# projects

application_id: 8643323
project_number: 1R43DK101147-01
project_title: Wireless Tibial Nerve Stimulation Therapy for Overactive Bladder
administering_ic: NIDDK
award_notice_date: 2014-05-23
opportunity_number: PA-13-088
application_type: 1
activity_code: R43
ic: DK
serial_number: 101147
program_official: KIRKALI, ZIYA
project_start_date: 2014-06-01
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1 DKUS-G (13)]
contact_pi_person_id: 10313138
contact_pi: DUKE, AUSTIN ROBERT
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 968130778
duns_number: 968130778
fips: US
organization_id: 10032915
organization_name: ROSELLINI SCIENTIFIC, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405111162
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-06-01
budget_end_date: 2016-05-31
project_abstract:
DESCRIPTION (provided by applicant): The goal of this SBIR Phase 1 proposal is to determine the feasibility of wireless neuromodulation for controlling bladder function. Overactive bladder (OAB) affects about 16.5% of the adult population in both the United States and Europe. Percutaneous electrical stimulation of the posterior tibial nerve (PTN) recently emerged as an effective yet minimally invasive alternative to failed conventional behavioral modifications drug treatments and more invasive surgical approaches. This therapy is commercially available as the Urgent PC(R) system (Uroplasty Inc Minnetonka MN). However the repeated office visits needed to achieve and sustain the clinical benefits of Urgent PC proves to be a great impediment to the use of this product. Thus while stimulation of the PTN remains a top target for reaching the untreated sufferers of OAB a clinically acceptable and practical method of implementing this treatment is lacking. As a result millions of patients remain untreated. The long-term goal of this project is to restore quality of life to those suffering with OAB by providig patients with a means of treating themselves in their own home as needed. This approach will overcome the primary weakness of the Urgent PC therapy. Rossellini Scientific is partnering with Stimwave Technologies to apply their wireless implant technology to a form factor and therapeutic treatment protocol appropriate for electrical PTN stimulation. In this Phase 1 proposal our first specific aim is to test the feasibility of using our wirelessly powered nerve stimulator to reflexively inhibit the urinary bladder - and hence increase bladder capacity - in an
acute animal model. We plan to expand our preliminary data that showed electrical nerve stimulation using a voltage-controlled capacitive discharge (VCCD) waveform requires less charge per pulse than traditional constant-current (CC) stimulation. We will determine whether VCCD or CC stimulation is most appropriate for electrically modulating bladder function. We will also determine target stimulation parameters for wireless neuromodulation of bladder function to be used in planned clinical trials. The second specific aim is to test the chronic performance of the implant in animals to ensure stability of device function. To conclude that our device and approach are feasible we must observe at least a 30% decrease in bladder pressure (induce relaxation) and that bladder volume is increased by e 50% under the conditions of this study. We must also find that our device effectively stimulates following 4 8 and 12 weeks of implantation. If our device is effective in these models then we will apply to the NIH for Phase 2
funding to carry out a clinical trial to test safety efficacy and patient compliance.

project_terms:
Acute;Adult;Affect;American;Animal Model;Animals;Behavior Therapy;Bladder;Bladder Control;Charge;Chronic;Clinical;Clinical Trials;Compliance behavior;Data;Devices;Electric Stimulation;Ensure;Europe;Felis catus;Frequencies (time pattern);Funding;Goals;Home environment;Human;Implant;Incontinence;Life;Maintenance;Marketing;Methods;Modality;Modeling;Nerve;Nerve Fibers;Neurostimulation procedures of spinal cord tissue;Office Visits;Operative Surgical Procedures;Overactive Bladder;Pain in lower limb;Patients;Performance;Pharmaceutical Preparations;Phase;Physiologic pulse;Population;Posterior Tibial Nerves;Quality of life;Rattus;Recruitment Activity;Relaxation;Reporting;Sleep;Small Business Innovation Research Grant;Social isolation;Structure of tibial nerve;Symptoms;System;Technology;Testing;Therapeutic;Treatment Protocols;Treatment outcome;United States;United States National Institutes of Health;Visit;Wireless Technology;Wit;base;chronic back pain;chronic pain;conventional therapy;design;effective therapy;foot;implantation;minimally invasive;neuroregulation;patient population;pressure;public health relevance;response;safety testing;voltage

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Overactive bladder (OAB) affects approximately 34 million Americans. It is a devastating condition that impairs mobility leads to social isolation disturbe sleep impaired domestic functionality diminished sexual performance and reduction in the ability to live independently. Due to lack of treatment options less than half of the patients wit this condition actually receive effective treatment. This is a proposal to develop a neuromodulation treatment for this unreached patient population.


application_id: 8643246
project_number: 5R01GM077422-06
project_title: Targeting Nucleic Acids with an Integrated Virtual and Actual Screen
administering_ic: NIGMS
award_notice_date: 2014-03-26
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: GM
serial_number: 077422
program_official: PREUSCH, PETER
project_start_date: 2007-02-01
project_end_date: 2016-03-31
study_section: Macromolecular Structure and Function B Study Section[MSFB]
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
other_pis: TRENT, JOHN O
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 remains an underrepresented target for small molecule therapeutic agents. There is mounting evidence to indicate that non-B DNA structures play prominent roles in gene expression and in the function of telomeres. Targeting these structural elements is an attractive and innovative strategy for the development of new therapeutic agents. The use of small molecules in such an antigene strategy is promising for many reasons. Targeting the gene before its amplification to produce multiple mRNA and protein molecules is advantageous because there are fewer targets to hit. In addition is easier to manipulate small molecules (rather than therapeutic DNA or RNA molecules) chemically to optimize binding and pharmacological properties. We seek renewal for our innovative and highly productive program to develop an integrated virtual and actual screening platform for the discovery of new lead compounds that bind selectively to unique DNA structures of biological significance. Progress during the initial funding period was outstanding and we achieved most of the specific aims proposed in our initial proposal. We have discovered several compounds that bind selectively to particular quadruplex structures a target of intense current interest. We propose studies that will continue to develop and optimize the integrated screening platform. During the next funding period we will focus on the discovery of lead compounds that bind selectively to biologically important quadruplex and DNA-RNA hybrid structures. In order to do this we will develop structural models for complex quadruplex structures using a novel approach that integrates molecular dynamics simulations with rigorous experimental validation. We will characterize the biophysical and functional properties of the novel quadruplex binders we have discovered during the initial funding period. Specific aims include: 1. Development and refinement of the virtual screening platform. 2. Development of higher-throughput assays for ligand binding. 3. Discovery of lead compounds that bind to functionally important nucleic acid structures. 4. Biophysical and biological characterization of novel G-quadruplex binding agents discovered during the initial funding period. The proposed studies will deliver an improved integrated platform for the discovery of novel lead compounds and a thorough characterization of several newly-discovered quadruplex binders with unique chemical scaffolds.

project_terms:
Active Sites;Antineoplastic Agents;Area;Beryllium;Binding (Molecular Function);Biological;Biological Assay;Chemicals;Complex;Computer Simulation;DNA;DNA Structure;Detection;Development;Dialysis procedure;Drug Targeting;Elements;Fluorescence;Fluorescence Resonance Energy Transfer;Funding;G-Quartets;Gene Expression;Gene Targeting;Genome;Hybrids;Indium;Intercalating Agents;Label;Laboratories;Lead;Libraries;Ligand Binding;Ligands;Measures;Messenger RNA;Methods;Metric;Modeling;Nucleic Acid Binding;Nucleic Acids;Oncogenes;Pharmaceutical Preparations;Play;Promotor (Genetics);Property;Proteins;RNA;RNA-Directed DNA Polymerase;Role;Specificity;Structural Models;Structure;Telomerase;Telomere Maintenance;Temperature;Therapeutic Agents;Validation;Work;antigene;c-myc Genes;cancer cell;high throughput screening;improved;innovation;interest;melting;molecular dynamics;novel;novel strategies;novel therapeutics;nucleic acid structure;overexpression;programs;quadruplex DNA;receptor;scaffold;screening;small molecule;telomere;therapeutic DNA;therapeutic RNA;virtual

public_health_relevance:
This project will develop an integrated computational and experimental screening platform for the discovery of new drugs that target specific structures of functional importance within the genome. The initial funding period for this project was successful and productive and we will continue our efforts. Several novel lead compounds were discovered that bind to functionally important quadruplex structures. We will characterize the biophysical and biological properties of these novel agents.


