
project_end_date: 2015-07-31
study_section: ZCA1-SRLB-X(M1)
contact_pi_person_id: 1878565
contact_pi: GUO, PEIXUAN
other_pis: LI, HENRY ;ROSSI, JOHN JOSEPH
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): This project is to organize an interdisciplinary team to work on RNA nanotechnology by constructing polyvalent RNA nanoparticles for specific targeting and delivery to cancer cells. RNA molecules can down-regulate specific gene expression in cancer cells. RNA is particularly attractive as a building block for bottom-up assembly in nanotechnology and nanomedicine. RNA can be manipulated as easily as DNA but possesses the versatility in structure and function similar to that of proteins. RNA contains single-stranded stem-loops for intra- or inter-RNA interactions which can serve as mounting dovetails providing advantages over external linking dowels in nanomachine assembly. This CNPP operation comprises of three major functions: the fundamental studies on therapeutic RNA nanoparticle construction; the conjugation and incorporation of therapeutic and targeting moieties to RNA nanoparticles; and the specific delivery of therapeutics to cancer cells. The team includes basic scientists with strong backgrounds in biomedical engineering chemistry and RNA and DNA nanotechnology; cancer biologists with extensive experience in ribozyme and siRNA delivery; and pharmaceutical cooperation focusing on RNA therapeutics with expertise in animal trials. The team will elucidate the principles underlying the RNA/RNA interactions in RNA nanoparticle assembly using phi29 motor pRNA system and RNA junction motifs to build polyvalent RNA oligomers containing aptamer siRNA ribozyme ligand imaging markers or drugs for cancer cell recognition and gene silencing. A new methodology of SELEX will be developed to screen for stable and high affinity RNA aptamers that target and enter cancer cells specifically. Simultaneous delivery and detection will be designed combining therapy and detection of subsequent therapeutic effects on apoptosis. Approaches of crossover chemical modification and cross-linking will be applied to make RNA nanoparticles stable in vivo. Novel fermentation approaches and industry scale production methods will be developed to produce large-scale stable RNA for clinical applications. Animal trials on pharmacokinetics bio-distribution toxicity gene silencing effects and cancer cell killing will be carried out on animal models of lung cancer ovarian cancer liver cancer and leukemia. RELEVANCE (See instructions): Cancer is a current and long term health care crisis and treatments necessitate the investigation of specific delivery to target cells. This application proposes to fabricate RNA nanoparticles to incorporate therapeutic SiRNA aptamers and ribosomes to accomplish targeted delivery. Therapeutic constituents will be selected for the treatment of lung cancer ovarian cancer liver cancer and leukemia.

project_terms:
Affinity;Animal Model;Animals;Apoptosis;Biodistribution;Biological Assay;Biological Models;Biomedical Engineering;Carcinoma;Catalytic RNA;Cell Culture Techniques;Cells;Chemicals;Chemistry;Chimera organism;Complex;DNA;Detection;Double-Stranded RNA;Drug Kinetics;Evaluation;Fermentation;Gene Expression;Gene Silencing;Healthcare;Image;Immunity;Industry;Instruction;Interferons;Investigation;Ligands;Link;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of ovary;Methodology;Methods;Modeling;Modification;Motor;Nanotechnology;Ovarian;Pharmaceutical Preparations;Pharmacologic Substance;Primary carcinoma of the liver cells;Principal Investigator;Production;Proteins;RNA;RNA Stability;Ribosomes;Scientist;Small Interfering RNA;Structure;System;Testing;Therapeutic;Therapeutic Effect;Time;Toxic effect;Work;Xenograft procedure;aptamer;cancer cell;cancer therapy;cancer type;cell killing;chemical synthesis;clinical application;crosslink;design;efficacy evaluation;experience;in vivo;leukemia;nanomachine;nanomedicine;nanoparticle;novel;operation;programs;scale up;screening;stem;targeted delivery;therapeutic target


application_id: 8548914
project_number: 5R25CA148005-04
project_title: The Development of an Interdisciplinary Oncology Palliative Care Curriculum
administering_ic: NCI
award_notice_date: 2013-08-26
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: 2015-08-31
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.    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_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.);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:
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.


application_id: 8547804
project_number: 5U01DA033276-02
project_title: A Phase 3 Double-Blind Efficacy Safety and Dose-Response Study of Lofexidine (S
administering_ic: NIDA
award_notice_date: 2013-08-01
opportunity_number: PAR-11-109
application_type: 5
activity_code: U01
ic: DA
serial_number: 033276
program_official: BISWAS, JAMIE
project_start_date: 2012-09-30
project_end_date: 2015-07-31
study_section: ZDA1-JXR-D(05)S
contact_pi_person_id: 2408657
contact_pi: GORODETZKY, CHARLES W.
other_pis: Not Applicable
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The proposed research is aimed at characterizing the safety and efficacy profiles to address FDA-defined gaps in the clinical development program for lofexidine hydrochloride an alpha-2 adrenergic agonist under development for the treatment of acute withdrawal from short-acting opioids. The program includes two linked studies to be conducted consecutively at the same sites: Study 1 will generate pivotal efficacy/safety data for two doses of lofexidine hydrochloride in 600 subjects about to undergo total and abrupt withdrawal from short- acting opioids who will be randomized under double-blind conditions to either placebo (N=150) or lofexidine (2.4 mg or 3.2 mg total daily dose; N=225/group) for 7 days of inpatient treatment. Subsequently all subjects will be permitted to continue under open-label conditions for up to an additional 7 days of inpatient/outpatient variable-dose treatment depending on the wishes of the Site Investigator and subject. Safety will be assessed by evaluation of adverse event (AE) clinical laboratory electrocardiogram (with special attention to
QTc) vital signs and physical exam data. Efficacy will be evaluated daily by subject- and observer-completed scales including the Short Opiate Withdrawal Scale of Gossop (SOWS-G) (the primary outcome measure is SOWS-G score area under the curve for Days 1-7) the Objective Opiate Withdrawal Scale (OOWS-Handelsman) the Visual Analog Scale for Efficacy (VAS-E) and the Modified Clinical Global Impressions scales for efficacy and side effects. Efficacy will also be evaluated by study retention completion rates concomitant medication use incidence of withdrawal-related AEs and subject treatment status 30 days post discharge. Study 2 will follow a similar 14-day dosing format but will be entirely open-label; and 200 to 400 subjects (different from those in Study 1) will receive lofexidine at a variable dose not to exceed
a total of 3.2 mg per day or a single dose of 0.8 mg in an inpatient outpatient or a combination of settings as per the normal standard of care at the enrolling site. Study 2 is a translational research design aimed at gathering "real-world" effectiveness and safety data to supplement the existing lofexidine safety database and enable appropriate product labeling for end-users. Safety will be evaluated for all treated subjects and for two cohorts: those with urines negative and those with urines positive for drugs of abuse so that all possible causes of reported AEs may be considered for analysis. Effectiveness will be evaluated by the Clinical Opiate Withdrawal Scale (COWS) rate of detoxification completion and subject treatment status 30 days post discharge. An open-label variable-dose real-world design as planned in Study 2 is common in Phase 3 drug development and together with Study 1 which will provide pivotal efficacy data needed to support the proposed product indication the program has been designed to address FDA registration requirements for lofexidine. On approval of an NDA lofexidine will be the first approved non-narcotic non-addictive drug indicated for treatment of opioid withdrawal in the US providing an important alternative therapy for this indication.

project_terms:
Abstinence;Acute;Address;Adrenergic Agonists;Adverse effects;Adverse event;Alternative Therapies;American;Applications Grants;Area Under Curve;Attention;Buprenorphine;Clinical;Data;Databases;Development;Dose;Double-Blind Method;Drug Metabolic Detoxication;Effectiveness;Electrocardiogram;Enrollment;Evaluation;FDA approved;Hydrochloride Salt;Incidence;Inpatients;Laboratories;Life;Link;Literature;Marketing;Medical;Methadone;Narcotics;Opiates;Opioid;Outcome Measure;Outpatients;Pharmaceutical Preparations;Phase;Placebo Control;Placebos;Product Labeling;Program Development;Publishing;Randomized;Reporting;Research;Research Design;Research Personnel;Safety;Severe Adverse Event;Signs and Symptoms;Site;Symptoms;Translational Research;United Kingdom;United States Food and Drug Administration;Urine;Visual;Withdrawal;Work;analog;base;cohort;design;drug development;drug of abuse;experience;impression;lofexidine;meetings;open label;opioid withdrawal;phase 3 study;primary outcome;programs;public health relevance;response;standard of care;therapy development;treatment duration;trend

public_health_relevance:
With a growing trend of millions of Americans becoming dependent on prescription and other short-acting opioid narcotics there is an unmet medical need for new detoxification treatments. The only drugs approved by the FDA for this indication (methadone and buprenorphine) are opioid replacement or substitution therapies which themselves have abuse potential. The proposed research program on lofexidine hydrochloride will: i) establish the dose range by examining the safety and efficacy of two different doses of lofexidine; ii) confirm that lofexidine may be used until the acute phase of opioid withdrawal is complete (i.e. up to 14 days); and iii) increase the safety database by employing a "real-world" strategy to study additional subjects and increase the likelihood of identifying potential safety issues that may be present in only a small percentage of users. NIDA's support of this development work on lofexidine is necessary to enable FDA approval of the first non-narcotic non-addictive treatment for opioid withdrawal.


application_id: 8547052
project_number: 5R01DK081555-05
project_title: Upstream Stimulatory Factor 2 regulation of renin in diabetic nephropathy
administering_ic: NIDDK
award_notice_date: 2013-09-04
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 081555
program_official: RYS-SIKORA, KRYSTYNA E
project_start_date: 2009-09-01
project_end_date: 2016-08-31
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
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
arra_indicator: N
project_abstract:
Diabetic nephropathy is the most common cause of end-stage renal failure and is highly prevalent in both type1 and type 2 diabetics. Hyperglycemia and the activation of the intrarenal renin-angiotensin system (RAS) indiabetes have been suggested to play a critical role in the pathogenesis of diabetic nephropathy. However themechanisms for the effectiveness of inhibitors of the RAS or for angiotensin II as a mediator of diabeticnephropathy are not well defined. Transforming growth factor - (TGF-) is a major effector leading to renalfibrosis in response to hyperglycemia. Preliminary data demonstrate that Upstream Stimulatory Factor (USF2)is an important transcription factor in high glucose-induced TGF- production in mesangial cells. ImportantlyUSF2 expression is increased in the kidneys of diabetic mice and correlates with the glomerular mesangialmatrix expansion. Furthermore over-expression of USF2 accelerates the development of diabeticnephropathy in a type 1 diabetic mouse model supporting the role of this transcription factor in thedevelopment of diabetic nephropathy. Our preliminary studies describe a novel effect of USF2 to promoterenin gene expression and angiotensin II formation in mesangial cells. This effect of USF2 was linked toglucose-induced regulation of TGF- production suggesting that this pathway may contribute to thedevelopment of diabetic nephropathy. The working hypothesis of this proposal is that USF2 stimulates therenal RAS to promote production of TGF- and the development of diabetic nephropathy. The proposedstudies will define the role of USF2 in the development of diabetic nephropathy focusing on regulation ofmesangial cell renin as the mechanistic target. In aim 1 the mechanisms by which USF2 regulates renin geneexpression and angiotensin II production in mesangial cells under normal or high glucose conditions will bedetermined. In aim 2 the role of USF2-mediated renin expression and angiotensin II production in highglucose induced TGF- levels and extracellular matrix protein (ECM) expression in mesangial cells will bedefined. In aim 3 the role of USF2-mediated up-regulation of the renal RAS in the development of diabeticnephropathy in vivo will be determined. Our approach utilizes both in vitro and in vivo studies to provide newinformation on the mechanisms of activation of the intrarenal RAS system in diabetes and will lead to thedevelopment of novel therapies to ameliorate this major complication of diabetes.

project_terms:
Albumins;Angiotensin II;Complications of Diabetes Mellitus;Data;Deposition;Development;Diabetes Mellitus;Diabetic Nephropathy;Diabetic mouse;Effectiveness;End stage renal failure;Excretory function;Exhibits;Extracellular Matrix;Extracellular Matrix Proteins;Fibrosis;Gene Expression;Genes;Glomerular Mesangial Cell;Glucose;Hyperglycemia;Hypertrophy;In Vitro;Injection of therapeutic agent;Insulin-Dependent Diabetes Mellitus;Kidney;Kidney Diseases;Lead;Link;Losartan;Mediating;Mediator of activation protein;Pathogenesis;Pathway interactions;Physiological;Plasma;Play;Production;Proteins;Regulation;Relative (related person);Renal function;Renin;Renin-Angiotensin System;Role;Small Interfering RNA;Streptozocin;Structure;System;Testing;Transforming Growth Factors;Transgenic Mice;Transgenic Organisms;Up-Regulation (Physiology);Wild Type Mouse;Work;aliskiren;diabetic;glomerular basement membrane;glomerular function;glomerulosclerosis;human USF2 protein;in vivo;inhibitor/antagonist;mesangial cell;mouse model;novel;protein expression;receptor;response;transcription factor;transcription factor USF;type I and type II diabetes;type I diabetic;urinary

public_health_relevance:
Diabetic nephropathy is the most common cause of end-stage renal failure and is highly prevalent in both type1 and type 2 diabetics. The proposed studies will provide new information on the mechanisms of activation ofthe intrarenal renin-angiotensin system in diabetes and will lead to the development of novel therapies toameliorate this major complication of diabetes.


application_id: 8546235
project_number: 5R01AR062083-02
project_title: Skeletal muscle biology in rheumatoid arthritis
administering_ic: NIAMS
award_notice_date: 2013-09-06
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AR
serial_number: 062083
program_official: BOYCE, AMANDA T
project_start_date: 2012-09-17
project_end_date: 2013-09-02
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1888793
contact_pi: CROFFORD, LESLIE J
other_pis: REID, MICHAEL B;WESTERBLAD, HAKAN
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):  Rheumatoid arthritis (RA) is the most common chronic inflammatory disease affecting up to 1% of the population. Beyond joint pain and stiffness muscle weakness is among the most prevalent symptoms of RA patients. Weakness affects most major muscle groups and limits basic activities such as walking sitting and rising from chairs opening containers dressing oneself and personal hygiene. Weakness also contributes to postural instability in RA predisposing individuals to fall-related injuries and dramatically lessens the overall quality of life. There is no drug therapy for RA-related weakness no clinical standard of care to address this debilitating problem. The goal of this project is to define processes that cause weakness in RA and identify biological targets for future drug development. Weakness far exceeds muscle atrophy in RA patients. Therefore the focus of our project is loss of contractile function as reflected by specific force i.e force per cross-sectional area. Our experimental model proposes that RA increases muscle exposure to proinflammatory cytokines that stimulate production of nitric oxide (NO) derivatives and reactive oxygen species (ROS) by muscle fibers. The resulting oxidative stress depresses specific force and causes weakness. Interventions that disrupt this chain of events are expected to preserve specific force opposing RA-related weakness. We will test this model by using muscles from RA patients and a well-established mouse model of RA (collagen-induced arthritis CIA) to address four specific aims: Specific Aim 1. To identify cytokines essential for RA-induced weakness. Specific Aim 2. To define changes in skeletal muscle oxidant production caused by RA. Specific Aim 3. To define cellular mechanisms of contractile dysfunction in RA. Specific Aim 4.To test therapeutic approaches for preserving muscle function in RA.

project_terms:
Activities of Daily Living;Address;Adverse effects;Affect;Animal Experiments;Animals;Antimetabolites;Antioxidants;Area;Arthralgia;Biochemical;Biological;Biology;Blood Circulation;Calcium;Chronic;Clinical;Collagen Arthritis;Data;Depressed mood;Disease;Endocrine;Event;Experimental Arthritis;Experimental Models;Exposure to;Folic Acid Antagonists;Functional disorder;Future;Goals;Homeostasis;Human;Hygiene;Individual;Inflammatory;Injury;Interleukins;Intervention;Joints;Limb structure;Link;Mediator of activation protein;Modeling;Mus;Muscle;Muscle Fibers;Muscle Mitochondria;Muscle Weakness;Muscle function;Muscular Atrophy;Neurons;Nitric Oxide;Nitric Oxide Synthase;Nitric Oxide Synthase Type I;Oxidants;Oxidation-Reduction;Oxidative Stress;Patients;Peroxonitrite;Pharmacologic Substance;Pharmacotherapy;Population;Process;Production;Proteins;Quality of life;Reactive Oxygen Species;Research;Rheumatoid Arthritis;Ryanodine;Skeletal muscle structure;Source;Sterile coverings;Stimulus;Sulfhydryl Compounds;Symptoms;Testing;Therapeutic;Tissues;Tumor Necrosis Factor-alpha;Walking;arthritis therapy;clinical care;clinically relevant;cytokine;design;drug development;falls;joint stiffness;mouse model;public health relevance;research study;response;standard of care

public_health_relevance:
Rheumatoid arthritis (RA) is the most common chronic inflammatory disease. Muscle weakness is among the most prevalent symptoms limiting basic activities of daily living predisposing individuals to fall-related injuries and lessening the quality of life. The goal of this project is to define the processes that cause weakness in RA and identify biological targets for future drug development.