application_id: 8642831
project_number: 3T42OH010278-02S3
project_title: Central Appalachian Region Educational Research Center Occupational Safety Core
administering_ic: NIOSH
award_notice_date: 2013-08-21
opportunity_number: PAR-10-217
application_type: 3
activity_code: T42
ic: OH
serial_number: 010278
suffix: S3
program_official: SANDERSON, LEE M
project_start_date: 2012-07-01
project_end_date: 2014-06-30
study_section: Special Emphasis Panel[ZOH1 JFK (50)]
contact_pi_person_id: 8433958
contact_pi: SANDERSON, WAYNE T.
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The Central Appalachian Regional Education and Research Center (CARERC) provides graduate and continuing education for occupational safety and health professionals for the period July 2012 to June 2014. Specifically we (1) provide interdisciplinary occupational safety and health education for graduate students; (2) enhance the research skills of students and faculty in the targeted disciplines; (3) encourage and conduct interdisciplinary research on a variety of occupational diseases and injuries; (4) deliver continuing education consultation and outreach to address environmental and occupational safety and health concerns in the Central Appalachian Region; and (5) translate research into prevention practice. CARERC's scope includes counties in eastern Kentucky western North Carolina eastern Tennessee western Virginia and southern West Virginia where elevated rates of occupational injuries and fatalities persist particularly in production agriculture forestry mining and transportation. CARERC combines the resources of the University of Kentucky College of Public Health (MPH DrPH and PhD in Occupational Epidemiology and MPH in Agricultural Safety and Health); the UK College of Nursing (PhD in Occupational Nursing); the UK College of Engineering (MS and PhD in Mine Safety & Health) and the Eastern Kentucky University (EKU) College of Justice & Safety (MS in Occupational Safety). CARERC collaborates with other regional institutions as well as industry labor and government in its Pilot Research Program (PRP) Outreach and Continuing Education (CE) Programs to enhance research capacity and catalyze the translation of research to practice. We plan to support the following number of trainees each year: 7 doctoral students 7 MPH and 10 MS students across the core programs. CARERC serves as a catalyst for interdisciplinary research in occupational safety and health and a centralized resource center for innovative education and training. We focus our recruiting and training in the Central Appalachian region to reduce occupational disease and injury of the working men and women in this area. This application is a resubmission of our Occupational Safety (OS) core and a supplement for our Occupational Epidemiology (OccEpi) core.    
   
Eastern Kentucky University has provided graduate education in occupational safety since 1991 when the Master of Loss Prevention and Safety (LPS) was first established using a NIOSH grant. It later became a Master of Safety Security and Emergency Management (SSEM). It was originally designed to serve as a graduate educational experience for those who completed undergraduate degrees within the department in the areas of fire and safety engineering technology and assets protection. Occupational safety was represented in the undergraduate curriculum as a concentration but it has evolved to become an independent degree. It was soon found that students from a broad spectrum of undergraduate degree programs such as business and criminal justice were also successful in the graduate SSEM program. The on campus program has graduated over 200 students as of spring 2012.

public_health_relevance:
PUBLIC HEALTH RELEVANCE   
Building on the strengths of our existing research programs and responding to the need for innovative coordinated occupational safety and health training in central Appalachia the proposed Central Appalachian Regional Education and Research Center (CARERC) will provide unprecedented levels of targeted instruction training and applied research while serving as a recognized source of knowledge and expertise.


application_id: 8642611
project_number: 5T32CA165990-02
project_title: Interdisciplinary Research Training in Cancer Biology
project_terms: Cancer Biology;Interdisciplinary Study;Research Training
administering_ic: NCI
award_notice_date: 2014-04-04
opportunity_number: PA-11-184
application_type: 5
activity_code: T32
ic: CA
serial_number: 165990
program_official: PERKINS, SUSAN N
project_start_date: 2013-04-01
project_end_date: 2016-03-31
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: EVERS, BERNARD MARK
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: 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
public_health_relevance:
This multidisciplinary training program represents a team-approach involving multiple PIs to mentor pre- doctoral students and post-doctoral fellows in fundamental aspects of cancer biology translational science of cancer and therapeutics and prepare them as independent investigators who can become fully integrated in multidisciplinary cancer care teams.


application_id: 8642497
project_number: 1F31AA022263-01A1
project_title: Effects of alcohol and the environment on driving ability in high-risk drivers
administering_ic: NIAAA
award_notice_date: 2013-09-11
opportunity_number: PA-11-111
application_type: 1
activity_code: F31
ic: AA
serial_number: 022263
suffix: A1
program_official: BLOSS, GREGORY
project_start_date: 2014-07-01
project_end_date: 2016-06-30
study_section: Epidemiology, Prevention and Behavior Research Study Section[AA-2]
contact_pi_person_id: 14733432
contact_pi: ROBERTS, WALTER MCRAINEY
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Alcohol-impaired driving is a significant problem in the United States. The proposed research seeks to expand our understanding of the factors leading people to drive while impaired by testing the acute effects of alcohol in a group characterized by increased risk for alcohol-intoxicated driving (i.e. adults with ADHD). The project will examine alcohol responses in this group with a focus on how atypical alcohol responses may place this group at heightened risk to drive after drinking. First the proposed research will examine how alcohol interacts with environmental factors to impair driving ability in
adults with ADHD. Previous research has shown that the effects of alcohol are more pronounced in certain environmental circumstances such as the presence of visual distraction or motivational conflict. These findings are important because such environmental circumstances are quite common outside of the laboratory so they may explain why some drivers show appreciable impairment even at blood alcohol concentrations (BACs) below the legal limit of intoxication (i.e. 80mg/100ml). The proposed research will examine the interaction of alcohol intoxication and environmental factors in a group of high-risk drinkers (i.e. adults wih ADHD) under several doses of alcohol. This will test whether high-risk environmental circumstances cause adults with ADHD to show heightened behavioral impairment under alcohol even at BACs below the legal limit of intoxication. Second the proposed project will examine whether adults with ADHD overestimate their ability to drive after consuming alcohol. Previous research has shown that subjective evaluation of impairment informs people's decisions to drive after drinking. It is also well known that individuals with ADHD show impaired self-evaluation processes so they may underestimate the degree to which alcohol impairs their driving ability (Knouse et al. 2005; Weafer et al. 2008). Further they may not perceive how driving in high-risk scenarios exacerbates their level of behavioral impairment. These specific aims will be achieved by examining the interactive effects of alcohol and environmental factors on objective and perceived driving ability in adults with and without ADHD.

project_terms:
Acute;Address;Adolescent;Adult;Affect;Alcohol abuse;Alcohol consumption;Alcoholic Intoxication;Alcohols;Appointment;Attention deficit hyperactivity disorder;Automobile Driving;Behavior;Blood alcohol level measurement;Cellular Phone;Characteristics;Commit;Conflict (Psychology);Disinhibition;Dose;Environment;Environmental Risk Factor;Evaluation;Impairment;Impulsivity;Incidence;Individual;Intoxication;Laboratories;Legal;Light;Limb structure;Modeling;Motor Vehicles;Pattern;Performance;Population;Positioning Attribute;Process;Relative (related person);Reporting;Research;Risk;Risk Factors;Safety;Speed (motion);Sum;Testing;Time;United States;Visual;alcohol effect;alcohol response;alcohol risk;behavioral impairment;distraction;drinking;driving under influence;fitness;high risk;impaired driving performance;inattention;peer;public health medicine (field);public health relevance;response;simulation;skills;trafficking;vehicular accident

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed project will examine how characteristics of the environment alter the effects of alcohol on driving ability in adults with and without ADHD. The project will also examine the degree to which adults with ADHD underestimate the degree to which alcohol has impaired their behavior which may increase their risk of driving after drinking.


application_id: 8642327
project_number: 3R01NS070899-04S1
project_title: Regulation signaling and dynamics of glucan phosphatases.
administering_ic: NINDS
award_notice_date: 2013-04-12
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: NS
serial_number: 070899
suffix: S1
program_official: STEWART, RANDALL R
project_start_date: 2010-07-01
project_end_date: 2015-04-30
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
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):  The objective of this grant is to elucidate the regulation downstream signaling and structural dynamics of the glucan phosphatase laforin. Mammalian cells store readily mobilized energy in the form of glycogen a water-soluble carbohydrate. Recessive mutations in genes encoding the E3 ubiquitin ligase malin or the dual specificity phosphatase laforin disrupt glycogen metabolism and result in a fatal neurodegenerative epilepsy called Lafora disease (LD). A hallmark of LD is poorly branched hyperphosphorylated insoluble carbohydrate accumulations called Lafora bodies (LBs) thought to be the causative agent of LD.  We established that malin is a single-subunit E3 ubiquitin ligase that ubiquitinates and triggers the degradation of multiple proteins involved in glycogen metabolism. In addition we discovered that laforin is the founding member of a unique class of phosphatases that dephosphorylate phospho-glucans. These results allowed us to propose molecular mechanisms that cause LD: 1) loss of malin results in LBs due to an imbalance in glycogen metabolism proteins i.e. protein levels are not properly maintained; 2) loss of laforin results in LBs due to glucan hyperphosphorylation that inhibits glucan branching; 3) laforin also acts as a targeting subunit for malin so that loss of laforin disrupts some malin-directed ubiquitination events. While we have made significant strides in determining the molecular mechanisms of LD we lack an understanding of how these enzymes are regulated. This proposal will elucidate the deficiencies in our current knowledge.  We recently identified novel phosphorylation and ubiquitination events on laforin. Phosphorylation and ubiquitination are post-translational modifications that direct changes in protein concentration enzymatic activity protein localization protein-protein interactions and structural dynamics. In Aim 1 we will define the in vivo conditions triggering laforin phosphorylation and characterize the functional consequences. We will utilize 1) overexpression and endogenous protein levels in tissue culture cells to monitor the status of laforin localization and modification 2) assay laforin function in vitro using purified proteins and 3) utilize a LD mouse model to verify our results. In Aim 2 we will utilize a similar strategy to determine the affects of ubiquitination on laforin function. In addition we will define the role of laforin in malin directed ubiquitination as we have recently discovered that laforin acts as a targeting protein for malin. In Aim 3 we will determine how perturbations of the structural components of glucan phosphatases contribute to LD. We will utilize Hydrogen- Deuterium exchange mass spectrometry to define the structural dynamics of laforin and x-ray crystallography to determine the structure of a glucan phosphatase. This proposal is built on our past discoveries and uses complementary approaches to advance our understanding of the intercalated events of cell metabolism neurodegeneration and epilepsy. Completion of this work will yield a better understanding of these complex events and will produce therapeutic insights for epilepsy and neurodegeneration.

project_terms:
5'-AMP-activated protein kinase;Affect;Binding (Molecular Function);Biological Assay;CNS degeneration;Carbohydrates;Cardiac;Cells;Cessation of life;Complex;Comprehension;Crystallography;Deterioration;Deuterium;Disease;Energy Metabolism;Enzymes;Epilepsy;Event;Family suidae;Genes;Glucans;Glycogen;Glycogen (Starch) Synthase;Glycogen Debranching Enzyme;Grant;Human;Human body;Hydrogen;In Vitro;Knowledge;Lafora Disease;Life;Link;Mammalian Cell;Mass Spectrum Analysis;Metabolism;Modification;Molecular;Monitor;Motor;Mutation;Myocardium;Myoclonic Epilepsies;Nerve Degeneration;Neurodegenerative Disorders;Neurologic;Parkinson Disease;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphorylation Site;Post-Translational Protein Processing;Progressive Myoclonic Epilepsies;Proteins;Regulation;Review Literature;Role;Seizures;Series;Signal Transduction;Single Seizures;Skeletal muscle structure;Specificity;Structure;Symptoms;Therapeutic;Tonic - clonic seizures;Ubiquitin;Ubiquitination;Water;Wolff-Parkinson-White Syndrome;Wolves;Work;base;design;glycogen metabolism;in vivo;insight;loss of function;loss of function mutation;member;mouse model;novel;overexpression;protein protein interaction;public health relevance;research study;sensor;tissue/cell culture;ubiquitin-protein ligase

public_health_relevance:
The focus of our work is to determine how loss of function of either of two proteins leads to thefatal neurodegenerative epilepsy called Lafora disease. Our proposal is built on our past discoveriesand uses complementary approaches to advance our understanding of the intertwined events of cellmetabolism neurodegeneration and epilepsy. Completion of this work will yield a bettercomprehension of these complex events and will produce therapeutic insights for epilepsy andneurodegeneration.


application_id: 8642154
project_number: 5R21CA173609-02
project_title: Targeting solid-tumor vasculature with coencapsulated arsenic- and platinum-based
administering_ic: NCI
award_notice_date: 2014-06-04
opportunity_number: PA-11-149
application_type: 5
activity_code: R21
ic: CA
serial_number: 173609
program_official: PRASANNA, PAT G
project_start_date: 2013-04-01
project_end_date: 2016-03-31
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 9918599
contact_pi: UPRETI, MEENAKSHI
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):  A major challenge the application of nanotechnology to cancer therapy is targeting of the nanomaterials specifically to the tumor itself. Although both
arsenic and platinum based drugs used in cancer therapy have displayed significant response in certain tumor types their therapeutic applications are limited by serious systemic toxicities limited bioavailability to the tumor site and development of drug resistance by tumor cells. We propose to address these challenges by preferentially targeting an arsenic-cisplatin nanoparticulate formulation encapsulated in liposomal vesicles called "nanobins" to the tumor site using the anti-angiogenic peptide anginex. This peptide specifically binds to galectin-1 a tumor endothelial cell specific antigen that is induced in response to radiation. The novel nanobin formulation developed by our collaborator (O'Halloran) to be used in the present project utilizes a gradient of cisplatin ions to facilitate stable coencapsulation of Arsenic trioxide. The
inclusion of the arsenic compound in the nanovesicle is expected to make the tumor targeted delivery more active against solid tumors by causing vascular damage and by overcoming resistance of tumor cells to conventional chemotherapy. The 33 amino acid small peptide anginex will be the galectin-1 targeting agent to deliver arsenic and platinum drugs co-encapsulated in a single liposomal vesicle to the irradiated tumor site. It is expected that targeted delivery of liposomal cytotoxic payloads like the dual-drug nanobins via the anginex peptide to radiation-induced galectin-1 in the tumor-vasculature will increase the therapeutic ratio of such novel strategies developed against solid tumors.

project_terms:
Acute;Address;Adverse effects;Amino Acids;Angiogenic Peptides;Antigens;Arsenic;Arsenic Trioxide;Arsenicals;Binding (Molecular Function);Biodistribution;Biological Availability;Blood Circulation;Blood Vessels;Cell Death;Cisplatin;Coculture Techniques;Combined Modality Therapy;Comorbidity;Development;Dose;Drug Delivery Systems;Drug Exposure;Drug Formulations;Drug resistance;Drug usage;Encapsulated;Endothelial Cells;Environment;FDA approved;Fluorescence Microscopy;Galectin 1;Goals;Half-Life;In Vitro;Ionizing radiation;Ions;Label;Ligands;Limb structure;Liposomes;Localized Malignant Neoplasm;Location;MEKs;Malignant Neoplasms;Mammary Neoplasms;Modality;Modeling;Monitor;Mus;Nanotechnology;Nude Mice;Peptides;Pharmaceutical Preparations;Pharmacotherapy;Pilot Projects;Platinum;Positron-Emission Tomography;Radiation;Radiation therapy;Research;Resistance;Role;Signal Transduction;Site;Solid Neoplasm;Structure;Technology;Testing;Therapeutic;Toxic effect;Translating;Treatment Efficacy;Tumor-Associated Vasculature;Up-Regulation (Physiology);Vascular Endothelial Cell;Vesicle;angiogenesis;base;cancer therapy;carbohydrate binding protein;chemotherapy;cytotoxic;cytotoxicity;effective therapy;fluorescence imaging;improved;in vivo;irradiation;nanomaterials;nanomedicine;nanoparticle;nanoparticulate;nanosized;nanovesicle;neoplastic cell;novel;novel strategies;overexpression;pre-clinical;public health relevance;response;standard care;targeted delivery;treatment response;tumor;tumor microenvironment;uptake

public_health_relevance:
Preferential target and delivery to the tumor site is capable of overcoming the limitation of acute systemic cytotoxicity and short half-life in circulation of therapeutic payloads. Targeted nanoparticle delivery of therapeutic molecules has the potential to provide safer and more effective therapies for cancer applications. Our central hypothesis is that dual drug delivery of Arsenic and cisplatin based nanoparticles via anginex targeted to radiation-induced tumor-vasculature associated Galectin-1 will improve the therapeutic potential for combination therapy strategies against solid tumors. The development of targeting ligands such as anginex for conjugation to drug loaded nanoparticles will serve as a model for highly selective radiation therapy-amplified drug delivery.