application_id: 8545862
project_number: 5R13GM058252-15
project_title: Interactive Learning Modules for Writing Grant Proposals
administering_ic: NIGMS
award_notice_date: 2013-09-16
opportunity_number: PA-08-149
application_type: 5
activity_code: R13
ic: GM
serial_number: 058252
program_official: SESMA, MICHAEL A
project_start_date: 1998-09-05
project_end_date: 2015-08-31
study_section: ZGM1-BRT-0(CO)
contact_pi_person_id: 8535385
contact_pi: FRAZIER, DONALD T
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract The overall objective of this application is to continue to empower faculty at institutions with high minority enrollment to develop and submit competitive research proposals. The original goal of our training partnership with NIGMS was to translate an innovative proven grant writing workshop into an interactive hypermedia course by placing learning modules on the internet for wide dispersal. Building on our past experience with over 250 faculty and postdoctoral fellows the competing renewal has three facets which will take place concurrently: 1) up-dating and revising the 15 modules to incorporate changes in NIH guidelines and to make them more interactive; 2) plan and implement on-site pre-course workshops to instruct faulty/postdoctoral fellows and corresponding research administrators in accessing and navigating the web-based course; 3) developing and implementing a new workshop initiative focused on training programs in particular the MORE divisions RISE Bridges IMSD and MARC applications. The focal-point of our program will continue to be focused on minority faculty and the individual research grant. In response to requests from our faculty participants to improve their research environment we recently developed a workshop for research administrators at minority-serving institutions. The training program component addresses the need to enhance the pipe-line of minority students entering into biomedical research. Through on-going scientific mentoring and writing process consultation we sustain a relationship with our participants well beyond the workshops and internet course.  Thus our collaborative partnership with NIGMS should motivate and improve the skills and abilities of researchers/grant writers at minority institutions increase the number of minorities engaged in biomedical research and thereby strengthen the overall research environment at minority institutions. Success in these areas would have a substantial impact on the health and well-being of our citizens.

project_terms:
Address;Administrator;Agreement;Applications Grants;Area;Biomedical Research;CCL7 gene;Consultations;Educational workshop;Enrollment;Environment;Faculty;Goals;Grant;Guidelines;Health;Hypermedia;Individual;Institutes;Institution;Internet;Learning;Mentors;Minority;Minority-Serving Institution;National Institute of General Medical Sciences;Online Systems;Participant;Peer Review;Personal Satisfaction;Postdoctoral Fellow;Process;Research;Research Activity;Research Personnel;Research Project Grants;Research Proposals;Research Support;Research Training;Rest;Site;Students;System;Training;Training Programs;Translating;Underrepresented Minority;Underserved Population;United States National Institutes of Health;Writing;abstracting;base;career;empowered;experience;improved;innovation;programs;response;role model;skills;success

public_health_relevance:
Project Narrative Our collaborative partnership with NIGMS should motivate and improve the skills and abilities of researchers/grant writers at minority institutions increase the number of minorities engaged in biomedical research and thereby strengthen the overall research environment at minority institutions. Success in these areas would have a substantial impact on the health and well-being of our citizens.


application_id: 8545180
project_number: 5R01GM092874-05
project_title: Regulation of EGFR Signaling by the Endocytic Pathway
administering_ic: NIGMS
award_notice_date: 2013-07-26
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 092874
program_official: AINSZTEIN, ALEXANDRA M
project_start_date: 2010-09-30
project_end_date: 2015-08-31
study_section: Molecular and Integrative Signal Transduction Study Section[MIST]
contact_pi_person_id: 1925445
contact_pi: CERESA, BRIAN P.
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of our laboratory is to understand how signal transduction by cell surface receptors is regulated. We would like to develop strategies for selectively activating or inhibiting these cellular activities and bypass limitations of the receptor (i.e. low receptor number or receptor desensitization). Extracellular ligands (growth factor hormone neurotransmitter etc.) bind to unique cell surface receptors that induce intracellular biochemical changes that are integrated to invoke specific changes in cell physiology. While the exquisite specificity of this system has been long appreciated the molecular mechanism by which it occurs is poorly understood. Understanding how an overlapping set of biochemical responses produces a specific physiology is the key to this problem. To understand this process we are using the prototypical receptor tyrosine kinase the epidermal growth factor receptor (EGFR) as a model. The EGFR is critical for many developmental and homeostatic processes; stimulation of the EGFR leads to a variety of cellular changes including cell proliferation differentiation migration and viability. Overexpression of the EGFR is associated with many cancers.  The magnitude and duration of signaling to these biochemical intermediates dictates how cell physiology is altered. One way this occurs is through the internalization and degradation of the receptor following ligand binding. In addition to activating intracellular signaling pathways ligand binding also causes most cells surface receptors to internalize via clathrin-coated pits. Once inside the cell the ligand:receptor complex moves through a series of well-defined endocytic stages until it ultimately reaches the lysosome where it undergoes degradation. It has been shown previously that disrupting EGFR endocytosis can alter the response of the cell. However these studies have been limited to distinguishing between cell surface and intracellular receptors. The overarching hypothesis of our research is that the endocytic pathway is a key positive and negative regulator of cell surface receptor signaling.  In Aim 1 we will selectively disrupt EGFR trafficking through the endocytic pathway. We will assess EGFR signaling at several endocytic stages and determine whether differences in signaling occur due to changes in the receptor itself receptor:effector interactions or the duration/magnitude of signaling. In Aim 2 we will build on our recent findings that spatially restricting the EGFR in cancer cells (MDA-MB-468 cells) dramatically changes cell growth and viability properties. We will determine how the intracellular EGFRs produce apoptotic signals and whether changing the trafficking and signaling of EGFRs in other cell lines can cause them to undergo EGFR-mediated apoptosis. Finally in Aim 3 we will explore how the endocytic pathway negatively regulates EGFR signaling. In these studies we will determine the mechanism of signal inactivation and determine if altering the rate of inactivation is sufficient to change EGFR signaling.    PUBLIC HEALTH RELEVANCE: The epidermal growth factor receptor (EGFR) is a fundamental cell surface protein that functions by detecting the presence of growth factors outside the cell and converting the information into biochemical changes within the cell. Proper function of the EGFR is necessary for development and homeostasis of the whole organism; overexpression/hyperactivation of the EGFR is associated with many cancers. The immediate goal of this research is to better understand the molecular mechanisms that regulate the biological and pathological functions of the EGFR and use that information for treatment of diseases associated with the EGFR.

project_terms:
Adenocarcinoma;Apoptosis;Apoptotic;Attenuated;Binding (Molecular Function);Biochemical;Biochemical Pathway;Biological;Biological Process;Bypass;Cell Death;Cell Line;Cell Proliferation;Cell Surface Proteins;Cell Surface Receptors;Cell Survival;Cell membrane;Cell physiology;Cell surface;Cells;Cellular biology;Chemosensitization;Clathrin;Communication;Complex;DNA biosynthesis;Development;Disease;Dynamin;EGF gene;EGFR Protein Overexpression;Early Endosome;Endocytosis;Epidermal Growth Factor Receptor;Epithelial;Goals;Growth;Growth Factor;Homeostasis;Hormones;Induction of Apoptosis;Kinetics;Laboratories;Ligand Binding;Ligands;Location;Lysosomes;MEKs;Malignant Neoplasms;Mammary gland;Mediating;Membrane;Modeling;Molecular;Molecular Target;Movement;Multivesicular Body;Neurotransmitters;Pathway interactions;Phosphorylation;Physiological;Physiology;Process;Property;Protein Biosynthesis;Protein Dephosphorylation;Proteins;Reagent;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Regulation;Research;Role;Series;Signal Pathway;Signal Transduction;Site;Small Interfering RNA;Specificity;Staging;System;Testing;Tyrosine Kinase Receptor Inhibition;Vesicle;Whole Organism;Wound Healing;attenuation;cancer cell;cell growth;cell type;coated pit;desensitization;extracellular;knock-down;late endosome;migration;overexpression;protein function;public health relevance;receptor;research study;response;tissue culture;tool;trafficking;tyrosine receptor

public_health_relevance:
Project NarrativeThe epidermal growth factor receptor (EGFR) is a fundamental cell surface protein that functions by detectingthe presence of growth factors outside the cell and converting the information into biochemical changes withinthe cell. Proper function of the EGFR is necessary for development and homeostasis of the whole organism;overexpression/hyperactivation of the EGFR is associated with many cancers. The immediate goal of thisresearch is to better understand the molecular mechanisms that regulate the biological and pathologicalfunctions of the EGFR and use that information for treatment of diseases associated with the EGFR.


application_id: 8544418
project_number: 5U54CA153604-04
project_title: Research Project
administering_ic: NCI
award_notice_date: 2013-08-28
opportunity_number: RFA-CA-09-032
application_type: 5
activity_code: U54
ic: CA
serial_number: 153604
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: 2013-09-01
budget_end_date: 2014-08-31
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;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: 8543942
project_number: 1P30GM106396-01
project_title: Animal Model Core
administering_ic: NIGMS
award_notice_date: 2013-06-21
opportunity_number: PAR-10-196
application_type: 1
activity_code: P30
ic: GM
serial_number: 106396
study_section: Special Emphasis Panel[ZGM1 TWD-C (C3)]
subproject_number: 8530
contact_pi_person_id: 1923745
contact_pi: CHESNEY, JASON A.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2013-07-01
budget_end_date: 2014-06-30
project_terms:
Animal Model;Animals;Antineoplastic Agents;Breast;Breeding;Centers of Research Excellence;Childhood;Clinic;Colon;Core Facility;Detection;Diagnosis;Diagnostic Imaging;Genotype;Goals;Instruction;Laboratories;Lung;Malignant Neoplasms;Methods;Modality;Modeling;Molecular Target;Monitor;Neuroblastoma;Pancreas;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Prostate;Research Personnel;Resources;Safety;Services;Site;Specimen Handling;Techniques;Testing;Therapeutic Agents;Time;Toxic effect;Transgenic Mice;Translations;Universities;Xenograft Model;cancer prevention;cancer type;cost;efficacy testing;efficacy trial;human disease;human subject;melanoma;mouse model;novel;novel strategies;novel therapeutics;pre-clinical;prevent;research study;response;safety testing;sample collection;success;tumor;tumor progression


application_id: 8543941
project_number: 1P30GM106396-01
project_title: Molecular Modelling Core
administering_ic: NIGMS
award_notice_date: 2013-06-21
opportunity_number: PAR-10-196
application_type: 1
activity_code: P30
ic: GM
serial_number: 106396
study_section: Special Emphasis Panel[ZGM1 TWD-C (C3)]
subproject_number: 8529
contact_pi_person_id: 7821204
contact_pi: TRENT, JOHN O
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: 2013-07-01
budget_end_date: 2014-06-30
project_abstract:
PROJECT SUMMARY (See instructions):  One of the overriding goals of the Brown Cancer Center is translational research. One way to achieve this is to provide a conduit for investigators studying particular molecular targets to conduct structure-based drug design. The Molecular Modeling Core Facility is an integral part of the COBRE which is used by all the COBRE investigators and many NIH funded investigators. It provides a natural entryway for structural biological approaches developed by COBRE scientists and through its close interaction with the NMR Center biophysicists molecular biologists chemists medicinal chemists computer scientists and biochemists. The overall goal of the Facility is rationalization prediction and design i.e. the rationalization of experimental data the prediction of new empirical experiments and the structure-based drug design of new agents. The aims of the Core are to: 1. provide equipment and expertise for a variety of modeling applications 2. facilitate structure-based drug design for drug discovery and drug development including facilitating testing of targeted compounds. 3. provide a bridge between crystallography NMR medicinal chemistry and other disciplines 4. provide a collaborative environment for the BCC 5. inform the Structural Biology Program of advances in the field and to implement them 6. educate the Structural Biology Program and others on possible enhancements to their research 7. train students on

project_terms:
Biological;Cancer Center;Centers of Research Excellence;Chemicals;Computers;Core Facility;Crystallography;Data;Discipline;Drug Design;Environment;Equipment;Funding;Goals;Instruction;Modeling;Molecular;Molecular Models;Molecular Target;New Agents;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phase;Rationalization;Research;Research Personnel;Route;Scientist;Structure;Students;System;Testing;Training;Translational Research;United States National Institutes of Health;base;design;drug development;drug discovery;molecular modeling;programs;research study;structural biology


application_id: 8543939
project_number: 1P30GM106396-01
project_title: Microarray Core
administering_ic: NIGMS
award_notice_date: 2013-06-21
opportunity_number: PAR-10-196
application_type: 1
activity_code: P30
ic: GM
serial_number: 106396
study_section: Special Emphasis Panel[ZGM1 TWD-C (C3)]
subproject_number: 8527
contact_pi_person_id: 1969307
contact_pi: ZACHARIAS, WOLFGANG
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: 2013-07-01
budget_end_date: 2014-06-30
project_terms:
Adopted;Animal Model;Applications Grants;Basic Science;Bioinformatics;Biological;Biometry;Cancer Center;Cells;Clinical;Clinical Research;Computer software;DNA;Data Analyses;Data Collection;Development;Disease;Educational workshop;Ensure;Experimental Designs;Gene Expression;Gene Expression Profile;Genes;Genetic Transcription;Genomics;Genotype;Goals;Human;Human Resources;Hybridization Array;In Vitro;Individual;Instruction;Internet;Investments;Knowledge;Logistics;Malignant Neoplasms;Manuscripts;Microarray Analysis;Molecular;Molecular Target;Mus;Mutation;Nursing Faculty;Pathologic;Phase;Polymorphism Analysis;Population;Preparation;Procedures;Process;Proteins;Protocols documentation;Provider;RNA;RNA amplification;Research;Research Personnel;Research Training;Resources;Sample Size;Sampling;Services;Single Nucleotide Polymorphism;Specimen;Technology;Time;Tissues;Training;Universities;base;comparative;density;instrument;novel;novel diagnostics;research study;tool


application_id: 8542486
project_number: 5F31AA020767-02
project_title: Sexual Assault Personality and Problem Drinking in College Women
administering_ic: NIAAA
award_notice_date: 2013-08-13
opportunity_number: PA-11-111
application_type: 5
activity_code: F31
ic: AA
serial_number: 020767
program_official: FREEMAN, ROBERT
project_start_date: 2012-09-09
project_end_date: 2014-07-25
study_section: Epidemiology, Prevention and Behavior Research Study Section[AA-2]
contact_pi_person_id: 10747927
contact_pi: ROHR, JESSICA COMBS
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): I propose to address the significant impact that sexual assault has on the mental health of college-aged women integrating personality factors and trauma to predict maladaptive behavioral consequences. One important and unexplained phenomenon is that some women respond to the trauma of sexual assault with symptoms of externalizing disorders most notably heavy alcohol consumption but others respond to the trauma with increases in internalizing dysfunction such as major depression and generalized anxiety disorder (Kilpatrick et al. 2003; Ullman & Nadjowski 2009a). It is crucial to identify which women are likely to respond to the trauma in which way given that (a) heavy alcohol consumption is associated with many problems including increased risk of re-victimization (Ullman & Nadjowski 2009b); and (b) there are different empiricallysupported treatments for the two different kinds of dysfunction (Hayes et al. 1999; Linehan 1993; Zapolski et al. 2010). The intent of the proposed research is to test this theoretical model: Women with elevations in personality traits that dispose them to engage in rash action when distressed (i.e. the trait of negative urgency) are more likely than other traumatized women to respond to the trauma with increases in rash actions such as heavy drinking. In contrast women with elevations in personality traits that dispose them to internalizing dysfunction are more likely than other traumatized women to respond to the trauma with increased symptoms of depression and anxiety but they are less likely to engage in increased heavy drinking. To date there are no longitudinal studies that measure personality functioning prior to sexual assault victimization andinvestigate personality-based prediction of different forms of post-trauma distress. The proposed study fills this important gap in the literature. I will assess the personality functioning drinkig behavior and sexual trauma histories of 1000 women prior to their first year of college and then again at the end of their first semester and then at the end of their first year in school. Pror research at my university suggests that approximately 17% of these women will experience sexual assault during their first year in college (Wilcox et al. 2007). Using a three-wave   longitudinal design I will conduct several regression equations using difference scores as dependent variable. In the first the interaction of negative urgency with sexual assault will predict increased problem drinking across the first year of college and that effect will be above and beyond the effect of initial problem drinking and initial trait depression. In the second the interaction of personality traits that dispose individuals to internalizing dysfunction with victimization will predict increased depression and anxiety across the first year above and beyond initial depression and anxiety and initial negative urgency. I will also test whether sexual assault is associated with increases in traits within the Neuroticism domain across the first year of college. A successful model test will guide clinical researchers to apply different interventions to different assault victims based on their personality characteristics.