application_id: 8641690
project_number: 5R01ES017244-04
project_title: Prevention of UV-induced carcinogenesis by cyanidin-3-glucoside
administering_ic: NIEHS
award_notice_date: 2014-03-26
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: ES
serial_number: 017244
program_official: REINLIB, LESLIE J
project_start_date: 2011-08-01
project_end_date: 2016-03-31
study_section: Special Emphasis Panel[ZRG1-OTC-N(03)M]
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): Epidemiological clinical and laboratory studies have implicated that ultraviolet radiation (UV) is a complete environmental carcinogen and that repeated exposures can lead to the development of melanoma and nonmelanoma skin cancers. In addition to sunscreens chemoprevention of skin cancer by natural non-toxic compounds is suggested as an effective strategy to prevent the incidence of skin cancer. Our in vitro and in vivo studies on cyanidin-3-glucoside (C3G) a compound found in blackberries and other foods show that this compound is able to inhibit NF-:B AP-1 COX2 and TNF1 activation/expression neoplastic transformation cancer cell migration and invasion and induction of apoptosis in HL60 cells. C3G also functions as an antioxidant by inhibiting the generation of reactive oxygen species and inducing antioxidant-regulative transcription factors. These preliminary studies indicate that C3G may function as a potential chemopreventive and chemotherapeutic agent. The overall hypothesis of this application is that C3G functions as an antioxidant and inhibits oxidative stress activation of transcription factors and inflammatory signaling proteins leading to protection against UVB-induced carcinogenesis. Specific Aim 1. In vitro and in vivo investigation of antioxidant properties of C3G. Electron spin resonance (ESR) spin trapping will be used to determine the reaction rates of C3G toward hydroxyl (7OH) and superoxide (O27-) radicals using Fenton reaction (Fe(II) + H2O2) and xanthine/xanthine oxidase as sources of these free radicals in a non-cellular system and to investigate antioxidant activities against UVB-induced 7OH and O27- radicals in a cellular system. Low frequency (in vivo) ESR will be also used to study antioxidant activities of C3G against UVB-generated O27- and 7OH radicals in the skin of SKH-1 hairless mice. Specific Aim 2. In vivo investigation of the effects of C3G on UVB-induced oxidative stress and activation of oxidative stress sensitive transcription factors. We will investigate the effects of C3G on UVB-induced lipid peroxidation protein oxidation and oxidative DNA damage in KSH mice. We will also study the effects of C3G on UVB-induced activation of activation protein (AP)-1 nuclear factor (NF)-:B and nuclear factor of activated T cells (NAFT) in transgenic mice. Specific Aim 3. Investigate the effects of C3G on UVB-induced inflammatory mediators. These inflammatory mediators include infiltrating leukocytes and myeloperoxidase (MPO) COX-2 PGE2 and several pro-inflammatory cytokines TNF-1 IL-2 and IL-6. Specific Aim 4. Investigation of the effects of C3G on UVB-induced tumorigenesis and early biomarkers. These markers include changes in thymine-positive cells proliferative cell nuclear antigen terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and apoptotic cells together with a change in p53 and p21/cip1- positive cell population in epidermis. These studies will provide a mechanistic rationale for an early on C3G efficacy in skin cancer prevention.

project_terms:
Acetates;Animal Model;Anthocyanins;Anthracenes;Antioxidants;Apoptosis;Apoptotic;Berry;Biological Markers;Cabbage - dietary;Cells;Chemicals;Chemoprevention;Chemopreventive Agent;Chronic;Chronic Disease;Clinical Research;Complement Factor B;Consumption;DNA Nucleotidylexotransferase;Development;Diet;Dinoprostone;EGF gene;Electron Spin Resonance Spectroscopy;Environmental Carcinogens;Enzymes;Epidemiologic Studies;Epidermis;Epigallocatechin Gallate;Exhibits;Family;Food;Free Radicals;Frequencies (time pattern);Generations;Glucosides;Grapes;Green tea (dietary);Growth Factor;HL-60 Cells;Human;Hydrogen Peroxide;Hydroxyl Radical;In Vitro;Inbred HRS Mice;Incidence;Individual;Induction of Apoptosis;Inflammation;Inflammation Mediators;Inflammatory;Interleukin-2;Interleukin-6;Investigation;Label;Laboratories;Laboratory Study;Lead;Leukocytes;Link;Lipid Peroxidation;MAP Kinase Gene;Malignant Neoplasms;Mediating;Mediator of activation protein;Methods;Micronutrients;Milk Thistle;Minerals;Mus;Neoplastic Cell Transformation;Non-Malignant;Nuclear;Nuclear Antigens;Oxidative Stress;PTGS2 gene;Peroxidases;Phytochemical;Pigments;Plants;Population;Prevention;Preventive;Property;Prostaglandins;Proteins;Reaction;Reactive Oxygen Species;Signal Pathway;Signaling Protein;Skin;Skin Cancer;Skin Carcinoma;Source;Spin Trapping;Stimulus;Sunlight;Sunscreening Agents;Superoxides;System;TNF gene;Therapeutic;Thymine;Topical application;Transgenic Mice;Tumor Necrosis Factor-alpha;UVB induced;Ultraviolet B Radiation;Ultraviolet Rays;Vitamins;Xanthine Oxidase;Xanthines;ascorbate;base;cancer cell;carcinogenesis;cell motility;cell transformation;chemotherapeutic agent;cyclooxygenase 2;cytokine;fruits and vegetables;high risk;in vivo;melanoma;member;nuclear factors of activated T-cells;oxidation;oxidative DNA damage;prevent;protein activation;public health medicine (field);public health relevance;reaction rate;silibinin;skin cancer prevention;transcription factor;tumorigenesis

public_health_relevance:
The incidence of UV-induced skin cancer is a major public health concern. Present study attempts to identify cyanidin-3-glucoside a plant-derived compound as a mechanism-based preventive agent against UV-induced skin cancers.


application_id: 8641352
project_number: 5K01DK096042-02
project_title: Enhancement of NAFLD risk by vinyl chloride: interaction of gut-liver-adipose axi
administering_ic: NIDDK
award_notice_date: 2014-03-04
opportunity_number: PAR-12-020
application_type: 5
activity_code: K01
ic: DK
serial_number: 096042
program_official: PODSKALNY, JUDITH M,
project_start_date: 2013-04-01
project_end_date: 2018-03-31
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 10438358
contact_pi: BEIER, JULIANE I
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Accounting;Adipocytes;Adipose tissue;Attenuated;Caco-2 Cells;Chemicals;Data;Development;Diet;Dietary Fatty Acid;Disease;Dose;Endotoxemia;Environmental Exposure;Environmental Pollutants;Fatty Liver;Fatty acid glycerol esters;Gastrointestinal tract structure;Health;Hepatocyte;Human;In Vitro;Individual;Inflammatory;Inflammatory Response;Intestines;Lactobacillus casei rhamnosus;Liver;Liver diseases;Mediating;Mediator of activation protein;Messenger RNA;Metabolic;Modeling;Mus;Nutrient;Obesity;Permeability;Play;Population;Predisposition;Probiotics;Process;Production;Proteins;Relative (related person);Relative Risks;Risk;Risk Factors;Role;SAPK;Safety;Signal Transduction;Stimulus;Supplementation;Surface;Testing;Tight Junctions;Toxic effect;Toxin;Treatment Protocols;United States;Vinyl Chloride;Work;cytokine;cytotoxic;disorder risk;feeding;gut microbiota;improved;in vivo;in vivo Model;intestinal epithelium;liver injury;macrophage;microorganism;non-alcoholic fatty liver;nonalcoholic steatohepatitis;novel;protective effect;public health relevance;response;toxicant