project_terms:
Address;Admission activity;Alcohol abuse;Alcohol consumption;Alcohols;Anxiety;Behavior;Behavioral;Binge Eating;Characteristics;Clinical;Development;Disease;Distress;Drug usage;Eating Behavior;Equation;Exanthema;Female;Functional disorder;Generalized Anxiety Disorder;Heavy Drinking;Individual;Intervention;Kentucky;Lead;Literature;Longitudinal Studies;Major Depressive Disorder;Measures;Mental Depression;Mental Health;Modeling;Moods;Neurotic Disorders;Outcome;Pathology;Pathway interactions;Personality;Personality Traits;Play;Process;Recording of previous events;Reporting;Research;Research Personnel;Research Proposals;Risk;Role;Schools;Specific qualifier value;Students;Symptoms;Testing;Theoretical model;Time;Trauma;Universities;Victimization;Woman;aged;assault;base;college;depressive symptoms;drinking;drinking behavior;effective intervention;experience;falls;high risk sexual behavior;longitudinal design;response;service intervention;sexual assault;sexual trauma;theories;trait

public_health_relevance:
For some women the experience of being sexually assaulted leads to increases in problem drinking behavior which is associated with many problems including increased risk for re-victimization. At present researchers are unable to predict which women will respond to the trauma in that way; as a result clinicians lack the capacity to identify which sexual assault victims would benefit most from alcohol-related interventions. The proposed research will test a model specifying premorbid personality characteristics that are proposed to interact with victimization to lead to problem drinking; a successful model test will enable clinicians to identify those women most likely to respond to their trauma with problem drinking behavior and thus permit the timely implementation of appropriate intervention services.


application_id: 8541664
project_number: 7R01EY012716-13
project_title: Functional state of developing retinogeniculate synapse
administering_ic: NEI
award_notice_date: 2012-09-21
opportunity_number: PA-07-070
application_type: 7
activity_code: R01
ic: EY
serial_number: 012716
program_official: STEINMETZ, MICHAEL A
project_start_date: 2001-05-01
project_end_date: 2012-11-30
study_section: Central Visual Processing Study Section[CVP]
contact_pi_person_id: 1864719
contact_pi: GUIDO, WILLIAM
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Description (provided by applicant): We have developed a mouse model of visual system development which characterizes the structural and functional changes occurring between retinal ganglion cell axons and their postsynaptic targets in the lateral geniculate nucleus (LGN) of thalamus. While many of the changes in retinogeniculate axon patterning and connectivity have been described a number of issues remain unresolved. For example we know little about the neural elements and intracellular signaling cascades that govern why certain retinal inputs are preserved and strengthened while others are weakened and eventually eliminated. While many of the inductive changes in connectivity rely on a spontaneous retinal activity and a Hebbian form of synaptic plasticity the role of visually evoked activity and the synaptic plasticity associated with the maintenance of newly remodeled connections has not been fully explored. Detailed morphological information about the growth and maturation of retinogeniculate synapses and the dendrites of LGN relay cells is also needed to fully appreciate how the remodeling of retinal connections occurs. The major goals of this renewal are: to use electrophysiological anatomical and biochemical techniques to detail the nature of L-type Ca2+ channel activity an event that appears essential for mediating activity dependent plasticity in LGN; to establish a link between L-type activity and the remodeling of retinogeniculate connections; to explore how alterations in visually evoked activity affect the maintenance of newly remodeled retinogeniculate connections; and to examine the dendritic morphology of developing LGN cells and determine how their structure-function relations are coordinated with the remodeling of retinal axons. Studies are done in wild-type pigmented mice as well as those in which L-type Ca2+ channel expression and activity has been severely attenuated by the targeted deletion of the 23 subunit. The developing retinogeniculate pathway in the mouse has emerged as a powerful model system to study the mechanisms underlying the remodeling of synaptic connections. Therefore these studies will provide valuable information about how the developing brain forms precise patterns of connections and offer further insight into the study and treatment of developmental and neurological disorders that result from the formation of abnormal patterns of connectivity. PUBLIC HEALTH RELEVANCE: These studies will provide valuable information about how the developing brain forms precise patterns of connections and offer further insight into the study and treatment of developmental and neurological disorders that result from the formation of abnormal patterns of connectivity.

project_terms:
3-Dimensional;Affect;Age;Attenuated;Axon;Biochemical;Biological Models;Brain;CREB1 gene;Cell Maturation;Cells;Cholera Toxin;Dendrites;Development;Dorsal;Elements;Event;Eye;Fiber;Figs - dietary;Goals;Growth;Health;In Vitro;Label;Lateral Geniculate Body;Lead;Length;Life;Link;Location;Maintenance;Mediating;Molecular;Morphology;Mus;Nature;Neurons;Pathway interactions;Pattern;Phase;Pigments;Play;Preparation;Prevalence;Process;Property;Retinal;Retinal Ganglion Cells;Role;Signal Transduction;Slice;Staging;Structure;Surgical sutures;Synapses;Synaptic plasticity;Techniques;Testing;Thalamic structure;Tissues;Tracer;Transgenic Mice;Visual;Western Blotting;attenuation;biocytin;developmental disease/disorder;developmental plasticity;experience;insight;membrane assembly;monocular;monocular deprivation;mouse model;nervous system disorder;postnatal;postsynaptic;reconstruction;relating to nervous system;research study;retinal axon;retinal stimulation;retinogeniculate;segregation;transcription factor;vision development

public_health_relevance:
These studies will provide valuable information about how the developing brain formsprecise patterns of connections and offer further insight into the study and treatment ofdevelopmental and neurological disorders that result from the formation of abnormalpatterns of connectivity.


application_id: 8540405
project_number: 5R01DA032254-02
project_title: A Novel Anti Obesity Drug Combination as a Pharmacotherapy for Cocaine Dependence
administering_ic: NIDA
award_notice_date: 2013-12-06
opportunity_number: PA-10-268
application_type: 5
activity_code: R01
ic: DA
serial_number: 032254
program_official: HAMPSON, AIDAN
project_start_date: 2012-09-15
project_end_date: 2015-12-31
study_section: Special Emphasis Panel[ZRG1-RPIA-N(09)F]
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): Cocaine (COC) dependence is a significant public health concern. A widely effective pharmacotherapy has not yet been identified for COC dependence. Innovative strategies are needed to identify an effective pharmacotherapy for COC dependence. Testing medications effective for disorders that share neurobiological substrates with drug dependence for example could yield treatments for managing COC dependence.  Obesity is also a significant public health concern. Although obesity and COC dependence are typically considered distinct clinical entities both diseases involve perturbations of central biogenic amine and/or hypothalamic-melanocortin systems. The obesity epidemic has spurred development of medications to promote weight loss. A combination of bupropion (BUP) and naltrexone (NTX) is effective for obesity. The overarching goal of this application is to demonstrate the initial efficacy safety and tolerability of BUP-NTX combinations for COC dependence. A mixed-model experiment will be conducted in which separate cohorts of non-treatment-seeking COC-dependent participants will be randomized to different maintenance doses of BUP (i.e. BUP is a between-subject factor). Participants (N=12) in each BUP cohort will be maintained concurrently on NTX (i.e. NTX is a within-subject factor). The reinforcing effects of intranasal COC will be determined after participants in each BUP cohort are maintained for 4-7 days on each of the NTX doses (i.e. COC is a within-subject factor). COC (0 25 50 100 mg) will be tested with multiple dose combinations of BUP (0 100 200 300 mg/day) and NTX (0 25 50 mg/day). The proposed study will also identify the optimal dose combination of BUP and NTX that most effectively attenuates the reinforcing effects of COC.  This research will provide critical information regarding the initial efficacy and optimal doses ofa novel drug combination BUP and NTX for COC dependence which will enhance the probability of success when advanced to a clinical trial. Innovations of the proposed research include: 1) testing a combination of marketed drugs that demonstrated modest efficacy when tested as mono-therapies; 2) the use of a sophisticated drug self-administration procedure; 3) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of BUP-NTX combinations for COC dependence; and 4) demonstrating the initial efficacy and optimal doses of a combination 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 COC dependence.

project_terms:
Abstinence;Accounting;Admission activity;Adult;Adverse effects;Age Reporting;American;Anti-Obesity Agents;Attenuated;Behavior Therapy;Behavioral;Biogenic Amines;Body Weight;Body Weight decreased;Bupropion;Clinical;Clinical Research;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Combination Drug Therapy;Development;Disease;Dopamine Uptake Inhibitors;Dose;Drug Addiction;Drug Combinations;Enrollment;Epidemic;Evaluation;Food;Goals;Human;Hypothalamic structure;Inpatients;Investigation;Laboratory Study;Maintenance;Modeling;Mono-S;Naltrexone;Narcotic Antagonists;Neurobiology;Obesity;Outcome Measure;Participant;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase II Clinical Trials;Physiological;Preventive Intervention;Probability;Procedures;Questionnaires;Randomized;Relative (related person);Research;Safety;Self Administration;System;Testing;United States;clinical practice;cocaine use;cohort;double-blind placebo controlled trial;drug market;indexing;innovation;interest;novel;programs;public health medicine (field);public health relevance;reinforcer;research study;secondary outcome;success

public_health_relevance:
The research proposed in this application will determine the initial efficacy safety and tolerability of a novel drug combination bupropion and naltrexone as
a pharmacotherapy for cocaine dependence. A rigorous inpatient human laboratory study will be conducted. The proposed study is innovative and important because it will provide the impetus for the conduct of double blind placebo-controlled trials to further demonstrate the efficacy of bupropion-naltrexone combinations for managing cocaine dependence.


application_id: 8539863
project_number: 1R56DK093847-01A1
project_title: Regulation of Hepatic Carbohydrate Metabolism by STBD1
administering_ic: NIDDK
award_notice_date: 2012-09-21
opportunity_number: PA-11-260
application_type: 1
activity_code: R56
ic: DK
serial_number: 093847
suffix: A1
program_official: PAWLYK, AARON C
project_start_date: 2012-09-21
project_end_date: 2014-08-31
study_section: Cellular Aspects of Diabetes and Obesity Study Section[CADO]
contact_pi_person_id: 10671183
contact_pi: CHENG, ALAN
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:
Project Summary/AbstractThe incidence of type 2 diabetes mellitus is reaching epidemic proportions becoming one of the majorcauses of morbidity and mortality across the globe. Despite periods of feeding and fasting plasma glucosein normal individuals remains in a narow range. Several studies have demonstrated that defects in thestimulation of non-oxidative glucose metabolism by insulin may be among the primary lesions in insulinresistance. In skeletal and cardiac muscle insulin stimulates glycogen accumulation through a coordinateincrease in glucose transport and regulation of glycogen metabolizing enzymes while in liver insulin blocksglucose output by inhibiting gluconeogenesis promoting glycogenesis and blocking glycogenolysis. Wehave made the important discovery of a novel signaling pathway involving ubquitination in the regulation ofglycogen metabolism. Our studies demonstrate that during glycogenolysis several enzymes involved in itsmetabolism translocate to the nucleus and interact with the E3 ubiquitin ligase Malin for subsequentproteasomal degradation. Additional studies indicate that the dual specificity phosphatase Laforin acts as amolecular scaffold for this process. A fundamental unanswered question is: how hormones such as insulinand glucagon regulate the cellular function of these proteins and how these novel pathways aredysregulated in metabolic diseases such as diabetes and obesity. This proposal will address thesequestions by examining the hypothesis that hormones such as insulin and glucagon regulate the formationof protein complexes involved in the degradation of glycogen-associated proteins. We have identifiedSTBD1 as a novel Laforin interacting protein (STBD1) that enhances glycogen synthesis and interacts withseveral other glycogen associated proteins. Our model suggests that STBD1 is critical for the assembly ofcomplexes targeted for Malin mediated degradation. We will test our model and reveal the mechanismsbehind these events by using a combination of biochemical cellular and transgenic techniques to addressthree specific aims: (1) to assess how liver specific STBD1 expression in mice affects whole body glucosehomeostasis in normal and diabetogenic states; (2) to investigate the role of STBD1 in regulating theproteasomal degradation of glycogen associated proteins by Malin; and (3) to determine the hormonal andcellular signals that regulate STBD1 function. Accomplishing these aims will provide new insight into howhormones control glycogen metabolism and how this process is dysregulated in metabolic disorders suchas diabetes and obesity. Importantly this can ultimately identify novel therapeutic avenues in thesediseases.'

project_terms:
Address;Affect;Binding (Molecular Function);Biochemical;Biological Assay;Blood Glucose;Cell Nucleus;Cell physiology;Complex;Data;Defect;Deposition;Diabetes Mellitus;Disease;Enzymes;Epidemic;Event;Fasting;Glucagon;Gluconeogenesis;Glucose;Glycogen;Glycogen Debranching Enzyme;Goals;Health;Hepatic;Hepatocyte;Hormonal;Hormones;Incidence;Individual;Insulin;Insulin Resistance;Intervention;Lafora Disease;Lead;Liver;Liver Glycogen;Mediating;Metabolic;Metabolic Diseases;Metabolism;Modeling;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Mus;Muscle;Mutation;Myocardium;Names;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Nutritional;Nutritional status;Obesity;Pathway interactions;Phosphoric Monoester Hydrolases;Physiological;Plasma;Primary Lesion;Principal Investigator;Process;Proteins;Regulation;Role;Signal Pathway;Signal Transduction;Skeletal muscle structure;Specificity;Starch;Techniques;Testing;Tissues;Transgenic Organisms;Ubiquitination;abstracting;base;blood glucose regulation;carbohydrate metabolism;fasting plasma glucose;feeding;glucose metabolism;glucose output;glucose transport;glycogen metabolism;glycogenesis;glycogenolysis;hormone regulation;insight;mutant;novel;novel therapeutics;overexpression;prevent;programs;protein complex;public health relevance;response;scaffold;small hairpin RNA;ubiquitin-protein ligase

public_health_relevance:
Public Health Relevance SectionThe regulation of glycogen metabolism by insulin and other hormones represents a keymeans to control the level of blood sugar in tissues such as muscle and liver. Thisproposal will investigate how newly identified enzymes and cellular pathways affect thisprocess. Results of this study could lead to novel therapies for type 2 diabetes that aredirected towards blocking glycogen breakdown while simultaneously enhancing itssynthesis.


application_id: 8539459
project_number: 5U18FD004619-02
project_title: CVM Vet-LRN Veterinary Diagnostic Laboratory Program
administering_ic: FDA
award_notice_date: 2013-08-15
opportunity_number: PA-12-194
application_type: 5
activity_code: U18
ic: FD
serial_number: 004619
project_start_date: 2012-09-01
project_end_date: 2017-08-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 11461164
contact_pi: NORTHINGTON, WADE A
other_pis: Not Applicable
congressional_district: 01
department: VETERINARY SCIENCES
primary_duns: 041980632
primary_uei: LHC2S92MXG63
duns_number: 041980632
uei: LHC2S92MXG63
fips: US
organization_id: 5591701
organization_name: MURRAY STATE UNIVERSITY
organization_city: MURRAY
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 420712393
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2013-09-01
public_health_relevance:
Project Narrative Agriculture is Kentucky's number one industry contributing $5 billion to the state's economy annually.  Livestock and livestock product sales generate 65% of the total agricultural revenues.  The Murray State University Breathitt Veterinary Center (BVC) is an animal disease diagnostic laboratory dedicated to protecting the invaluable assets of the region by providing the fastest most accurate and most dependable animal disease diagnostic services possible.  The BVC with a staff of 45 employees is housed in a 44000 sq. ft. facility located on 15 acres of land in Hopkinsville KY.  The facility is centrally located to serve a 200 mile radius including Western Kentucky Southern Indiana and Illinois and Northwestern Tennessee.  The BVC professional staff includes nine members with Doctorates in Veterinary Medicine and/or Masters and PhD degrees in the fields of Pathology Microbiology Virology Immunology and Toxicology.  The professional staff is supported by laboratory bench personnel each of who hold a minimum of a Bachelor's degree and several have Masters degrees.  The laboratory provides full administrative secretarial/clerical and maintenance staff in support of diagnostic and research activities.  The BVC is accredited for all species by the American Association of Veterinary Laboratory Diagnosticians (AAVLD) through December 2014.  The BVC is a member of the USDA National Animal Health Laboratory Network (NAHLN) the Centers for Disease Control Laboratory Response Network (LRN) and the FDA Vet-Laboratory Response Network (Vet-LRN) (See attached FDA Vet-LRN Acceptance Letter).  The center's scope of activity includes the scientific disciplines of Pathology Microbiology Molecular Diagnostics Clinical Pathology Toxicology Serology and Virology.  The BVC processes 24000+ diagnostic cases per year to include over 190000 tests.   The FDA CVM Vet-LRN desires to expand the national laboratory capacity to provide increased sample analyses in the event of animal food or drug related illnesses or other large-scale animal food/feed emergency events requiring surge capacity testing of implicated diagnostic or animal food samples.   Objective:  The objective of this grant application is to provide a cooperative agreement between the FDA CVM Vet-LRN and the BVC whereby the BVC will participate in the Vet-LRN Veterinary Diagnostic Laboratory Program.  The FDA CVM Vet-LRN grant program is a mutually beneficial opportunity in which the FDA CVM Vet-LRN adds to the national laboratory capacity and the BVC receives support to advance its scope of activity.  Funding provided through the cooperative agreement will be used to provide equipment supplies training and proficiency testing under the aegis of the Vet-LRN Veterinary Diagnostic Program on an annualized basis for a five year period.