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


application_id: 8640999
project_number: 5R21NS079960-02
project_title: Neuronal Regeneration of Stroked Brain with Perlecan Domain V
administering_ic: NINDS
award_notice_date: 2014-03-24
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: NS
serial_number: 079960
program_official: BOSETTI, FRANCESCA
project_start_date: 2013-04-01
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: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Stroke is a leading cause of death and significant morbidity. Unfortunately there is still a critical need for new ischemic stroke therapies to reduc this significant societal burden as tissue plasminogen activator (t-PA) the only FDA approved ischemic stroke pharmaceutical therapy has a limited therapeutic window and engenders significant risk. Furthermore experimental therapies based solely on neuroprotection have largely failed to translate to human stroke. Instead better therapies may emerge from an innovative approach based on improved understanding of the brain's own post-stroke repair mechanisms - identifying and exploiting endogenous agents that are both neuroprotective and promote brain repair. To this end we have recently determined that the c-terminal fragment of the extracellular matrix component perlecan termed domain V (DV) is persistently generated after ischemic stroke. When exogenously administered as a recombinant protein DV is both neuroprotective and angiogenic (a reparative process) culminating in the restoration of stroke affected motor function in rats and mice. Preliminary data now suggest that DV increases neuronal repopulation of the infarcted and ischemic areas in vivo and enhances neurite extension and connectivity in vitro. Furthermore we have recently demonstrated that DV treatment suppresses glial scar formation in the ischemic core thereby alleviating a potentially significant barrier to neuronal regeneration. Therefore we hypothesize that post-stroke administered DV will provide a lasting stable recovery in part by increasing the amount of new neurons that reach and establish themselves at the injury site. To that end we now propose the following specific aims: 1) Determine the effect of long-term DV stroke therapy on neuronal repopulation and connectivity in the infarcted and ischemic areas 2) Determine in mechanistic detail the potential of DV to influence neurite extension in vitro. For specific aim 1 stroke willbe induced by transient focal cortical ischemia using the tandem ipsilateral common carotid and middle cerebral artery occlusion model in 3-month-old male C57/Bl6 mice. BrdU injection followed by motor tests and immunohistochemistry of the infarcted and ischemic areas for BrdU and neuronal markers 4-8 weeks post-stroke will be performed to determine if DV initially administered 7 days after stroke to minimize the influence of its neuroprotective effect provides stable recovery and neuronal repopulation. Signs of animal illness will be monitored to assess potential adverse effects of long-term DV treatment. For specific aim 2 DV's effects on neurite extension and the potential role of the previously identified neuronal DV receptor alpha2beta1 integrin will be determined via neurite extension assays with wild-type or alpha2beta1 null adult mouse neurospheres. The successful completion of these studies will be significant by providing new insight into the brain's response to ischemic injury and by further supporting our long-term goal of establishing DV as a novel stroke therapy for humans.

project_terms:
Adult;Adverse effects;Affect;Alteplase;Animal Model;Animals;Area;Binding (Molecular Function);Biological Assay;Blocking Antibodies;Brain;Brain Injuries;Bromodeoxyuridine;Cause of Death;Cerebral Ischemia;Cicatrix;Data;Enhancers;Extracellular Matrix;FDA approved;Generations;Goals;Growth;Human;Immunohistochemistry;In Vitro;Infarction;Injection of therapeutic agent;Injury;Integrin alpha2beta1;Integrins;Investigational Therapies;Ipsilateral;Ischemia;Ischemic Stroke;Knockout Mice;Knowledge;Label;Length;Life;Link;Long-Term Effects;Longitudinal Studies;Measurement;Middle Cerebral Artery Occlusion;Modeling;Monitor;Morbidity - disease rate;Motor;Mus;Natural regeneration;Nerve Regeneration;Neurites;Neurons;Neuroprotective Agents;Neurotransmitters;Outcome;Pharmacologic Substance;Process;Protein Fragment;Rattus;Recombinant Proteins;Recovery;Risk;Rodent;Role;Site;Synapses;Tertiary Protein Structure;Testing;Therapeutic;Time;Translating;Weight;angiogenesis;arm;base;brain repair;brain tissue;cell type;cellular imaging;improved;in vivo;injured;innovation;insight;male;nerve stem cell;neuroprotection;novel;perlecan;post stroke;public health relevance;receptor;repaired;response;restoration;stroke;stroke recovery;stroke therapy;tissue regeneration

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Stroke is a leading cause of death and significant morbidity 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 self-repair of injured brain tissue. Therefore we propose to study the long-term benefits of a stroke- generated protein fragment in a stroke animal model with the goal of developing a new type of human stroke therapy.


application_id: 8640985
project_number: 5R01NS065842-07
project_title: Perlecan Domain V is a Novel Promoter of Brain Repair after Stroke
administering_ic: NINDS
award_notice_date: 2014-03-24
opportunity_number: PA-08-099
application_type: 5
activity_code: R01
ic: NS
serial_number: 065842
program_official: KOENIG, JAMES I
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.

project_terms:
Affect;Affinity Chromatography;Animal Model;Antibodies;Binding (Molecular Function);Biological Assay;Blood capillaries;Brain;Brain Injuries;Brain-Derived Neurotrophic Factor;C-terminal;Cause of Death;Cell Proliferation;Cell secretion;Coculture Techniques;Data;Endothelial Cells;Extracellular Matrix;Generations;Goals;Hour;Human;In Vitro;Integrins;Investigation;Knowledge;Mediating;Middle Cerebral Artery Occlusion;Modeling;Mus;Mutant Strains Mice;Neurons;Neurotrophic Tyrosine Kinase Receptor Type 2;Outcome;Peptide Hydrolases;Process;Promotor (Genetics);Protein Fragment;Proteins;Research Priority;Role;Signal Pathway;Signal Transduction Pathway;Surface Plasmon Resonance;Testing;Therapeutic;Tube;acute stroke;angiogenesis;base;brain repair;brain tissue;capillary;disability;empowered;improved;in vivo;injured;innovation;migration;neurogenesis;novel;perlecan;post stroke;precursor cell;public health relevance;repaired;research study;stroke;stroke rehabilitation;stroke therapy

public_health_relevance:
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.


application_id: 8640219
project_number: 5R01NS077284-04
project_title: Role of FUS in ALS
administering_ic: NINDS
award_notice_date: 2014-04-25
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: NS
serial_number: 077284
program_official: GUBITZ, AMELIE
project_start_date: 2011-08-15
project_end_date: 2017-04-30
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD-M]
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS also known as Lou Gehrig's disease) is a progressive and fatal neurodegenerative disease. A general symptom of ALS is muscle weakness and wasting triggered by denervation at neuromuscular junctions. The majority of ALS cases are sporadic and approximately 10% are familial. Several ALS genes have been identified as their mutation can lead to familial ALS including two genes encoding RNA processing proteins TDP-43 and fused in sarcoma/translocated in liposarcoma (FUS/TLS). FUS is a ubiquitously expressed multi-domain RNA-binding protein. In neurons and glial cells FUS is almost exclusively localized to the nucleus but is also reported to transport mRNA for local translation in dendrites in neurons. In addition FUS plays a role in a variety of processes including nucleocytoplasmic shuttling of mRNA transcriptional regulation and mRNA splicing. However little is known regarding how FUS mutations cause motor neuron degeneration and ALS which is the focus of this study.  We recently published that the C-terminus of FUS where the ALS-causing mutations are clustered functions as an effective nuclear localization sequence (NLS). Our newly generated data suggest that a FUS- interacting protein Gemin3 plays a critical role in the perturbations caused by FUS mutations. Gemin3 can be sequestered by ALS mutant FUS which causes reduced Gemin3-positive nuclear structures (Gems) decreased assembly of snRNPs and attenuated spliceosome activity. The Drosophila model we established showed motor function deficiency when FUS was over-expressed in motor neurons. Interestingly Gemin3 was also reported to be required for larval motor function in Drosophila. Moreover we generated FUS/Gemin3 double transgenic flies and showed that expression of Gemin3 rescued the phenotypes of FUS transgenic flies. We thus hypothesize that the ALS-related FUS mutants or WT FUS with deregulated over-expression can accumulate in cytoplasm and sequester Gemin3 which results in decreased assembly of snRNPs in cytoplasm and compromised spliceosome function in the nucleus. To test the central hypothesis three specific aims have been designed to determine the role of FUS in ALS.  Aim 1 is to understand the regulation of FUS subcellular localization by the localization sequence elements within FUS as well as by its RNA binding ability. In Aim 2 we will first determine the molecular mechanism how FUS and Gemin 3 interact. We will further characterize how FUS mutations disturb Gemin 3- mediated snRNP assembly and spliceosome activity. Aim 3 will test the molecular mechanisms defined in Aims 1 and 2 using the Drosophila model. We will first determine whether motor neuron death and neuromuscular denervation are prominent in the transgenic flies with motor neuron-specific FUS expression. FUS-mediated Gemin3 sequestering and subsequent spliceosome changes will be especially tested in flies since Gemin3 over-expression rescued the motor function deficit phenotype caused by FUS. Furthermore the significance of FUS subcellular localization and RNA binding in producing toxicity in motor neurons will be investigated. Lastly we will carry out RNA-Seq experiment to determine the FUS-mediated splicing alterations.  This project will utilize the combination of cellular and Drosophila models to investigate the FUS- mediated ALS etiology. The findings are expected to provide critical insights into the mechanisms by which FUS mutations perturb the RNA processing pathways and ultimately lead to the disease.