application_id: 8539265
project_number: 5U01CE001675-05
project_title: Green Dot across the Bluegrass: Evaluation of a primary prevention intervention t
administering_ic: NCIPC
award_notice_date: 2013-08-14
opportunity_number: RFA-CE-09-003
application_type: 5
activity_code: U01
ic: CE
serial_number: 001675
project_start_date: 2009-09-01
project_end_date: 2015-08-31
study_section: ZCE1-JXS(09)
contact_pi_person_id: 1894149
contact_pi: COKER, ANN 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: 2013-09-01
project_abstract:
DESCRIPTION (provided by applicant):     Problem Statement: While rates of lifetime forced sexual intercourse have increased in Kentucky over the past five years among high school students Kentucky is working to reduce this trend. Through CDC assistance Kentucky Association of Sexual Assault Programs Inc. (KASAP) is ready to implement the "Green Dot" bystander intervention program for primary prevention of sexual violence (SV). Importance: We now have the unique and time-sensitive opportunity to evaluate a statewide bystander intervention which will be implemented by KASAP Educators across Kentucky through high schools beginning in 2010. Green Dot empowers students to actively question peer support for SV and become change agents who can play a significant role in ending SV. Innovation: While several bystander intervention programs have been implemented few been empirically evaluated and none have been evaluated on a statewide basis using the same intervention protocol. Purpose: To evaluate the statewide application of Green Dot among high schools students. We hypothesize that students in high schools with Green Dot will over time report lower rates of SV compared with students in comparable high schools randomized not to have Green Dot. This reduction in SV will be mediated through a reduction in social norms supporting SV and an increase in bystander behaviors. Specific Aims: To prospectively determine whether relative to students in high schools without Green Dot those in schools with Green Dot (Aim 1) report lower rates of SV (Aim 2) a greater frequency of bystander behaviors and (Aim 3) fewer social norms supporting SV. Finally because Green Dots draws on social diffusion of innovation theory we propose (Aim 4) to determine how Green Dot influences bystander behaviors in the first and second order social networks of students who do and do not receive Green Dot training. Methods: A population-based controlled intervention trial will be used to test the efficacy of Green Dot. Both panel and web-based cohort survey methods will be used to provide baseline and prospective data on student's attitudes supporting SV bystander behaviors and SV experiences. Setting: In each of the 13 KASAP regions 2 demographically comparable high schools with at least 200 students per grade will be recruited to participate in Green Dot either as the intervention or control site. Schools will be randomly assigned to the intervention. Study Population: All students in participating high schools will be invited to complete anonymous panel surveys beginning spring 2010 through 2014; we anticipate that 6500 students in Green Dot and 6500 in control schools will complete surveys each year. We estimate that 650 students receiving Green Dot training and 650 students not so trained will complete the web-surveys (2011-2014). External sources of data to document SV will be obtained from high schools. Implications for Prevention: This state-wide population-based multi-site controlled intervention trial will provide an empirical test of a promising intervention which if proven effective could result in the primary prevention of SV and a reduction in the health and academic consequences of SV.

public_health_relevance:
Determining whether a promising primary prevention intervention to reduce sexual violenceperpetration is effective in reducing violence in a real world setting (high schools acrossKentucky) can result in an important opportunity to prevent the short and longer term healthconsequences of sexual violence. Sexual violence defined to include physically forced sexualactivity coerced sexual activity and sexual harassment is common (~25%) has health andacademic consequences and is preventable; thus this form of violence can be a high impacttarget for primary prevention efforts.


application_id: 8538937
project_number: 5R42DE018839-03
project_title: Delivery of Polyphenols in Gum for Treatment of Gingivitis
administering_ic: NIDCR
award_notice_date: 2013-09-10
opportunity_number: PA-09-114
application_type: 5
activity_code: R42
ic: DE
serial_number: 018839
program_official: GANNOT, GALLYA
project_start_date: 2009-07-23
project_end_date: 2015-08-31
study_section: Special Emphasis Panel[ZRG1-MOSS-K(11)B]
contact_pi_person_id: 1883677
contact_pi: MILLER, CRAIG S
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 793506218
duns_number: 793506218
fips: US
organization_id: 10013455
organization_name: FOUR TIGERS, LLC
organization_city: PARIS
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403612425
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2013-09-01
budget_end_date: 2015-08-31
project_abstract:
DESCRIPTION (provided by applicant):  Periodontitis represents a polymicrobial disease in which a complex microbial ecology that matures in biofilms in the subgingival sulcus triggers a chronic immune-inflammatory lesion that destroys soft and hard tissues of the periodontium. Despite the great improvement in oral health in recent years gingivitis and periodontal disease remain prominent and affect about half of all adults above the age of 30 years in the U.S. with an even higher prevalence in the underserved and developing and undeveloped countries. The ability to identify therapeutics to enable more effective control and/or prevention of gingival inflammation is a critical facet of current commercial strategies to improve oral health of the population. To address the unmet need for safe cost-effective anti-gingivitis product/technology that promotes high patient compliance and could be incorporated into daily use we have developed a novel direct compression chewing gum formulation that contains freeze-dried blackberry powder (FBP) which is anti-inflammatory antibacterial and antiviral. Our preliminary findings suggested this gum product is commercially viable and potentially effective for the prevention and/or treatment of gingivitis. The goal of this Phase II STTR proposal is to manufacture the chewing gum containing FBP that delivers bioactive phytochemicals to the oral cavity and test its efficacy in preventing biofilm formation and gingivitis in humans. Studies willdetermine the final gum product specifications and manufacturing method. A cGMP batch will be manufactured and Quality Control testing and Quality Assurance release will be performed. Submission and approval of an Investigational New Drug Application (IND) for an initial clinical study will be pursued based on guidance from our pre-IND meeting with FDA. In a randomized double-blind single center clinical efficacy study we will assess the chewing gum's ability to reduce i) levels of several plaque-forming bacteria species on enamel and in saliva using the retrievable enamel chip model and ii) clinical gingival inflammation oral microbial burden and saliva biomarkers of inflammation in humans. These studies if successful will lead to a subsequent IND submission to complete multi-center trials and eventual NDA submission of the product for registration as a "Botanical Drug Product" as addressed under the FDA Guidance Document of the same title. Four Tigers LLC has partnered with WindStone Farms the largest blackberry farm in the eastern part of the United States to develop and commercialize health and medical products derived from blackberries. The investigators have assembled a highly interdisciplinary team encompassing collaborations between the agriculture industry oral biologists small business and Tom's of Maine a large healthcare company that focuses on all-natural products that together will lead to the manufacture and commercial availability of an innovative blackberry chewing gum that releases and delivers natural bioactive substances from freeze-dried fruit powder that will help prevent/treat gingivitis.

project_terms:
Address;Adult;Affect;Age;Agriculture;Anthocyanins;Anti-Bacterial Agents;Anti-Infective Agents;Anti-Inflammatory Agents;Anti-inflammatory;Antiviral Agents;Bacteria;Berry;Biological Assay;Biological Factors;Biological Markers;Botanicals;Businesses;Cardiovascular system;Characteristics;Chewing Gum;Chronic;Clinical;Clinical Research;Clinical Trials;Collaborations;Complex;Compliance behavior;Country;Data;Dental Care;Dental Enamel;Dental Hygiene;Dental Plaque;Development;Diabetes Mellitus;Disease;Double-Blind Method;Drug Delivery Systems;Drug Formulations;Ecology;Event;Exhibits;Farming environment;Freeze Drying;Fruit;Fusobacterium nucleatum;Genetic;Gingiva;Gingivitis;Goals;Health;Healthcare;High Prevalence;Human;Immune;Immune response;Immunology;In Vitro;Incidence;Industry;Infection;Inflammation;Inflammation Mediators;Inflammatory;Investigational New Drug Application;Lead;Lesion;Low Birth Weight Infant;Maine;Mastication;Measures;Medical;Methods;Microbial Biofilms;Military Personnel;Modeling;Mouth Diseases;Oral;Oral Medicine;Oral cavity;Oral health;Pattern;Periodontal Diseases;Periodontic specialty;Periodontitis;Periodontium;Pharmaceutical Preparations;Pharmacy (field);Phase;Phytochemical;Population;Porphyromonas gingivalis;Powder dose form;Predisposition;Prevention;Property;Protocols documentation;Quality Control;Randomized;Reactive Oxygen Species;Reporting;Research;Research Personnel;Resources;Risk;Risk Marker;Saliva;Severities;Simulate;Small Business Technology Transfer Research;Streptococcus mutans;Systemic disease;Technology;Testing;Therapeutic;Tigers;Tissues;Tooth Loss;Translational Research;Underserved Population;United States;antimicrobial;bactericide;base;clinical efficacy;commercialization;cost;cost effective;improved;innovation;meetings;microbial;novel;polyphenol;prevent;quality assurance

public_health_relevance:
This project presents the unique collaboration between the agriculture industry oral biologists small business and a large healthcare company that will lead to the manufacture and commercial availability of an innovative blackberry chewing gum that releases and delivers natural bioactive substances from freeze-dried fruit powder that will help prevent/treat gingivitis. Use of this novel adjunctive oral hygiene aid could greatly reduce the cost of dental care by preventing oral disease before it occurs and can be used by those who lack access to conventional oral hygiene measures.


application_id: 8538334
project_number: 5R03CA171604-02
project_title: Apple peel extract inhibits Cr(VI)-induced lung cancer
administering_ic: NCI
award_notice_date: 2013-08-15
opportunity_number: PAR-11-079
application_type: 5
activity_code: R03
ic: CA
serial_number: 171604
program_official: SEIFRIED, HAROLD E
project_start_date: 2012-09-01
project_end_date: 2014-08-31
study_section: ZCA1-SRLB-2(M1)
contact_pi_person_id: 10011919
contact_pi: ZHANG, ZHUO
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):  Cr(VI)-containing compounds are well established environmental carcinogens. Although the mechanisms of Cr(VI) carcinogenesis remain to be investigated various studies indicate that Cr(VI)-induced generation of reactive oxygen species (ROS) plays a key role. Many naturally occurring substances present in the human diet have been identified as potential chemopreventive agents. Investigations using animal models and epidemiological studies indicate that consumption of phytochemicals might reduce the incidence of cancers and other chronic diseases. These plant-derived phytochemicals are rich sources of naturally occurring antioxidants. Our preliminary studies have shown that oral administration of apple peel extract decreased the number of nonmalignant and malignant skin tumors induced by 12-O-tetradecanolyphorbol-13-acetate (TPA) in 7 12-dimethyl Benz (a) anthracene-initiated mouse skin. Apple peel extract is able to directly scavenge hydroxyl radial (OH) and superoxide radical (O2-). Our preliminary studies have also shown that apple peel extract inhibited Cr(VI)-induced "OH radical generation in cellular system. The mechanisms involve direct scavenging of OH radical and chelation of Cr(V) by apple peel extract to make this chromium intermediate less reactive toward hydrogen peroxide(H2O2) for OH radical generation. Our preliminary data have shown that apple peel extract inhibited Cr(VI)-induced expressions of inflammatory proteins including NF-?B and TNF-. We hypothesize that apple peel extract may function as an antioxidant and as a chemopreventive agent against Cr(VI)-induced lung cancer via inhibition of Cr(VI)-induced oxidative stress. Aim 1 will use in vivo electron spin resonance (ESR) to investigate inhibition of Cr(VI)-generated free radicals by apple peel extract in living animals (BALB/c mice). Two approaches will be used: (a) to investigate the chelation of Cr(V)-NADPH complex or change of its structure by apple peel extract; and (b) to investigate the inhibition of apple peel extract on Cr(VI)-induced free radical generation. Aim 2 will investigate the protectionof apple peel extract against Cr(VI)-induced lung inflammation chronic oxidative lung tissue injury and cell proliferation using BALB/c mice. There are increasing studies supporting the association among oxidative stress chronic inflammation and cancer development. Because oxidative stress plays an important role in inflammation cell proliferation and tissue injury itis likely that inhibition of oxidative stress will protect Cr(VI)-induced chronic lung injury and an inflammatory microenvironment leading to the protection in Cr(VI)-induced lung cancer. In this aim we will Investigate the protection of apple peel extract against Cr(VI)-induced inflammation chronic oxidative lung injury and cell proliferation using female BALB/c mice.

project_terms:
Acetates;Animal Model;Animals;Antioxidants;Apple;Benz(a)Anthracenes;California;Carcinogens;Cell Proliferation;Chemopreventive Agent;Chromium;Chronic;Chronic Disease;Complex;Consumption;Data;Development;Diet;Electron Spin Resonance Spectroscopy;Environmental Carcinogens;Epidemiologic Studies;Equilibrium;Exposure to;Female;Free Radicals;Frequencies (time pattern);Fruit;Generations;Glutathione Reductase;Goals;Human;Hydrogen Peroxide;Hydroxyl Radical;Inbred BALB C Mice;Incidence;Inflammation;Inflammatory;Inhalation Exposure;Injury;International Agency for Research on Cancer;Investigation;Life;Lung Inflammation;Malignant Neoplasms;Malignant neoplasm of lung;Measurement;Molecular;Mus;NADP;NADPH Oxidase;Non-Malignant;Nose;Occupational;Occupational Groups;Oral;Oral Administration;Oxidative Stress;Oxygen;Phytochemical;Plants;Play;Podophyllum peltatum;Process;Protective Agents;Proteins;Radial;Reaction;Reactive Oxygen Species;Reducing Agents;Role;Skin;Skin Cancer;Source;Structure;Structure of parenchyma of lung;Superoxides;System;TNF gene;Tissues;Water;benzanthracene;carcinogenesis;carcinogenicity;chelation;in vivo;instrument;lung injury;tumorigenesis

public_health_relevance:
The Cr(VI)-containing compounds are well established environmental carcinogens. Oxidative stress is considered to play an important role in the mechanism of Cr(VI)-induced carcinogenesis. The goal of this proposal is to develop apple peel extract as an antioxidant and a protective agent against Cr(VI)-induced oxidative stress and lung cancer.


application_id: 8537865
project_number: 5R25CA153954-04
project_title: The University of Kentucky Cancer Nanotechnology Training Center (UK CNTC)
administering_ic: NCI
award_notice_date: 2013-07-29
opportunity_number: RFA-CA-09-014
application_type: 5
activity_code: R25
ic: CA
serial_number: 153954
program_official: FARRELL, DOROTHY F
project_start_date: 2010-09-03
project_end_date: 2015-07-31
study_section: ZCA1-RTRB-2(M1)
contact_pi_person_id: 7875468
contact_pi: ANDERSON, BRADLEY D
other_pis: EVERS, BERNARD MARK
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 University of Kentucky Cancer Nanotechnology Training Center (UK CNTC) will provide advanced multidisciplinary training for predoctoral students and postdoctoral fellows toward the goal of creating a new type of cancer researcher who is skilled and ready to pursue a career in cancer nanotechnology research. Nationally and internationally recognized faculty members at the University of Kentucky will collaborate to create a fertile environment for the novel exploration of nanotechnology and cancer. Expertise covers a broad multidisciplinary range of scientific areas in gastrointestinal cancer lung cancer gliomas radiation medicine surgery cancer screening imaging and pharmacokinetics and dynamics. Among these faculty are 16 nanotechnology researchers in the Departments of Chemical Engineering Materials Engineering Electrical Engineering Chemistry and Pharmaceutical Sciences and 18 biomedical scientists or clinical oncologists in the Colleges of Pharmacy or Medicine. Based on existing research collaborations we propose cancer nanotechnology projects composed of multidisciplinary focus area teams with the goal of training future leading researchers in the field of cancer nanotechnology in the following four areas: (1) early detection and diagnosis in lung colon and ovarian cancer; (2) treatment of gastrointestinal tumors and metastases; (3) lung cancer treatment; and (4) glioma therapy. Specific Aim 1 is to expand the core expertise of participants in the UK CNTC through cross-disciplinary laboratory research training projects of up to two years involving innovative applications of nanotechnology to address specific unmet needs in cancer detection and therapy. Our trainees will be at the forefront of research that will be driven toward developing novel cancer therapies and diagnostic strategies based on nanotechnology. Through these activities the trainees will obtain a detailed understanding of the molecular basis of cancer the unresolved clinical problems in treating and diagnosing the disease and acquire expertise in the field of nanotechnology. In Specific Aim 2 the CNTC will provide trainees with problem-based and experiential training through seminars workshops short courses clerkships and laboratory training modules that will build their research skills and confidence as members of multi-disciplinary research teams. Each trainee will be immersed in individualized problem-based instruction and a broad multidisciplinary training through core courses short courses participation in seminars undergraduate and early graduate student mentoring and outreach activities designed to educate the public. Trainees will be guided through these programs with effective mentorship and an evaluation program (Specific Aim 3) that will assess the effectiveness of trainee progress and development. Finally Specific Aim 4 is to highlight the accomplishments of CNTC trainees both regionally and nationally. As such our trainees will learn to envision articulate and perform nanotechnology-centered research focused on developing novel solutions to the outstanding clinical problems associated with cancer.    PUBLIC HEALTH RELEVANCE: The University of Kentucky Cancer Nanotechnology Center will provide a systematic and unique multidisciplinary training environment focusing on laboratory hands-on research to create a workforce capable of using nanotechnology for solving intractable cancer research problems. Trainees of the Center will be immersed in a research environment designed to take advantage of the multiple research strengths of faculty at the University of Kentucky and will emerge with a broad yet detailed knowledge of cancer diagnostics interventions and related nanotechnology applications including drug delivery early detection and treatment.