project_terms:
Amyotrophic Lateral Sclerosis;Attenuated;C-terminal;Cell Nucleus;Cells;Cessation of life;Collaborations;Complex;Cytoplasm;DNA Repair;Data;Dendrites;Denervation;Disease;Drosophila genus;Elements;Etiology;Familial Amyotrophic Lateral Sclerosis;Future;Gemin3;Genes;Knowledge;Lead;Locomotion;Mediating;Messenger RNA;Modeling;Molecular;Motor;Motor Neurons;Muscle Weakness;Mutation;Names;Neurodegenerative Disorders;Neuroglia;Neuromuscular Junction;Neurons;Nuclear;Nuclear Structure;Outcome;Pathology;Pathway interactions;Phenotype;Physiological;Play;Process;Proteins;Proteomics;Publishing;RNA Binding;RNA Processing;RNA Splicing;RNA-Binding Proteins;Reagent;Regulation;Reporting;Research;Role;Small Nuclear Ribonucleoproteins;Spliceosome Assembly Pathway;Spliceosomes;Symptoms;Testing;Toxic effect;Transcriptional Regulation;Transgenic Organisms;Translations;design;fly;in vivo;insight;interest;liposarcoma;mRNA Precursor;motor neuron degeneration;mutant;nerve supply;neuromuscular;novel;nucleocytoplasmic transport;protein TDP-43;research study;sarcoma;tool;transcriptome sequencing;wasting

public_health_relevance:
Several amyotrophic lateral sclerosis (ALS) genes have been identified as their mutation can lead to familial ALS including two genes encoding RNA processing proteins TDP-43 and fused in sarcoma (FUS). The major challenge in the field is that little is known how FUS mutations cause motor neuron degeneration in ALS. We propose to test the hypothesis that the ALS-related FUS mutants or WT FUS with deregulated over- expression can accumulate in cytoplasm and sequester Gemin3 which results in decreased assembly of snRNPs in cytoplasm and compromised spliceosome function in the nucleus. To test the central hypothesis three specific aims have been designed to determine the role of FUS in ALS. We have produced novel preliminary data developed unique tools generated nearly all critical reagents and established collaborations with leading experts. We propose to use the combination of cellular and Drosophila models to test the hypothesis. The findings are expected to provide critical insights into the mechanisms by which FUS mutations perturb the RNA processing pathways and ultimately lead to the disease. The knowledge generated in the proposed research will also provide much-needed future direction for developing ALS treatment.


application_id: 8640205
project_number: 5K23NR013480-03
project_title: Cognitive Therapy for Depressive Symptoms in Hospitalized Patients with Heart Fai
administering_ic: NINR
award_notice_date: 2014-03-12
opportunity_number: PA-11-194
application_type: 5
activity_code: K23
ic: NR
serial_number: 013480
program_official: HUSS, KAREN
project_start_date: 2012-04-01
project_end_date: 2015-06-30
study_section: ZNR1-REV-W(09)
contact_pi_person_id: 8622756
contact_pi: DEKKER, REBECCA
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This Mentored Patient-Oriented Research Career Development Award will enhance my ability to achieve my long-term career goal of becoming an independent cardiovascular nurse researcher with expertise in testing psychological interventions to improve biobehavioral outcomes of patients with heart failure (HF). One third of hospitalized patients with HF experience major depressive disorder and up to half of patients experience depressive symptoms. Patients with HF and depressive symptoms have worse health-related quality of life and are twice as likely to be rehospitalized or die; thus there is acritical need to test interventions for the treatment of depressive symptoms in this population. Inthis project I will receive formal training and mentorship in cognitive therapy and the conduct ofclinical trials. I will use the skills and competencies I gain to complete the proposed randomizedcontrolled pilot study which will test the feasibility and efficacy of nurse delivered cognitive therapy for depressive symptoms in patients who are hospitalized with HF. The intervention is an innovative streamlined approach to cognitive therapy consisting of one brief 30-minute session initiated in-person during hospitalization and four 30-minute sessions delivered via phone after discharge. A total of 36 patients with HF who are hospitalized and experiencing moderate to severe depressive symptoms will be randomized to receive either the cognitive therapy intervention or usual care. Data demonstrating feasibility and efficacy of this interventio will be used to develop an R01 application to conduct a larger randomized controlled trial. This study will fill an important gap in the evidence base for depression treatment in patients with HF by demonstrating the feasibility and efficacy of a nurse-delivered cognitive therapy intervention for hospitalized patients with HF. This contribution is significant because interventions designed to treat depressive symptoms may decrease the risk of hospital readmission and improve health-related quality of life among patients with HF who have depressive symptoms.

project_terms:
Address;Adherence (attribute);Antidepressive Agents;Care given by nurses;Cessation of life;Cognitive;Cognitive Therapy;Conduct Clinical Trials;Data;Discipline of Nursing;Dyspnea;Fatigue;Goals;Health;Health Care Costs;Heart;Heart failure;Hospital Readmission;Hospitalization;Hospitals;Human;Intervention;Knowledge;Lead;Length;Long-Term Effects;Major Depressive Disorder;Mental Depression;Mental Health;Mentored Patient-Oriented Research Career Development Award;Mentorship;Mission;Morbidity - disease rate;Mortality Vital Statistics;Nurses;Outcome;Participant;Patients;Persons;Pilot Projects;Population;Psychological Tests;Quality of life;Randomized;Randomized Controlled Trials;Recruitment Activity;Research;Research Personnel;Research Project Grants;Risk;Symptoms;Techniques;Telephone;Testing;Time;Training;Vulnerable Populations;biobehavior;cardiovascular nursing;career;cost effective;depressive symptoms;design;evidence base;experience;group intervention;health related quality of life;high risk;improved;innovation;nursing intervention;post intervention;programs;psychologic;public health medicine (field);skills;symptom management;therapy design;treatment as usual;treatment strategy

public_health_relevance:
People with heart failure often experience depressive symptoms which lead to poor quality of life and an increased risk of death and hospitalization. The intervention for depressive symptoms proposed in this project is designed to be delivered by nurses to a large number of patients. The knowledge gained from this project will help fulfill the need for new treatment strategies for depressive symptoms in people with heart failure that subsequently improve quality of life lower risk of rehospitalization and decrease health care costs.


application_id: 8640178
project_number: 5R01EB012135-05
project_title: Phi29 Motor Nanopore for Single Molecule Sensing
administering_ic: NIBIB
award_notice_date: 2014-03-27
opportunity_number: PA-08-052
application_type: 5
activity_code: R01
ic: EB
serial_number: 012135
program_official: ATANASIJEVIC, TATJANA
project_start_date: 2011-04-01
project_end_date: 2016-01-16
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 1878565
contact_pi: GUO, PEIXUAN
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): All linear double-stranded (ds) DNA viruses package their genome into a preformed procapsid via an ATP-driving motor. The central component of the phi29 DNA-packaging motor is the portal connector composed of twelve copies of the protein gp10 which form a dodecamer channel that acts as a pathway for the translocation of dsDNA. With a diameter of 3.6 nm at its narrowest end it is one of the largest among typical channel proteins that have been incorporated into lipid membranes. Explicit engineering and pore modifications of the phi29 connector are possible due to its available crystal structure thus inspiring the use of such a system as a module in biomedical applications or nanodevices.  The short-term objective of this proposal is to demonstrate the utility of the lipid-embedded channel of the phi29 DNA packaging motor as a highly sensitive device for capture and fingerprinting of chemicals and biopolymers in real time at single molecule resolution using electrophysiological assays. The connector will be reengineered for added functionality and various approaches will be undertaken to modulate the dimensions of the pore. Alteration of the charge distributions will be made by mutagenesis in a controlled fashion to ensure optimal sensing. The channel will be designed to act as a stochastic biosensor and functionalized with recognition groups to bind various analytes of interest. Methods to increase the stability and lifetime of the lipid/connector complex will be developed to facilitate high throughput electrophysiological measurement of a single pore with provisions for rapid and efficient sample and buffer exchange. The long-term objective is to develop the channel into a robust sensing device for detecting biomolecules or chemicals at extremely low concentrations in the presence of many contaminants for a wide range of applications in biotechnology earlier disease diagnosis environmental surveillance custom quarantine drug testing and national security.    PUBLIC HEALTH RELEVANCE: The membrane embedded nanopore of bacteriophage phi29 biomotor will be reengineered characterized and developed into a single pore sensor for detection of biomolecules and chemicals. The combination of capture and fingerprinting with multiple identification parameters for single molecule detection in real time will make the system highly sensitive to detect molecules at extremely low concentrations in the presence of many contaminants.

project_terms:
Affinity;Ala-Trp-Arg-His-Pro-Gln-Phe-Gly-Gly;Antibodies;Antigens;Area;Automobile Driving;Bacteriophages;Binding (Molecular Function);Biological;Biological Assay;Biological Models;Biopolymers;Biosensor;Biotechnology;Biotin;Buffers;Caliber;Cells;Characteristics;Charge;Chemicals;Complex;Custom;Cysteine;DNA;DNA Packaging;Data;Detection;Devices;Dimensions;Disulfide Linkage;Double Stranded DNA Virus;Engineering;Ensure;Event;Exhibits;Fingerprint;Frequencies (time pattern);Genome;Goals;Housing;Infection;Ions;Kinetics;Length;Life;Ligands;Lipid Bilayers;Lipids;Maleimides;Measurement;Membrane;Membrane Lipids;Methods;Modification;Molecular Conformation;Monitor;Motor;Mutagenesis;Nanotechnology;National Security;Nature;Nickel;Pathway interactions;Pattern;Peptides;Phage Display;Property;Proteins;Quarantine;RNA;RNA-Protein Interaction;Reaction;Regulation;Resolution;Sampling;Shapes;Signal Transduction;Streptavidin;Structure;System;Time;Transportation;Virion;base;chemical fingerprinting;design;disease diagnosis;drug testing;ds-DNA;instrument;interest;macromolecule;nanodevice;nanopore;novel;patch clamp;protein protein interaction;proteoliposomes;public health relevance;research study;sensor;single molecule;thioester;time use

public_health_relevance:
PROJECT NARRATIVE The membrane embedded nanopore of bacteriophage phi29 biomotor will be reengineered characterizedand developed into a single pore sensor for detection of biomolecules and chemicals. The combination ofcapture and fingerprinting with multiple identification parameters for single molecule detection in real time willmake the system highly sensitive to detect molecules at extremely low concentrations in the presence of manycontaminants.


application_id: 8639973
project_number: 5F32HL116186-02
project_title: Nutrient excess alters resolution of inflammation in diabetes and obesity
administering_ic: NHLBI
award_notice_date: 2014-02-26
opportunity_number: PA-11-113
application_type: 5
activity_code: F32
ic: HL
serial_number: 116186
program_official: MEADOWS, TAWANNA
project_start_date: 2013-03-01
project_end_date: 2014-07-31
study_section: Special Emphasis Panel[ZRG1-F06-T(20)L]
contact_pi_person_id: 11169883
contact_pi: HELLMANN, JASON L
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall objective of this study is to determine whether systemic inflammation in diabetes and obesity persists because of a failure of endogenous pathways that normally resolve inflammation. Our working hypothesis is that chronic inflammation in T2D and obesity is sustained in part due to a deficiency in specialized pro-resolving lipid mediator (SPM)-stimulated resolution which impairs wound healing. To test this hypothesis we will assess the development and resolution of acute inflammation in wild type and obese-diabetic mice and determine how SPM pathways are affected by nutrient excess. We will also perform a targeted lipidomic analysis of adipose tissue and plasma obtained from obese diabetic and non-diabetic humans undergoing bariatric surgery to elucidate whether SPM biosynthesis is associated with inflammation and metabolic parameters. Utilizing these approaches we will be able to elucidate how diabetes impacts resolution of inflammation and determine how SPM pathways are modulated in obese and diabetic humans. Lastly to test the efficacy of SPM in treating clinically-relevant manifestations of diabetes we will determine whether promoting resolution will decrease inflammation and enhance wound healing in a rodent model of cutaneous wound healing. We expect that this project will generate new knowledge regarding the mechanisms that sustain chronic inflammation in T2D and move the field forward by testing the efficacy of SPM in preventing not just systemic insulin resistance bu also specific clinical manifestations of diabetes such as impaired wound healing. In addition these studies will determine the association between insulin resistance and SPM pathways in obese humans which has not been previously assessed. Completion of these translational studies will lead to a better understanding of the mechanisms that sustain chronic inflammation in obesity and diabetes; an understanding that will open up new avenues for exploring a novel set of therapies for attenuating inflammation and promoting wound healing in diabetic patients.

project_terms:
Acute;Adipose tissue;Affect;Anabolism;Animal Model;Anti-Inflammatory Agents;Anti-inflammatory;Apoptotic;Atherosclerosis;Attenuated;Blood Vessels;Cells;Centers for Disease Control and Prevention (U.S.);Chronic;Clinical;Cutaneous;Defect;Development;Diabetes Mellitus;Diabetic mouse;Diet;Epidemic;Event;Explosion;Failure (biologic function);Fibrosis;Healed;Homeostasis;Human;Hyperglycemia;Immune response;Impaired wound healing;Infection;Infiltration;Inflammation;Inflammatory;Injury;Insulin Resistance;Interruption;Intervention;Knowledge;Lead;Leukocytes;Liquid Chromatography;Measures;Mediating;Mediator of activation protein;Metabolic;Microbe;Molecular;Natural immunosuppression;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Obesity;Omega-3 Fatty Acids;Pathway interactions;Patients;Peritoneal;Phagocytes;Phagocytosis;Phase;Physiological;Plasma;Population;Process;Recurrence;Resolution;Retinal Diseases;Risk;Rodent Model;Testing;Time;Tissue Expansion;Tissues;Work;Wound Healing;Zymosan;bariatric surgery;base;clinical application;clinically relevant;db/db mouse;diabetic;diabetic patient;efficacy testing;healing;improved;insulin sensitivity;lipid mediator;liquid chromatography mass spectrometry;macrophage;microbial;non-diabetic;novel;novel therapeutics;peripheral blood;prevent;public health medicine (field);public health relevance;response;tandem mass spectrometry;tissue regeneration;tissue repair;translational study

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Results of this project will provide a new understanding of the mechanistic basis whereby diabetics suffer from delayed wound healing and chronic inflammation. These studies could lead to the development of new therapeutics aimed at resolving inflammation.