project_terms:
Address;Applied Research;Archives;Area;Basic Science;Cancer Biology;Cancer Center;Cancer Detection;Cancer Diagnostics;Chemical Engineering;Clinical;Collaborations;Colon Carcinoma;Development;Diagnosis;Discipline;Doctor of Pharmacy;Drug Delivery Systems;Drug Kinetics;Early Diagnosis;Early treatment;Educational workshop;Effectiveness;Electrical Engineering;Engineering;Ensure;Environment;Environment Design;Ethics;Evaluation;Faculty;Feedback;Fostering;Funding;Future;Gastrointestinal Neoplasms;Glioma;Goals;Grant;Hour;Image;Immersion Investigative Technique;Instruction;International;Intervention;Journals;Kentucky;Knowledge;Laboratories;Laboratory Finding;Laboratory Research;Learning;Link;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Malignant neoplasm of ovary;Medicine;Mentors;Mentorship;Mission;Molecular;Monitor;Nanotechnology;Neoplasm Metastasis;Oncologist;Participant;Performance;Pharmaceutical Chemistry;Pharmacy facility;Postdoctoral Fellow;Program Effectiveness;Program Evaluation;Published Comment;Publishing;Radiation;Research;Research Personnel;Research Project Grants;Research Training;Rotation;Science;Screening for cancer;Solutions;Students;Suggestion;System;Therapeutic Human Experimentation;Time;Training;Translating;Universities;Update;Work;Writing;anticancer research;base;biomedical scientist;cancer diagnosis;cancer surgery;cancer therapy;cancer type;career;clinical conference;college;design;disease diagnosis;graduate student;improved;in vivo;innovation;interest;meetings;member;molecular imaging;multidisciplinary;novel;outreach;outreach program;pre-doctoral;programs;public health relevance;skills;training project;web site

public_health_relevance:
The University of Kentucky Cancer Nanotechnology Center will provide a systematic and uniquemultidisciplinary training environment focusing on laboratory hands-on research to create aworkforce capable of using nanotechnology for solving intractable cancer research problems.Trainees of the Center will be immersed in a research environment designed to take advantageof the multiple research strengths of faculty at the University of Kentucky and will emerge with abroad yet detailed knowledge of cancer diagnostics interventions and related nanotechnologyapplications including drug delivery early detection and treatment.


application_id: 8537861
project_number: 5U18FD004620-02
project_title: FDA Vet-LRN Veterinary Diagnostic Laboratory Cooperative Agreement Program fundin
administering_ic: FDA
award_notice_date: 2013-08-16
opportunity_number: PA-12-194
application_type: 5
activity_code: U18
ic: FD
serial_number: 004620
project_start_date: 2012-09-01
project_end_date: 2017-08-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 11450267
contact_pi: GASKILL, CYNTHIA LYNN
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2013-09-01
public_health_relevance:
Gaskill UKVDL Project NarrativeThis FDA Vet-LRN Cooperative Agreement Program will strengthen the overall food safety system bydeveloping increased capacity and capabilities to detect adulteration which could affect animals raised forhuman consumption or companion animals consuming ingredients used in both animal and human foodproducts.


application_id: 8537600
project_number: 3R44OD010958-03S1
project_title: A non-surgical embryo transfer (NSET) device for producing gene-modified mice
administering_ic: OD
award_notice_date: 2012-09-06
opportunity_number: PA-10-050
application_type: 3
activity_code: R44
ic: OD
serial_number: 010958
suffix: S1
program_official: O'NEILL, RAYMOND R
project_start_date: 2008-10-01
project_end_date: 2014-02-28
study_section: Special Emphasis Panel[ZRG1-IMST-J(15)B]
contact_pi_person_id: 9710810
contact_pi: FATH-GOODIN, ANGELIKA
other_pis: SPEAR, BRETT
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The use of research animals in research has been essential to development of vaccines and study of most human diseases. Modern rodent research is increasingly powerful with the ability to manipulate the genomes of mice and rats such that they closely mimic complex human diseases such as Alzheimer's and artherosclerosis. Generating transgenic mice and rats requires that embryos that are manipulated by researchers be transferred into recipient female mice where they can complete their development. Up to this point these transfers have required surgical procedures in which the embryo is implanted into the uterus. Recently a device has been developed that enables these embryo transfers to be performed without surgery which eliminates the post-operative recovery period thereby reducing pain of the animals. This proposal investigates and expands upon the utility of this embryo transfer device by establishing the optimal ages and mouse strains for embryo transfer (Aim 1) determining whether embryonic stem cells can be effectively and efficiently transferred with this device (Aim 2) determining whether the device is useful for artificial inseminations (Aim 3) directly visualizing the device in the uterus which may enable design improvements (Aim 4) and quantifying measures of stress relative to surgical procedures to support widespread adoption of this procedure in the research community (Aim 5). The primary project objective is to produce data that will prove the efficacy of this embryo transfer device and thereby enable researchers to replace surgical procedures with a non-surgical method that is equally effective. Proving that this non-surgical transfer method is effective under a range of conditions will expand its use over this range of applications and thereby maximize its impact in enabling researchers to refine and reduce the number of surgical procedures performed in mice.    PUBLIC HEALTH RELEVANCE: Animal use in research is essential for biomedical research and with the developing abilities to genetically engineer mice for research; these animals are becoming even more important as they can be modified to mimic most human diseases. Genetic engineering of mice requires as one of many other things the ability to transfer embryos into mice where they complete their development. This project supports further development of a device that enables these embryo transfers to be performed without surgery and therefore greatly reduces the pain category that these research animals experience and thereby supports progress in biomedicine.

project_terms:
Address;Adoption;Age;Alzheimer's Disease;Animal Experimentation;Animals;Artificial Insemination;Biomedical Research;Blastocyst Transfer;Categories;Collaborations;Communities;Complex;Data;Development;Device Designs;Devices;Embryo;Embryo Transfer;Ethics;Female;Fertilization in Vitro;Gene-Modified;Generations;Genetic Engineering;Genetically Engineered Mouse;Harvest;Implant;In Vitro;Mammalian Oviducts;Measures;Mediating;Methods;Mouse Strains;Mus;Operative Surgical Procedures;Pain;Performance;Phase;Positioning Attribute;Postoperative Period;Procedures;Production;Rattus;Recovery;Relative (related person);Research;Research Personnel;Rodent;Staging;Stress;Technology;Testing;Transgenic Mice;Uterus;Veterinarians;animal pain;biomarker;blastocyst;cost;design;egg;embryonic stem cell;experience;human disease;in vivo;mouse genome;prospective;public health relevance;sperm cell;success;vaccine development

public_health_relevance:
NarrativeAnimal use in research is essential for biomedical research and with the developing abilities togenetically engineer mice for research; these animals are becoming even more important asthey can be modified to mimic most human diseases. Genetic engineering of mice requires asone of many other things the ability to transfer embryos into mice where they complete theirdevelopment. This project supports further development of a device that enables these embryotransfers to be performed without surgery and therefore greatly reduces the pain category thatthese research animals experience and thereby supports progress in biomedicine.


application_id: 8537402
project_number: 5R03DE021460-02
project_title: Integrated Analysis: Epigenetic Regulation of Gene Expression During Orofacial De
administering_ic: NIDCR
award_notice_date: 2013-07-29
opportunity_number: PAR-10-041
application_type: 5
activity_code: R03
ic: DE
serial_number: 021460
program_official: HARRIS, EMILY L
project_start_date: 2012-09-01
project_end_date: 2015-08-31
study_section: ZDE1-JR(11)
contact_pi_person_id: 7842814
contact_pi: MUKHOPADHYAY, PARTHA
other_pis: BROCK, GUY
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): The long-term objectives of this proposal are to elucidate the role of epigenetic regulation of gene expression during mammalian orofacial development. Formation of the mammalian orofacial tissue is a multifaceted synchronized developmental process involving cell migration proliferation differentiation apoptosis and synthesis of extracellular matrix. All these critical cellular processes are under the control of avariety of genes encoding growth and differentiation factors signaling mediators transcription factors and extracellular matrix proteins whose expression is controlled in turn by epigenetically-modulated regulatory elements. Disruption of any one of these processes can lead to orofacial clefting. Emerging evidence strongly supports the importance of epigenetic mechanisms controlling the expression of key genes critical for orofacial ontogenesis. Recent studies from our lab have demonstrated that precise patterns of differential gene methylation and expression occur in embryonic orofacial tissue. Preliminary data revealed several epigenetically regulated genes which have documented critical roles in orofacial morphogenesis. We thus propose to test the hypothesis that regulation of differentially-expressed genes via differentially methylated regions is essential for proper development of the embryonic orofacial region. Three hypothesis-driven specific aims will be pursued: 1) Differentially expressed genes encoding mRNAs are epigenetically regulated during orofacial development. 2) Differentially expressed and epigenetically regulated gene transcripts are essential for the regulation of specific biological processes as well as phenotypic outcomes associated with orofacial development and 3) Selected differentially-expressed target genes are epigenetically regulated via differentially methylated regions during orofacial development.

project_terms:
Adopted;Apoptosis;Back;Bioinformatics;Biological;Biological Process;Breathing;Candidate Disease Gene;Cell physiology;Cleaved cell;Complex;Congenital Abnormality;CpG dinucleotide;Data;Development;Developmental Process;Differentiation and Growth;Embryo;Embryonic Development;Epigenetic Process;Extracellular Matrix;Extracellular Matrix Proteins;Gene Expression;Gene Expression Regulation;Gene Targeting;Genes;Global Change;Goals;Human;Impairment;Infant;Investigation;Lead;Mediator of activation protein;Messenger RNA;Methods;Methylation;Modification;Molecular;Morphogenesis;Outcome;Pathway interactions;Pattern;Process;Regulation;Regulatory Element;Research Proposals;Role;Signal Pathway;Signal Transduction;Speech;Testing;Time;Tissues;Transcript;base;bisulfite;cell motility;design;feeding;insight;mRNA Expression;mouse model;novel;novel strategies;orofacial;transcription factor

public_health_relevance:
Orofacial clefts are amongst the most prevalent birth defects in humans which can lead to difficulties in infant feeding breathing and speech impairment. Studies proposed in the current application are designed to advance our understanding of the complex mechanisms that control development of the orofacial region. This research proposal will adopt a novel bioinformatic approach and will utilize a mouse model that mimics human orofacial development to investigate the role of epigenetic regulation of gene expression during mammalian orofacial development. Successful completion of the proposed studies will provide a better insight of the specific control mechanisms that are important in orofacial development and will ultimately reveal potential mechanisms of clefting.


application_id: 8537062
project_number: 3R01GM085231-05S1
project_title: Role of SR-BI in LPS detoxification
administering_ic: NIGMS
award_notice_date: 2012-09-04
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: GM
serial_number: 085231
suffix: S1
program_official: DUNSMORE, SARAH
project_start_date: 2008-08-06
project_end_date: 2015-05-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8132330
contact_pi: LI, XIANG-AN
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
project_abstract:
DESCRIPTION (provided by applicant): Scavenger receptor BI (SR-BI) is an HDL receptor that regulates HDL cholesterol levels by mediating the delivery of HDL cholesterol esters to the liver. We recently report a novel and potentially clinically important function of SR-BI in protection against LPS-induced death. LPS challenge resulted in 90% fatality of SR-BI null mice whereas all the wild type littermates survived. More importantly using a cecum ligation and puncture (CLP) septic model we demonstrate that CLP treatment induced 100% fatality of SR-BI null mice whereas only 28.5% fatality of wild type littermates. Our findings indicate that SR-BI is critical for survival during sepsis in mice. We hypothesize that SR- BI prevents LPS-induced death by facilitating LPS clearance and suppressing inflammatory reactions. Understanding the mechanism whereby SR-BI prevents LPS- induced death will elucidate a novel mechanism for survival during sepsis and may reveal a strategy for intervention of sepsis. PUBLIC HEALTH RELEVANCE: Sepsis is a severe disease caused by bacterial infection. Sepsis can rapidly develop to septic shock when an overwhelming infection leads to low blood pressure and multi-organs dysfunction. Septic shock is one of the major causes of death that claims over 215000 lives and costs $16.7 billion per year in America alone. Death rate of septic shock is high exceeding 50% due to the poor understanding of the disease and the lack of efficient therapies. Lipopolysaccharides (LPS) play a central role in sepsis. LPS is released by bacteria in sepsis. It stimulates our body to generate too much inflammatory factors which causes tissue damage and death. Great efforts have been made to find effective treatments for sepsis including the application of antibodies to neutralize LPS. However it proven that simply neutralizing LPS without LPS removal is not protective against LPS toxicity. We recently reported that a protein called SR-BI is highly protective against septic death. The preliminary studies suggest that SR-BI prevents septic death by enhancing the removal of LPS. The purpose of this application is to determine the mechanism of how SR-BI removes LPS which may provide a novel strategy for the intervention of sepsis.

project_terms:
Address;Americas;Animals;Antibodies;Bacteria;Bacterial Infections;Binding (Molecular Function);Biological Assay;Bone Marrow;Bone Marrow Transplantation;CD14 Antigen;Cause of Death;Cecum;Cells;Cessation of life;Chinese Hamster Ovary Cell;Co-Immunoprecipitations;Complex;Cross-Over Studies;Death Rate;Disease;Drug Metabolic Detoxication;Excision;Functional disorder;HDL cholesteryl ester;HDL receptor;Health;Hepatic;Hepatocyte;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Hypotension;Infection;Inflammatory;Intervention;Knockout Mice;Label;Ligation;Lipopolysaccharides;Liver;Mediating;Modeling;Molecular;Mus;Mutate;Organ;Play;Predisposition;Process;Proteins;Puncture procedure;Reaction;Relative (related person);Reporting;Role;SR-BI receptor;Sepsis;Septic Shock;Serum;TLR4 gene;Techniques;Tissues;Toxic effect;Transgenic Mice;Transplantation;Wild Type Mouse;Work;cell type;cost;cytokine;effective therapy;in vivo;macrophage;macrophage scavenger receptors;mutant;novel;novel strategies;prevent;receptor;response;septic;uptake


application_id: 8536968
project_number: 5R03NS077193-02
project_title: Glutamate-evoked calcium signaling in spinal cord after nerve injury
administering_ic: NINDS
award_notice_date: 2013-08-13
opportunity_number: PA-11-262
application_type: 5
activity_code: R03
ic: NS
serial_number: 077193
program_official: OSHINSKY, MICHAEL L
project_start_date: 2012-09-01
project_end_date: 2014-08-31
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):  A fundamental gap exists in understanding the cellular mechanisms that initiate and maintain neuropathic pain. This gap represents an important problem because current analgesic drugs rarely provide sufficient efficacy without serious side effects. The long-term goal is to understand the mechanisms that lead to injury-induced central sensitization and establish clinically relevant therapeutic targets for chronic pai. The objective in this application is to evaluate the contribution glutamate receptor subtypes to dorsal root stimulation (DRS)-evoked Ca2+ transients in the dorsal horn and correlate enhanced Ca2+ responses with the magnitude of pain-like behavior. Based on preliminary data suggesting that glutamate-evoked Ca2+ responses in mouse spinal cord slices are potentiated after nerve injury the central hypothesis is that nerve injury increases AMPA receptor signaling in the dorsal horn leading to increases in [Ca2+]i that results in central sensitization and neuropathic pain. The rationale for the proposed project is that [Ca2+]i in dorsal horn neurons is essential for central sensitization and pain hypersensitivity. The central hypothesis will be teste by pursuing three specific aims: AIM 1 tests the hypothesis that glutamate-mediated activation of neuronal ionotropic AMPA receptors drives Ca2+ signaling. Electrophysiological recordings and real-time fluorescent labeling of astrocytes will be used to evaluate the cell types that respond to dorsal root stimulation (DRS) with a rise in [Ca2+]i. Next the relative contribution ofglutamate receptor subtypes will be determined by quantifying DRS-evoked [Ca2+]i transients in the presence of selective antagonists. AIM 2 tests the hypothesis that peripheral nerve injury potentiates DRS-evoked Ca2+ responses and this will correlate with the magnitude of hyperalgesia. To allow for a correlation analysis between behavior and [Ca2+]i a variant model of nerve injury has been developed that gradually elicits robust allodynia in 1 week and then resolves in 4 weeks. Behavioral hyperalgesia will be evaluated and compared to DRS-evoked [Ca2+]i in spinal cord slices from sham traditional and variant nerve injured animals sacrificed at 7 14 and 21 d after injury. AIM 3 tests the hypothesis that PKM mediates SNI-induced increases in hyperalgesia Ca2+ signaling and AP frequency in dorsal horn. We will administer multiple PKM inhibitors to sham and SNI mice and measure pain- like behavior Ca2+ transients and/or AP frequency. Based on our preliminary results we predict that PKM blockade will reverse injury-induced hyperalgesia increases in [Ca2+]i and AP frequency.  This project employs innovative wide-field calcium imaging simultaneously from numerous cells in spinal cord slices from adult mice. The proposed research is significant because it reveals the Ca2+ channels that regulate DRS-evoked Ca2+ transients and is a critical first step in understanding nerve injury-induced potentiation of neuronal Ca2+ signaling. Ultimately this knowledge will establish clinically relevant therapeutic targets for alleviating chronic pain.

project_terms:
6-Cyano-7-nitroquinoxaline-23-dione;AMPA Receptors;Action Potentials;Adult;Adverse effects;Analgesics;Animals;Astrocytes;Attenuated;Behavior;Behavioral;Calcium;Calcium Signaling;Cells;Chemosensitization;Chronic;Data;Development;Dose;Frequencies (time pattern);Fura-2;Glutamate Receptor;Glutamates;Goals;Healthcare;Hyperalgesia;Hypersensitivity;Image;Injury;Knowledge;Label;Lead;Ligation;Measures;Mediating;Mission;Modeling;Mus;Nerve;Neurons;Operative Surgical Procedures;Pain;Pain Measurement;Pain management;Peripheral Nerves;Peripheral nerve injury;Physiological;Population;Posterior Horn Cells;Receptor Signaling;Relative (related person);Research;Signal Transduction;Skin;Slice;Specificity;Spinal Cord;Stimulus;Substantia Gelatinosa;Tactile;Techniques;Testing;Time;Variant;allodynia;base;cell type;central pain;central sensitization;chronic pain;clinically relevant;dorsal horn;inhibitor/antagonist;injured;innovation;kainate;nerve injury;neurotransmission;painful neuropathy;response;sciatic nerve;spinal nerve posterior root;therapeutic target

public_health_relevance:
Chronic pain management is a major scientific and health care challenge as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. This project is relevant to NINDS's mission because it will 1) determine mechanisms that lead to injury-induced central sensitization and 2) establish clinically relevant therapeutic targets for alleviating chronic pain. This Research Plan employs highly innovative wide-field calcium imaging from numerous cells in a single spinal cord slice from adult mice.


application_id: 8535829
project_number: 5R01NS037717-13
project_title: Transcriptional control of oligodendrocyte differentiation and myelination
administering_ic: NINDS
award_notice_date: 2013-09-10
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 037717
program_official: MORRIS, JILL A
project_start_date: 2000-03-01
project_end_date: 2016-05-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 1906514
contact_pi: QIU, MENGSHENG
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Oligodendrocytes are myelinating glial cells found in all regions of the centralnervous system. The major function of oligodendrocytes is to form myelin sheathsaround axons to ensure the rapid and faithful transmission of electrical signals.During development oligodendrocytes precursor cells (OPCs) have to go through aseries of morphological and molecular changes before they become fullydifferentiated into mature myelinating oligodendrocytes. The differentiation andmyelination processes of oligodendrocytes are tightly controlled by transcriptionfactors. Recent studies have demonstrated that Sox10 transcription factor directlystimulates OPC differentiation and myelin gene expression. However OPCdifferentiation is tightly regulated by other transcription factors (TFs) includingNkx2.2 Olig1 Hes5 and Id4 all of which are expressed in undifferentiated OPC cellsin the developing central nervous system. While Nkx2.2 and Olig1 function topromote OPC differentiation Hes5 and Id4 act as inhibitors of OPC maturation. Thefunctional relationship of these four regulatory TFs in the control of OLdifferentiation has not been determined. In this application we hypothesize thatNkx2.2 enhances OPC maturation indirectly by suppressing the expression or functionof Hes5 and Id4 but functions synergistically with Olig1 in promoting OPCdifferentiation. These hypotheses will be tested in the first two aims of the proposal.Recent data showed that Nkx2.2 is rapidly down-regulated in differentiated OLs andover-expression of Nkx2.2 in oligodendrocyte cell line inhibits MBP gene expressionraising the possibility that Nkx2.2 switches its role to become a repressor of myelingene expression in mature OLs to prevent excessive myelin production. Thispossibility will be examined in the third aim of the proposal. Finally we will test thehypothesis that persistent expression of Sox10 in mature OLs functions to maintainmyelin gene expression and myelin sheath stability. The interplay of Sox10 andNkx2.2 in myelinating OL cells may be responsible for the delicate balance of myelinproduction and structural maintenance. This line of study could help us understand molecular pathways that controlaxonal myelination process and provide insights into the development of molecularapproaches to stimulate oligodendrocyte regeneration and remyelination indemyelinating diseases.

project_terms:
Axon;Binding (Molecular Function);Cell Differentiation process;Cell Line;Cell Maturation;Cells;Chickens;Cues;Data;Demyelinating Diseases;Development;Embryo;Ensure;Equilibrium;Gene Expression;Genes;Genetic;Knowledge;Maintenance;Molecular;Mutation;Myelin;Myelin Sheath;Natural regeneration;Neuraxis;Neuroglia;Neurologic;Nkx-2.2 protein;Oligodendroglia;Pathway interactions;Patients;Principal Investigator;Process;Production;Promotor (Genetics);Proteins;Regulation;Role;Series;Signal Transduction;Spinal Cord;Spinal cord injury patients;Testing;Transcriptional Regulation;Transgenic Animals;Undifferentiated;axon regeneration;inhibitor/antagonist;insight;mutant;myelination;oligodendrocyte precursor;precursor cell;premature;prevent;programs;remyelination;transcription factor;transmission process

public_health_relevance:
The proposed studies will provide important information on the function and regulationsof transcription factors that control oligodendrocyte differentiation and myelin geneexpression in the developing central nervous system. Knowledge obtained from thisstudy can help us understand the molecular pathways that govern the differentiation andmyelination of oligodendrocytes and provide cues for promoting oligodendrocyteregeneration and axonal remyelination in neurological patients and spinal cord injurypatients.


application_id: 8535826
project_number: 5R01MH092317-02
project_title: Predicting trajectories of flourishing and failing in new nursing home residents
administering_ic: NIMH
award_notice_date: 2013-07-16
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: MH
serial_number: 092317
program_official: ROWLAND, LAURA
project_start_date: 2012-08-23
project_end_date: 2015-07-31
study_section: Social Psychology, Personality and Interpersonal Processes Study Section[SPIP]
contact_pi_person_id: 1908020
contact_pi: MEEKS, SUZANNE
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Admission to a nursing home represents a crisis point with implications for physical recovery mental illness and quality of life. In this project we will follow a sample of nursing home residents from admission through the first year of nursing home residence. Our purpose is to examine not only predictors of traditional mental illness and well-being outcomes but also what factors determine the shape and direction of change over time for individual residents. There are two specific aims: (1) to identify psychological social physical and demographic resources and processes that promote resilience and predict change in mental illness (depression and anxiety) and mortality during the year following admission to a nursing home; and (2) to identify psychological social physical and demographic resilience resources and processes that predict change in flourishing (quality of life positive affect and social engagement). We will collect data from 400 newly admitted nursing home residents their families nursing home staff members and from medical charts. These data will include residents' pre-admission psychological social and physical characteristics that will facilitate or detract from their capacity for resilience including demographic and personality characteristics social networks physical health and disability cognitive impairment and mental health history. We will evaluate levels of depression anxiety and quality of life at admission and then measure resident experiences with treatment activity and social interactions during the nursing home stay and resident regulation of positive and negative affect that should promote resilience. We will also use blood draws to collect information on biomarkers indicative of stress response at the time of admission and after a year. We will assess residents quarterly for one year a total of 4 assessments after the baseline evaluation. Results of this study will contribute to improving care for older adults who enter nursing facilities in three ways. First results will highlight attributes associated with resilience and risk that can be measured at the time of admission and used to prioritize interventions. Second we will identify resiliency processes that are potential treatment targets for improving mental illness outcomes and promote flourishing. Finally inclusion of indicators of flourishing in addition to measures of mental illness will permit conceptual exploration of the notion of flourishing at the end of life broadening our goals for care to include not only absence of mental illness but also the promotion of well-being.

project_terms:
Address;Admission activity;Affect;Affective;American;Anxiety;Behavioral;Biological Markers;Blood;Caring;Characteristics;Cognitive;Data;Dimensions;Discipline of Nursing;Elderly;Emotional;Ethnicity aspects;Evaluation;Family;Friends;Functional disorder;Gender;Goals;Health Care Costs;Impaired cognition;Individual;Institution;Intervention;Life;Long-Term Care;Measures;Mediating;Mediator of activation protein;Medical;Mental Depression;Mental Health;Mental disorders;Mortality Vital Statistics;National Institute of Mental Health (U.S.);Nursing Homes;Outcome;Personal Satisfaction;Personality;Prevention;Process;Promotor (Genetics);Quality of life;Recording of previous events;Recovery;Regulation;Religion and Spirituality;Research;Resources;Risk;Risk Factors;Sampling;Severity of illness;Shapes;Social Interaction;Social Network;Societies;Strategic Planning;Time;United States National Institutes of Health;Work;allostasis;biological adaptation to stress;cohort;disability;end of life;experience;frailty;improved;innovation;member;nursing home length of stay;optimism;physical conditioning;psychologic;residence;resilience;social;social cognition

public_health_relevance:
Forty-five percent of Americans over the age of 65 will use a nursing home in 2010 and about 24% will stay for a year or more usually at the end of their lives. These residents often suffer from comorbid physical cognitive and mental disorders that diminish quality of life at the end of life and represent a costly burden to society. Prevention or amelioration of depression and anxiety and improving well-being are important for maximizing life quality and decreasing health care costs for nursing home residents.


application_id: 8535601
project_number: 5R21AI095811-02
project_title: Genetic Regulation of Macrophage Polarization
administering_ic: NIAID
award_notice_date: 2013-07-05
opportunity_number: PA-10-069
application_type: 5
activity_code: R21
ic: AI
serial_number: 095811
program_official: QUILL, HELEN R
project_start_date: 2012-08-23
project_end_date: 2015-07-31
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 1901005
contact_pi: MCGILLIS, JOSEPH P.
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): The long term objective of this research is to understand the genetic regulatory networks that orchestrate macrophage Mf polarization. A specific goal in this proposal is to identify and characterize 'master genetic regulators' that determine which genes are selectively expressed by Mfs in different physiological and pathologic conditions. Preliminary studies suggest that one such regulator is a histone deacetylase Hdac9. Mfs are located throughout the body and are involved in inflammatory processes tissue repair and innate and adaptive immune responses. Naive Mfs can be activated or polarized to different functional states that have distinct and often opposing regulatory and functional roles in inflammation. They can significantly influence many disease processes including infectious disease autoimmune disease and cancer. Classically activated Mfs M1 are phagocytic secrete pro-inflammatory mediators and promote pathogen destruction and clearance. Alternatively activated Mfs M2 promote tissue repair and secrete cytokines and growth factors that are anti-inflammatory or immunosuppressive. Despite intense interest in Mf polarization and the functions of polarized Mfs there is a large gap in the understanding of the genetic regulatory networks that regulate the activation of naive Mfs into M1and M2 states. Our central hypotheses is that there are genetic regulatory networks controlled by a discrete cascade of transcription factors that promote polarization of naive or 'resting' Mfs to M1 and M2 states and that HDAC9 plays a fundamental role by promoting expression of genes required by M2 Mfs while simultaneously repressing genes expressed in M1 Mfs. This project will use a novel cellular system of Mf polarization as an experimental platform to address this central hypothesis. The specific aims are to: 1) confirm upregulation of HDAC 9 in the M2 phenotype and determine which HDAC9 isoform(s) is(are) expressed in M2 Mfs 2) confirm experimentally that HDAC9 regulates polarization of the M2 macrophage phenotype and 3) identify genes targeted by HDAC9 (M2 genes that are upregulated and M1 genes that are suppressed). Achieving these goals will provide important insights on how Mf polarization is regulated. This information could have a significant impact on therapeutic approaches that would target Mf functions in a wide range of disease processes.

project_terms:
Address;Anatomy;Anti-Inflammatory Agents;Anti-inflammatory;Apoptosis;Autoimmune Diseases;Autoimmunity;Biological Models;Bone Marrow;Cell physiology;Cells;Chronic;Commit;Communicable Diseases;Data;Development;Disease;Environment;Experimental Models;Family;Gene Expression;Gene Targeting;Genes;Genetic;Goals;Growth Factor;Histone Deacetylase;Immune response;Immune system;Immunity;Immunosuppressive Agents;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Lead;Location;Malignant Neoplasms;Mediator of activation protein;Microarray Analysis;Myeloid Progenitor Cells;NF-kappa B;Natural Immunity;Pathologic;Pathologic Processes;Pathway interactions;Phenotype;Physiological;Plastics;Play;Process;Protein Isoforms;Proteins;Regulation;Regulator Genes;Regulatory T-Lymphocyte;Research;Rest;Role;Signal Transduction;System;T-Lymphocyte;Therapeutic;Tissue-Specific Gene Expression;Tissues;Transcription Repressor/Corepressor;Up-Regulation (Physiology);adaptive immunity;angiogenesis;base;cytokine;genetic regulatory protein;insight;interest;macrophage;member;neuronal survival;novel;novel strategies;novel therapeutics;pathogen;progenitor;response;selective expression;skeletal muscle differentiation;small hairpin RNA;tissue repair;transcription factor

public_health_relevance:
Macrophages are key cells of the immune system and serve many different functions under differing physiologic and pathologic conditions. This project will identify genetic mechanisms that regulate how macrophages function by characterizing the role of a key regulatory protein HDAC9 that may have a major role in regulating macrophage responses. Understanding the role of this and other factors that regulate macrophage functions should provide new and novel approaches to understanding and targeting macrophage functions in a wide variety of disease processes.


application_id: 8535365
project_number: 1R21DA035641-01
project_title: Buprenorphine Treatment and Health Reform: Availability Utilization and Quality
administering_ic: NIDA
award_notice_date: 2013-04-10
opportunity_number: RFA-DA-13-001
application_type: 1
activity_code: R21
ic: DA
serial_number: 035641
program_official: DUFFY, SARAH Q
project_start_date: 2013-05-01
project_end_date: 2014-04-30
study_section: Special Emphasis Panel[ZDA1 NXR-B (13)]
contact_pi_person_id: 8146786
contact_pi: KNUDSEN, HANNAH
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): Although its implementation is likely to vary across states due to the recent Supreme Court decision passage of the Affordable Care Act (ACA) is expected to dramatically impact the delivery of substance use disorder (SUD) treatment through changes to treatment financing and greater integration of mainstream health care and SUD treatment. The evolving system of buprenorphine treatment for opioid use disorders (OUDs) is a prime example of integration. While this system has grown substantially in the past decade research is limited regarding how physicians are implementing this lifesaving treatment and whether they are delivering HIV- related services. It is unknown how the ACA will impact the delivery of buprenorphine treatment. The proposed study seeks 1 year of R21 support to establish study feasibility and 4 years of R33 support to conduct a longitudinal study of buprenorphine implementation that integrates multi-level data on state-level variations in ACA implementation with longitudinal surveys of buprenorphine-prescribing physicians. The primary aim of the R21 phase is to determine the feasibility of conducting a longitudinal study that integrates physician-level and state-level data collection through research procedures linked to 4 milestones encompassing the construction of the physician sample survey development through qualitative and cognitive interviews and generation of a protocol for longitudinal collection of state-level data on ACA implementation. The three specific aims of the proposed R33 study are: (1) To estimate cross-sectional and longitudinal models of buprenorphine utilization as well as the implementation of high-quality clinical practice behaviors (CPBs) and HIV-related services in buprenorphine treatment in the context of states' implementation of the ACA; (2) To examine the relative importance of patient payment source (e.g. Medicaid private insurance or out-of-pocket) and other patient characteristics on physician decision-making during buprenorphine treatment; and (3) To model the state-level associations between the implementation of the ACA and two state-level outcomes: utilization of buprenorphine within Medicaid and the number of physicians holding the X-license for prescribing buprenorphine. These aims will be accomplished through ongoing collection of policy and administrative data at the state-level with 4 annual surveys of a nationally representative sample of 1200 physicians who hold the X-license to prescribe buprenorphine. This longitudinal survey design will support fielding four unique conjoint analyses each addressing a key domain of physician decision-making while also collecting data on CPBs over time. Data analysis will include cross-sectional multivariate models of decision-making and multi-level longitudinal analyses of CPB adoption and implementation to test theory-driven hypotheses. By measuring the quality availability and utilization of buprenorphine treatment in the US this research may identify treatment gaps for which interventions may be developed to improve treatment quality for OUDs while contributing to scientific knowledge regarding the impact of the ACA on US treatment services.

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

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


application_id: 8534903
project_number: 3R01EY022238-01S1
project_title: Functional studies of DICER1 and Alu RNA in geographic atrophy
administering_ic: NEI
award_notice_date: 2012-09-03
opportunity_number: PA-10-067
application_type: 3
activity_code: R01
ic: EY
serial_number: 022238
suffix: S1
program_official: SHEN, GRACE L
project_start_date: 2012-02-01
project_end_date: 2017-01-31
study_section: Biology and Diseases of the Posterior Eye Study Section[BDPE]
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 made the surprising observation that there is an abundance of Alu repetitive RNA in the RPE of human eyes with GA that accumulates in response to a dramatic deficiency in the RNase DICER1 and induces RPE degeneration (Kaneko et al. Nature 2011). Our findings which introduce a novel cell survival function for DICER1 independent of its canonical miRNA biogenesis function and the concept that Alu RNA can directly promote human pathology provide new mechanistic insights into GA pathogenesis. However we still lack an integrated understanding of how DICER1 is dysregulated in GA and precisely how Alu RNA induces 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 DICER1/Alu RNA dysregulation contributes to GA pathogenesis and develop a novel therapeutic strategy via the following Aims: (1) Generate a spatiotemporal map of DICER1 and Alu RNA in relation to the locus of pathology in GA and early AMD eyes; (2) Decipher the mechanisms by which Alu RNA triggers a new inflammatory cell death pathway we have identified; (3) Define the molecular regulation of DICER1 in the RPE in the context of GA and the function of a novel DICER1 splice variant; (4) Create a new animal model of GA having human-like features of the disease and validate an antisense therapeutic strategy targeting Alu RNA. 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 perfectly aligned with the 5-year goals of the NEI's Retinal Diseases Program strategic plan.

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 in the eyes of patients with GA. The goal of this project is to understand how this newly discovered pathway causes GA and to test drugs that will be suitable for entry into clinical trials.


application_id: 8534797
project_number: 5R25GM102776-02
project_title: Kentucky Bridge to a Biomedical Doctorate for Appalachian Students
administering_ic: NIGMS
award_notice_date: 2013-08-12
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_terms:
Achievement;Address;Admission activity;Appalachian Region;Attention;Award;Biomedical Research;Books;Country;County;Data;Data Reporting;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;Unemployment;Universities;Work;Writing;abstracting;base;career;college;experience;improved;meetings;news;programs;skills;sobriety;success;symposium;undergraduate education


application_id: 8531906
project_number: 5R01DK082419-05
project_title: Group X sPLA2: Regulator of Lipolysis and Glucose Homeostasis
administering_ic: NIDDK
award_notice_date: 2013-08-05
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 082419
project_start_date: 2009-08-01
project_end_date: 2015-07-31
study_section: Integrative Physiology of Obesity and Diabetes Study Section[IPOD]
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
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
budget_start_date: 2013-08-01
project_abstract:
DESCRIPTION (provided by applicant): Obesity is now the most common metabolic disorder in industrialized countries and represents one of the most prevalent risk factors for the development of type 2 diabetes. While the close relationship between obesity and diabetes has long been recognized understanding how an expanded fat mass results in the progressive development of insulin resistance and type 2 diabetes has proven difficult. One possible mechanism linking obesity and insulin resistance is the excess mobilization of free fatty acids (FFAs) from adipocyte stores which leads to derangements in insulin signaling either through direct actions of FFAs or through ectopic lipid deposition in non-adipose tissues. We recently developed a novel mouse model that lacks the expression of GX secretory phospholipase A2 (GX KO mice). Unexpectedly these mice have significantly increased adiposity compared to wild-type littermates. The increase in adiposity is associated with adipocyte hypertrophy which appears to be due at least in part to a defect in 2-adrenergic stimulated lipolysis. However despite a marked increase in adiposity GX KO mice show improved response to glucose challenge compared to wild- type mice suggesting that insulin sensitivity may be protected in these mice. Based on our preliminary findings we hypothesize that GX sPLA2 expressed by adipose tissue macrophages modulates the equilibrium between adipocyte lipid storage and lipid catabolism. As a consequence GX sPLA2 regulates adipocyte hypertrophy adipose tissue inflammation FFA flux and whole body insulin sensitivity. To test these hypotheses we propose the following 3 specific aims: Aim 1. To test the hypothesis that reduced FFA flux in adipose tissue of GX sPLA2-deficient mice is associated with increased insulin sensitivity and reduced adipose tissue inflammation. This will be achieved by a) determining whether decreased FFA mobilization in adipose tissue of GX KO mice is associated with increased glucose uptake and insulin sensitivity in non-adipose tissue; b) determining whether GX sPLA2 deficiency protects against high fat diet-induced insulin resistance; and c) defining the effect of GX sPLA2 deficiency on adipose tissue inflammation in mice. Aim 2. To define the role of macrophage-expressed GX sPLA2 in adipose tissue. This will be achieved by performing a bone marrow transplant experiment in which wild-type and GX KO mice will be reconstituted with bone marrow cells derived from either wild-type or GX KO mice. Adipocyte hypertrophy adipose tissue inflammation and insulin sensitivity will be assessed in each of the groups of transplanted mice. Aim 3. To test the hypothesis that GX sPLA2 positively regulates TAG mobilization. This will be achieved by a) determining whether GX sPLA2 alters the rate of TAG synthesis or hydrolysis in adipocytes; and b) determining whether GX sPLA2 promotes TAG mobilization by activating hormone sensitive lipase. Results from these studies have the potential to provide important insights into a novel mechanism regulating lipolysis and may identify new targets for modulating adipocyte hypertrophy and FFA flux to reduce insulin resistance. PUBLIC HEALTH RELEVANCE: In the U.S. obesity is now the most common risk factor for the development of type-2 diabetes. Studies in humans and animal models suggest that inefficient storage of fat during long-term exposure to nutrient excess may trigger pathological inflammatory responses that disrupt the ability of insulin to function. The goal of this proposal is to test the hypothesis that enhancing the capacity of adipose tissue to store fat will have a beneficial effect on inflammation and insulin sensitivity. This proposal could provide new strategies to prevent or treat diabetes.

project_terms:
Adipocytes;Adipose tissue;Adrenergic Agents;Animal Model;Biology;Blood Circulation;Bone Marrow Cells;Bone Marrow Transplantation;Cardiovascular Diseases;Catabolism;Cell physiology;Data;Defect;Deposition;Developed Countries;Development;Diabetes Mellitus;Diet;Dyslipidemias;Endocrine;Endocrine Glands;Equilibrium;Exhibits;Exposure to;Fatty acid glycerol esters;Functional disorder;Glucose;Goals;Health;Hepatic;Hormones;Human;Hydrolysis;Hypertrophy;Impairment;Individual;Inflammation;Inflammatory Response;Insulin;Insulin Resistance;Link;Lipids;Lipolysis;Metabolic;Metabolic Diseases;Metabolic syndrome;Metabolism;Mus;Non-Insulin-Dependent Diabetes Mellitus;Nonesterified Fatty Acids;Nutrient;Obesity;Peripheral;Phospholipase A2;Play;Production;Proteins;Regulation;Risk Factors;Role;Study models;Testing;Tissues;Transplantation;Triglycerides;Wild Type Mouse;adipokines;adrenergic;base;blood glucose regulation;energy balance;glucose metabolism;glucose uptake;group X secretory phospholipase A(2);improved;insight;insulin secretion;insulin sensitivity;insulin signaling;macrophage;mouse model;novel;prevent;reconstitution;research study;response;sterol esterase

public_health_relevance:
In the U.S. obesity is now the most common risk factor for the development of type-2diabetes. Studies in humans and animal models suggest that inefficient storage of fatduring long-term exposure to nutrient excess may trigger pathological inflammatoryresponses that disrupt the ability of insulin to function. The goal of this proposal is to testthe hypothesis that enhancing the capacity of adipose tissue to store fat will have abeneficial effect on inflammation and insulin sensitivity. This proposal could provide newstrategies to prevent or treat diabetes.


application_id: 8530649
project_number: 1R01DA035552-01
project_title: Long-lasting cocaine-metabolizing enzyme for cocaine addiction treatment
administering_ic: NIDA
award_notice_date: 2013-03-14
opportunity_number: RFA-DA-13-004
application_type: 1
activity_code: R01
ic: DA
serial_number: 035552
program_official: SHIH, MING L
project_start_date: 2013-04-01
project_end_date: 2016-02-29
study_section: Special Emphasis Panel[ZDA1 GXM-A (11)]
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
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): Cocaine abuse is a major medical and public health problem. There is still no FDA-approved anti-cocaine medication. Disastrous medical and social consequences of cocaine abuse have made the development of an anti-cocaine medication a high priority. Enhancing cocaine metabolism by administration of human butyrylcholinesterase (BChE) is recognized as an efficient treatment strategy for cocaine overdose and addiction. However the catalytic efficiency (kcat/KM) of wild-type BChE against the naturally occurring (-)- cocaine is low (kcat = 4.1 min-1 and KM = 4.5 M). Nevertheless we have recently designed and discovered a set of BChE mutants known as cocaine hydrolases (CocHs) with >1000-fold improved catalytic efficiency against (-)-cocaine compared to wild-type BChE. In vivo evidences and clinical data for the first one of our discovered and patented CocHs have demonstrated that our discovered CocHs are promising candidates for development of an anti-cocaine medication. Our recently designed discovered and patented CocHs are significantly more potent. Built on our success in rational design and discovery of the CocHs the currently proposed investigation is focused on rational design preparation and preclinical testing of a novel type of long-lasting
CocH entities denoted as Fc-CocH obtained from fusion of CocH with Fc portion of human antibody IgG1. The specific aims are: (1) to design new molecular entities of Fc-CocH that potentially have not only a high catalytic efficiency against (-)-cocaine but also a long biologicl half-life; (2) to prepare and test the designed Fc-CocHs for their in vitro activities; (3) to characterize the in vivo potency pharmacokinetics and immunogenicity of Fc-CocHs in rats and rhesus monkeys; (4) to evaluate the actual effects of the promising Fc-CocHs (identified in Aim 3) on the physiological and behavior responses of animals to cocaine by performing cardiovascular assays and self-administration assays in rhesus monkeys. Accomplishment of this proposed investigation will result in the identification and development of the best possible Fc-CocH entity that has not only a high in vivo potency in blocking physiological effects of cocaine but also a long biological half- life without immunogenicity. The long-lasting Fc-CocH entity optimized in this investigation is expected to be highly effective and safe as a novel exogenous enzyme suitable for cocaine addiction treatment in humans.

project_terms:
Animals;Antibodies;Behavior;Binding (Molecular Function);Binding Sites;Biological;Biological Assay;Butyrylcholinesterase;Cardiovascular system;Clinical;Clinical Data;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Computer Simulation;Data;Development;Dose;Drug Kinetics;Enzymes;FDA approved;Goals;Half-Life;Human;Hydrolase;IgG1;Immunoglobulin G;In Vitro;Investigation;Investigational Drugs;Lead;Legal patent;Macaca mulatta;Medical;Metabolism;Molecular;Neuraxis;Neurons;Pharmaceutical Preparations;Pharmacodynamics;Physiological;Plasma;Preclinical Testing;Preparation;Proteins;Rattus;Schedule;Self Administration;Testing;Vaccines;addiction;base;cocaine overdose;design;immunogenicity;improved;in vitro Assay;in vitro activity;in vivo;large scale production;mutant;novel;novel therapeutics;public health medicine (field);public health relevance;response;small molecule;social;stable cell line;success;therapy development;treatment strategy

public_health_relevance:
Accelerating cocaine metabolism has been recognized as a promising treatment strategy for cocaine overdose and abuse. The long-lasting cocaine-metabolizing enzymes to be tested in this project are promising candidates for an efficient anti-cocaine medication.


application_id: 8528689
project_number: 5R00HL087924-05
project_title: Granule exocytosis and neutrophil activation
administering_ic: NHLBI
award_notice_date: 2013-07-12
opportunity_number: PA-07-297
application_type: 5
activity_code: R00
ic: HL
serial_number: 087924
program_official: MONDORO, TRACI
project_start_date: 2011-09-01
project_end_date: 2015-07-31
study_section: NSS
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:
The postulated role of exocytosis in mediating various functional responses associated with neutrophil activation has not been directly tested. We will use a novel approach; generating TAT-fusion proteins containing the coiled-coil domains of different SNARE proteins; to test the hypothesis that blocking exocytosis of distinct granule subsets will prevent specific neutrophil phenotypic changes and this strategy may be used to prevent neutrophil-mediated tissue damage in vivo. The specific objectives of the mentored phase of this proposal are: 1) To determine the ability of TAT-fusion proteins containing the SNARE domains of SNAP-23 syntaxins and VAMPs to inhibit exocytosis of each of the four neutrophil granule subsets. The training goal of this aim is to develop molecular biology and cell biology skills that will allow the applicant to address experimental questions at new levels and apply them in the independent phase of this proposal. 2) To determine the most effective way to administer the TAT-SNARE fusion proteins in vivo and to determine the effect of these fusion proteins on models of acute neutrophil-dependent inflammation in rats. The training goals of this aim are to learn animal models of neutrophil-dependent inflammation and to establish the ability of TAT-fusion proteins to inhibit neutrophil exocytosis in vivo. 3) Define other proteins that interact with SNARE proteins by proteomic analysis. The training goal of this aim is to develop the ability to perform proteomic analysis. The state-of-the-art techniques acquired during the mentored phase will greatly increase the expertise that will allow the PI to become a successful independent investigator. For the independent phase the specific objectives are: 1) To determine the specific functional responses that are regulated by neutrophil granule exocytosis; 2) To define the mechanisms by which inhibition of neutrophil exocytosis in vivo blocks the inflammatory response; and 3) To investigate the molecular mechanisms by which exocytosis is stimulated. The training the applicant will receive will make her unique in the combination of experience interest and state-of-the-art technology and will maximize her potential to become an independent NIH-funded investigator.

project_terms:
Acute;Address;Animal Model;Cellular biology;Chimeric Proteins;Chronic;Coiled-Coil Domain;Cytoplasmic Granules;Development;Exocytosis;Funding;Goals;Human;Inflammation;Inflammatory Response;Knowledge;Lead;Learning;Mediating;Mentors;Modeling;Molecular;Molecular Biology;Neutrophil Activation;Phase;Proteins;Proteomics;Rattus;Reperfusion Injury;Research Personnel;Rheumatoid Arthritis;Role;S-nitro-N-acetylpenicillamine;SNAP receptor;Techniques;Technology;Testing;Tissues;Training;United States National Institutes of Health;Vasculitis;experience;in vivo;interest;neutrophil;novel strategies;novel therapeutics;prevent;response;skills;syntaxin

public_health_relevance:
Neutrophils participate in a number of acute and chronic human illnesses including ischemia/reperfusion injury vasculitis and inflammatory arthritis. The new knowledge developed from this proposal will have a significant impact on the development of novel therapeutic strategies for these illnesses. Additionally the mentoring plan will lead to the transition to independence of the applicant.


application_id: 8528655
project_number: 5R21HD069897-02
project_title: Consortium to Evaluate a Novel Violence Prevention Program on College Campuses
administering_ic: NICHD
award_notice_date: 2013-06-27
opportunity_number: PAS-10-226
application_type: 5
activity_code: R21
ic: HD
serial_number: 069897
program_official: BURES, REGINA M
project_start_date: 2012-08-10
project_end_date: 2015-06-30
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 8001935
contact_pi: WILLIAMS, CORRINE M
other_pis: Not Applicable
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_abstract:
DESCRIPTION (provided by applicant): Up to 25% of women may be sexually assaulted during college and one-third of college students have experienced physical aggression from dating partners. While most students neither participate in nor condone violence many respond passively to a campus culture that may tacitly support violence as evidenced by violent media images jokes trivializing violence against women and sexual harassment. Growing awareness that all members of the campus community can play a significant role in ending dating and sexual violence (DV/SV) has led to an increase in violence prevention interventions for college students. However very few of these programs have been empirically evaluated. A significant barrier to progress in intervention research is the infrastructure required to implement and evaluate interventions across multiple sites. For this project the intervention will be Green Dotan innovative primary prevention intervention to reduce DV/SV among college students which was developed at the University of Kentucky. The intervention consists of one-hour persuasive speeches followed by a six to either hour bystander intervention training called Students Educating and Empowering to Develop Safety (SEEDS). In addition we are creating booster sessions that will be provided to all students who have completed SEEDS training to assist with additional skills-building that may be required. As a developmental project the proposed research will consist of three phases: 1) pilot work to create survey modules resulting in a questionnaire that contains measures which are standardized across campuses to evaluate the effectiveness of the intervention and is a manageable length; 2) data collection at UK to streamline data collection procedures when other colleges are brought on; and 3) recruitment of additional implementation and control college sites. The University of Kentucky will operate as the coordinating center for the multi-site evaluation and will continue to serve as the pilot site or data collection and refinement of study methodology. The University of South Carolina has agreed to serve as an implementation site and the University of Cincinnati has agreed to serve as a control site. We will recruit an additional eight colleges (four control and four interventionsites) during the project period. By beginning with this R21 to conduct developmental work and begin problem solving we can help to ensure the success of subsequent projects. If Green Dot is then determined to be effective across multiple campuses in preventing violence and the associated sequelae of adverse academic as well as physical and mental health outcomes experienced by so many college students then the potential impact of this study is indeed groundbreaking. Additionally the lessons learned from establishing a multi-site public health intervention trial with one coordinating center responsible for all data collection via online surveys has implications for the study of other health issues.

project_terms:
Address;Awareness;Behavior;Behavioral Risk Factor Surveillance System;Communities;Data Collection;Development;Diffuse;Diffusion of Innovation;Educational Intervention;Effectiveness of Interventions;Ensure;Ethnicity aspects;Evaluation;Evaluation Studies;Faculty;Forcible intercourse;Foundations;Funding;Goals;Health;Hour;Image;Institutional Review Boards;Intervention;Intervention Studies;Intervention Trial;Kentucky;Learning;Length;Measures;Mental Health;Methodology;Modeling;Monitor;Outcome;Participant;Phase;Physical aggression;Play;Positioning Attribute;Pregnancy;Prevention program;Preventive Intervention;Primary Prevention;Problem Solving;Procedures;Questionnaires;Race;Randomized;Recruitment Activity;Research;Research Infrastructure;Risk Assessment;Role;Safety;Selection Criteria;Sexual Harassment;Site;South Carolina;Speech;Structure;Students;Surveys;System;Testing;Training;United States;Universities;Violence;Woman;Women's Health;Work;base;binge drinking;college;dating violence;dating violence prevention;empowered;experience;high school;innovation;interest;member;novel;peer;physical conditioning;programs;public health medicine (field);public health priorities;sexual assault;sexual violence;skills;success;theories;tool;university student;violence against women;violence prevention;willingness

public_health_relevance:
Preventing dating and sexual violence among college students is a public health priority due to adverse academic and physical and mental health consequences. This study will create the foundation for a large multi-site evaluation of the violence prevention intervention Green Dot which will have a revolutionary impact if Green Dot is ultimately determined to be effective in preventing violence across multiple campuses. Additionally the lessons learned from establishing a multi-site public health intervention trial with one coordinating center responsible for all data collection via online surveys has implications for the study of other health issues.


application_id: 8527961
project_number: 3U18IP000420-02S1
project_title: Anti-Influenza Therapy in Hospitalized Patients with Community-Acquired Pneumonia
administering_ic: NCIRD
award_notice_date: 2012-08-16
opportunity_number: RFA-IP-10-007
application_type: 3
activity_code: U18
ic: IP
serial_number: 000420
suffix: S1
program_official: YEE, EILEEN
project_start_date: 2010-09-01
project_end_date: 2014-02-28
study_section: ZIP1-GCA(17)
contact_pi_person_id: 8816315
contact_pi: RAMIREZ, JULIO ALBERTO
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):  Pneumonia and influenza combined is the leading cause of infectious disease-related death in the world. The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) have developed guidelines for the management of community-acquired pneumonia (CAP). These guidelines recommend early initiation of empiric antibiotic therapy to cover the most likely typical and atypical bacteria that may cause CAP. Several studies have indicated associations between delayed time to administration of empiric antibiotic therapy with increased clinical failure and mortality. This well documented association of a delay in appropriate antibacterial therapy and worse clinical outcomes in patients with bacterial CAP has not been evaluated in patients with influenza CAP. Since results of current diagnostic tests for influenza may be delayed and several tests have low sensitivity anti-influenza treatment for patients with influenza CAP is frequently initiated late or not at all. We hypothesize that as happens with bacterial CAP hospitalized patients with influenza CAP will benefit from early initiation of empiric antiviral therapy soon after hospitalization.  To test our hypothesis we plan a prospective randomized multicenter clinical trial of hospitalized patients with CAP. Patients will be randomized to empiric antibacterial therapy as recommended by IDSA/ATS guidelines (Group A) versus a combination approach of empiric antibacterial plus anti-influenza therapy (Group B). The primary study outcome is development of clinical failure during 30 days after enrollment. The secondary study outcome is the cost-effectiveness of the intervention. Other clinical outcomes that will be compared between study groups include: time to clinical stability duration of hospitalization development of cardiovascular events re-hospitalization short-term mortality (30 days) and long-term mortality (1 year).  The primary aim of this study is to compare in hospitalized patients with influenza CAP the rate of clinical failure between Group A and Group B. We hypothesize that patients in Group B (empiric anti-influenza therapy) will have a statistically significant decrease in the rate of clinical failure when compared with patients in Group A (guideline-recommended approach). We estimate that empiric anti-influenza therapy will decrease the rate of clinical failure in hospitalized patients with influenza CAP from approximately 30% to 14%. Considering this effect size we will need to randomize 200 patients with influenza CAP 100 in group A and 100 in group B to allow for the detection of significant differences in the proposed outcomes with 80% power with 1=0.05. Since influenza CAP is expected to occur in 20% of all hospitalized patients with CAP we will enroll a total number of 1000 patients with CAP to achieve the goal of 200 patients hospitalized with influenza CAP. Data from this clinical trial will change our current approach to empiric therapy of hospitalized patients with CAP. This study will provide evidence that to optimize patients' outcomes hospitalized patients with CAP should receive early empiric antibacterial plus anti-influenza therapy. )    PUBLIC HEALTH RELEVANCE: Pneumonia may be caused by a bacterium or a virus. Our current treatment of a hospitalized patient with pneumonia includes initial treatment for bacteria (antibacterials). In this study we plan to treat hospitalized patients with pneumonia with drugs against bacteria (antibacterials) and viruses (antivirals). We plan to prove that patients that receive a combination of antibacterials plus antivirals will have better recovery from pneumonia.

public_health_relevance:
Pneumonia may be caused by a bacterium or a virus. Our current treatment of a hospitalizedpatient with pneumonia includes initial treatment for bacteria (antibacterials). In this study weplan to treat hospitalized patients with pneumonia with drugs against bacteria (antibacterials)and viruses (antivirals). We plan to prove that patients that receive a combination ofantibacterials plus antivirals will have better recovery from pneumonia.


application_id: 8527809
project_number: 5P20GM103538-10
project_title: Center for the Biologic Basis of Oral/Systemic Disease (CBBOSD)
administering_ic: NIGMS
award_notice_date: 2013-08-27
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: GM
serial_number: 103538
program_official: DOUTHARD, REGINE
project_start_date: 2004-09-23
project_end_date: 2015-01-31
study_section: ZRR1-RI-B(01)
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: 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 DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The link between chronic oral infections and general health has been recognized since the early 20th century. During the last 2 decades retrospective epidemiological studies and prospective longitudinal as well as intervention studies have supported that these chronic oral infections with accompanying chronic inflammation associate with various systemic diseases and their sequelae. This continuation application for the Center for the Biologic Basis of Oral/System Diseases (CBBO/SD) addresses major initiatives of the National Institute of Dental and Craniofacial Research (NIDCR) regarding improving oral and general health ofthe U.S. population. The CBBO/SD is organized into 3 cInical projects: Project 1: Chronic Inflammation at the Oral and Cervico/Vaginal Mucosa; Project 2: Physiology of the Stress Response in Patients with Temporomandibular Disorders and Fibromyalgia; Project 3: Coordinated Oral-Intestinal Immune Response in Patients with Inflammatory Bowel Diseases; and 2 translational science projects: Project 4: Ontogeny of Innate Immune Responses at Mucosal Surfaces; and Project 5: Gene Therapy for Orofacial Pain. These projects enlist junior investigators from the Colleges of Dentistry Nursing and Medicine as well as senior mentors/co-investigators from multiple colleges at UK. The thematic interface of the projects focuses on the contribution of chronic inflammation to oral and systemic diseases. They engage populations of expectant women patients with chronic orofacial pain and inflammatory bowel disease. These clinical projects interact with the translational projects at the level of a common understanding of innate immune responses and inflammation and novel therapeutic intervention strategies forthe chronic orofacial pain. The CBBO/SD provides an infrastructure for development of the junior faculty by providing grants management support educational opportunities a biostatistics/bioinformatics core and a clinical research center. The continuation of the CBBO/SD is supported by the success during the initial tenure of the center in transitioning junior investigators towards independent funding coupled with substantial investment from the university and individual colleges.

project_terms:
Acute Disease;Address;Advanced Glycosylation End Products;Aging;Aging-Related Process;Bacterial Infections;Biochemical;Bioinformatics;Biological;Biological Markers;Biometry;Cardiovascular system;Cells;Chronic;Clinical;Clinical Research;Clinical Trials;Communication;Complex;Coupled;Culture Techniques;Data;Dental;Dental Plaque;Dental caries;Dentistry;Development;Diabetes Mellitus;Diagnosis;Diagnostic;Discipline;Discipline of Nursing;Disease;Disease Progression;Documentation;Early Diagnosis;Ecology;Ensure;Epidemiologic Studies;Event;Faculty;Fibromyalgia;Focal Infection;Food Webs;Funding;Gene Expression Profile;Genetic Markers;Genetic Structures;Genome;Goals;Grant;Growth;Health;Health Sciences;Immune response;Immunology;Individual;Infant;Inflammation;Inflammatory Bowel Diseases;Inflammatory Response;Institutes;Internet;Intervention;Intervention Studies;Intestines;Investigation;Investments;Kentucky;Link;Literature;Low Birth Weight Infant;Mediating;Medicine;Mentors;Methods;Microbial Biofilms;Microbiology;Molecular;Mouth Diseases;Mucous Membrane;National Institute of Dental and Craniofacial Research;Nature;Oral;Oral cavity;Oral health;Orofacial Pain;Osteoporosis;Pathogenesis;Patients;Periodontal Diseases;Periodontitis;Periodontium;Physiological;Physiology;Population;Population Group;Preventive;Process;Property;Proteome;Research;Research Design;Research Infrastructure;Research Personnel;Research Support;Research Training;Risk;Science;Scientist;Signal Transduction;Site;Specificity;Strategic Planning;Streptococcus mutans;Surface;System;Systemic disease;Temporomandibular Joint Disorders;Tissues;Translational Research;Underserved Population;Universities;Vagina;Validation;Viral;Virulence;Virus Diseases;Woman;base;biological adaptation to stress;cerebrovascular;clinical practice;college;craniofacial;diabetes management;gene therapy;health disparity;improved;information gathering;infrastructure development;microbial;microorganism;new technology;novel strategies;novel therapeutic intervention;oral infection;oral tissue;prevent;programs;prospective;research clinical testing;response;success;tool;type I and type II diabetes


application_id: 8527767
project_number: 5R01DK083761-04
project_title: TGF-Beta Signaling Effectors in Prostate Growth Regulation/Tumor Progression
administering_ic: NIDDK
award_notice_date: 2013-08-02
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 083761
program_official: RANKIN, TRACY L
project_start_date: 2010-08-15
project_end_date: 2015-07-31
study_section: Special Emphasis Panel[ZRG1-DKUS-B(03)M]
contact_pi_person_id: 7875447
contact_pi: KYPRIANOU, NATASHA
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Transforming growth factor- (TGF-) is a negative regulator of normal benign and malignant prostate growth. While serving a growth-inhibitory/apoptotic role in the normal prostate overproduction of TGF-  1 in the aging prostate contributes to the development of benign prostate hyperplasia (BPH) and prostate cancer. We previously established that activation of TGF-s  signaling leads to apoptosis induction and loss of TGF  RII receptor (T2RII) contributes to prostate tumorigenic growth. Overexpression of T2RII in human prostate cancer cells enables apoptosis-mediated-growth suppression in response to TGF-  in vitro and in vivo. Using the LNCaP T2RII prostate cancer cells (androgen-sensitive and TGF-  responsive) as a model it was shown that TGF- 1 induces apoptosis and this effect was enhanced by androgens. Recent proteomic-based approaches identified two new intracellular effectors of TGF- pathway that act independent of Smads to regulate apoptotic outcomes in prostate cancer cells. In this proposal we hypothesize that TGF-  1 signaling via changes in Smad4-independent intracellular effectors and cross-talk with the androgen receptor (AR) regulates prostate growth and functional inactivation of this network accelerates the manifestation of the malignant phenotype and tumor progression. The following four Specific Aims will test this hypothesis: Specific Aim 1 will characterize the functional involvement of Smad- independent signaling effectors prohibitin and cofilin as novel mediators of TGF- action in prostate benign and malignant epithelial cells. Specific Aim 2 will identify the significance of the androgen receptor (AR) in the signaling interaction between TGF-1 and androgens towards apoptosis and epithelial to mesenchymal transition (EMT) of prostate tumor epithelial cells. Specific Aim 3 will establish the role of cofilin as a novel regulator of the ability of prostate (stroma) fibroblasts to direct TGF-  signaling in the context of the tumor microenvironment. Specific Aim 4 will characterize the in vivo physiological consequences of a functionally impaired TGF- signaling on prostate growth tumor initiation and progression using a conditional knockout mouse DNT2RII to generate double transgenics upon crossing with the TRAMP transgenic mouse model. These studies will provide new insights into the mechanistic deregulation of TGF signaling network that contributes to prostate growth and tumor progression. Understanding how cells read TGF-  will enable both the delineation of the transcriptional programs that mediate specific TGF-  effects and provide a framework for defining the mechanism via which TGF-  1 growth inhibitory/apoptotic responses in normal benign and pre-malignant prostate cells might be selectively replaced by invasive and metastatic responses in cancer cells.    PUBLIC HEALTH RELEVANCE: The long term objective of the application is to characterize the functional interplay between the TGF-  1 and androgen signaling pathways that independently of Smad effectors and in the context of tissue microenvironment contribute to deregulation of TGF  1 mediated effects on prostate growth during tumor initiation and progression. The application will also pursue the mechanism converting TGF-  from a tumor suppressor in normal and benign prostate growth to a tumor promoter in advanced metastatic cancer.

project_terms:
Actins;Adhesions;Aging;Androgen Receptor;Androgens;Apoptosis;Apoptosis Promoter;Apoptotic;Benign;Benign Prostatic Hypertrophy;Bypass;Cells;Complex;Cytoskeleton;Defect;Development;Disseminated Malignant Neoplasm;Dominant-Negative Mutation;Embryonic Development;Epithelial;Epithelial Cell Proliferation;Epithelial Cells;Event;Extracellular Matrix;Family;Fibroblasts;Genetic Transcription;Goals;Growth;Growth Factor;Human;In Vitro;Induction of Apoptosis;Inhibition of Apoptosis;Knockout Mice;LNCaP;Laboratories;Ligands;Link;MAP Kinase Gene;Malignant - descriptor;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mediator of activation protein;Modeling;Molecular;Neoplasm Metastasis;Outcome;Pathway interactions;Phosphotransferases;Physiological;Physiological Processes;Premalignant;Promotor (Genetics);Prostate;Prostatic Neoplasms;Proteins;Proteomics;Reading;Receptor Signaling;Regulation;Research;Resistance;Role;Signal Pathway;Signal Transduction;Testing;Tissues;Transforming Growth Factor beta;Transforming Growth Factors;Transgenic Mice;Transgenic Organisms;Tumor Promoters;Tumor Suppressor Proteins;Tumorigenicity;Work;base;cancer cell;cell growth;cell motility;cofilin;epithelial to mesenchymal transition;evidence base;in vivo;insight;malignant phenotype;migration;mouse model;novel;overexpression;programs;prohibitin;prostate cancer cell;prostate carcinogenesis;public health relevance;receptor;response;tissue repair;trafficking;tumor initiation;tumor microenvironment;tumor progression;tumorigenic

public_health_relevance:
NARRATIVEThe long term objective of the application is to characterize the functionalinterplay between the TGF-1 and androgen signaling pathways thatindependently of Smad effectors and in the context of tissue microenvironmentcontribute to deregulation of TGF1 mediated effects on prostate growth duringtumor initiation and progression. The application will also pursue the mechanismconverting TGF- from a tumor suppressor in normal and benign prostategrowth to a tumor promoter in advanced metastatic cancer.


application_id: 8526808
project_number: 1F31NS083292-01
project_title: Methylglyoxal and TRPA1 contribution to neuropathic pain in type 2 diabetes
administering_ic: NINDS
award_notice_date: 2013-02-27
opportunity_number: PA-11-111
application_type: 1
activity_code: F31
ic: NS
serial_number: 083292
program_official: PORTER, LINDA L
project_start_date: 2013-04-01
project_end_date: 2016-09-30
study_section: Special Emphasis Panel[ZRG1 F02B-M (20)]
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:
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: 8526328
project_number: 5R01AG038651-03
project_title: Role of impaired cognitive states & risk factors in conversion to mixed dementias
administering_ic: NIA
award_notice_date: 2013-08-29
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: 2013-09-01
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.;SCHMITT, FREDERICK ;TYAS, SUZANNE LEIGH;WHITE, LON RAY;XIONG, CHENGJIE ;YU, LEI