application_id: 8638993
project_number: 5R43NS083218-02
project_title: SYSTEM FOR AUTOMATED NONINVASIVE MONITORING OF MOUSE SLEEP AND BEHAVIOR
administering_ic: NINDS
award_notice_date: 2014-04-17
opportunity_number: PA-11-134
application_type: 5
activity_code: R43
ic: NS
serial_number: 083218
program_official: HE, JANET
project_start_date: 2013-04-01
project_end_date: 2015-03-31
study_section: Special Emphasis Panel[ZRG1-ETTN-K(10)B]
contact_pi_person_id: 11491614
contact_pi: O'HARA, BRUCE F
other_pis: SUNDERAM, SRIDHAR
congressional_district: 06
department: Unavailable
primary_duns: 964938455
primary_uei: D9DRUX8SM4V9
duns_number: 964938455
uei: D9DRUX8SM4V9
fips: US
organization_id: 10032136
organization_name: SIGNAL SOLUTIONS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The basic functions of sleep are still unknown. Abnormal sleep patterns can manifest as a variety of disorders-sleep apnea parasomnias REM (rapid eye movement sleep) behavioral disorder (RBD) narcolepsy-many of which are influenced by heredity. There is an increasing focus on characterizing mouse behaviors for genetic and drug studies. However discovering the genes responsible for sleep and related disorders requires time-consuming large-scale behavioral screening of phenotypes to correlate observed traits with genetics. Behavioral monitoring of mice is usually limited to actigraphic measurements such as video tracking wheel-running and photoelectric beam-breaking. Although many of these methods are noninvasive and have potential for high-throughput (HT) application they monitor mainly locomotor activity without providing information about sleep-wake state and sleep architecture which are important for investigating sleep disorders. The current gold standard for sleep analysis in mammals is electroencephalography (EEG) with electromyography (EMG). While EEG can be used to accurately determine sleep-wake state it is invasive and resource-intensive (surgery recovery etc.) which limits its application in large
scale genetic studies with rodents. EEG is therefore a critical barrier to the discovery of genes that promote sleep disorders. Signal Solutions LLC has developed a sensor cage environment for noninvasive HT behavioral monitoring that is being used by many prominent research groups to identify genes responsible for different traits related to sleep and circadian rhythms. The system is based on analysis of the signal generated by a pressure- sensitive piezoelectric sensor attached to the cage floor and can already discriminate sleep from wakefulness with high accuracy and track changes in respiratory effort when the animal is relatively inactive. The Sunderam Lab at the University of Kentucky has used Signal Solutions' "piezo" system to develop techniques and obtain preliminary data suggesting that pressure changes associated with respiratory effort may distinguish REM and non-REM (NREM) stages of sleep as verified by simultaneous EEG/EMG recordings. The specific aims of this application are to determine whether the piezo system can noninvasively: 1. Discriminate sleep-wake state (sleep/wake REM/NREM) and behavior within wake (e.g. quiet vs. active high activity feeding grooming) at a level comparable to EEG/EMG by classifying piezo signal features; 2. Identify outliers in a cohort and differentiate strains of mice with known sleep differences on the basis of specific sleep traits (percent time in each state mean bout frequency and duration sleep-onset REM); and 3. Develop the capability to apply and quantify responses to sensory stimulation for selective sleep restriction and startle reflex measurement. The purpose of this investigation is to
integrate and test these additional capabilities in the piezo system. The envisioned end product is a sensor cage and software interface for high-throughput monitoring of sleep- wake state and behavior in small animals (e.g. KO mice QTL analyses) to identify genetic factors responsible for sleep/circadian disorders as well as behavioral effects of pharmacological manipulation sensory stimulation or neural injury (e.g. traumatic brain injury epilepsy). This system will be
particularly advantageous for prescreening potentially interesting phenotypes and reserving invasive EEG analysis for further confirmation. The current system for classifying sleep vs. wake is essentially as good as EEG/EMG; REM/NREM would be extremely valuable as a first pass screen. Medical targets of interest are sleep/circadian disorders sleep apnea obesity/diabetes REM/NREM sleep deprivation and stress among others. Potential clients include academic research labs as well as industrial labs interested in behavioral monitoring on a large scale (e.g. drug screening) and upgrades to existing users.

project_terms:
Affect;Animal Experimentation;Animals;Anxiety;Behavior;Behavior Disorders;Behavior Therapy;Behavior assessment;Behavioral;Behavioral Genetics;Behavioral Research;Benchmarking;Brain;Characteristics;Circadian Rhythm Sleep Disorders;Circadian Rhythms;Classification;Client;Cognitive;Computer software;Confidentiality;Data;Detection;Diabetes Mellitus;Discrimination (Psychology);Disease;Electroencephalography;Electromyography;Environment;Epilepsy;Evaluation;Event;Feedback;Floor;Frequencies (time pattern);Genes;Genetic;Genetic Screening;Goals;Gold;Government;Grooming;Health;Heredity;Home environment;Injury;Investigation;Kentucky;Letters;Mammals;Measurement;Medical;Mental Depression;Methodology;Methods;Monitor;Motor Activity;Motor Seizures;Mouse Strains;Mus;Narcolepsy;Neurosciences;Obesity;Operative Surgical Procedures;Outcome;Pattern;Performance;Persons;Pharmaceutical Preparations;Phase;Phenotype;Play;Polysomnography;Preclinical Drug Evaluation;Protocols documentation;Quantitative Trait Loci;REM Sleep;REM Sleep Parasomnias;Recovery;Reflex action;Research;Resources;Rodent;Role;Running;Sensory;Signal Transduction;Sleep;Sleep Apnea Syndromes;Sleep Architecture;Sleep Deprivation;Sleep Disorders;Sleep Stages;Small Business Innovation Research Grant;Solutions;Stress;System;Techniques;Technology;Testing;Time;Traumatic Brain Injury;Universities;Wakefulness;actigraphy;awake;base;brain research;cohort;data acquisition;feeding;gene discovery;high throughput analysis;high throughput screening;interest;nerve injury;nervous system disorder;neuropsychiatry;non rapid eye movement;novel;pressure;programs;prototype;public health relevance;respiratory;response;screening;sensor;sleep onset;software development;somatosensory;success;tool;trait

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Discovery of genes that play a role in sleep and circadian rhythm disorders requires extensive screening of behavior usually in mice preferably with invasive and resource-intensive brain signal (EEG) recordings to score sleep stage (REM NREM) and wake behavior. The goal of this research is to develop and validate a methodology for using a noninvasive pressure-sensitive piezoelectric ("piezo") sensor platform to distinguish different stages of sleep and behavior without the need for EEG. This would make large-scale behavioral screening feasible and limit the need for EEG verification to only the most interesting phenotypes thus identified. Beyond the ability to stage sleep and behavior a novel method is proposed here to selectively restrict sleep using sensory stimulation whenever a particular event or stage of sleep is detected from the piezo signal. This method if validated will be helped us analyze the effects of restriction of total sleep or particular stages of sleep on health and performance. It will also be useful for assessing how reflexive brain responses are altered by injury (e.g. TBI) or neuropsychiatric disorders (e.g. anxiety depression) or other diseases.


application_id: 8638593
project_number: 1R21AA022189-01A1
project_title: The role of hepatocyte cAMP/PDE4 in alcohol-induced liver steatosis and injury
administering_ic: NIAAA
award_notice_date: 2014-02-04
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: AA
serial_number: 022189
suffix: A1
program_official: RADAEVA, SVETLANA
project_start_date: 2014-02-05
project_end_date: 2016-01-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 11058066
contact_pi: GOBEJISHVILI, LEILA
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): Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the United States. Steatosis is the initial most frequent hepatic manifestation that occurs in response to acute as well as chronic ethanol consumption. Although steatosis is reversible it is now established that the severity of steatosis predicts the
progression of liver disease to more advanced stages including fibrosis and cirrhosis. Alcohol causes hepatic steatosis by enhancing de novo lipogenesis and impairing fatty acid beta-oxidation system with subsequent susceptibility to injury by inflammatory cytokines particularly TNF. However gaps remain in our understanding of alcohol-responsive mechanisms that contribute to dysregulation of genes involved in hepatic steatosis and subsequent cytokine hepatotoxicity. Cyclic AMP (cAMP) through activation of protein kinase A (PKA) has been shown to modulate genes involved in lipid metabolism and apoptosis.!cAMP levels are tightly regulated through biosynthesis by adenyl cylases (ACs) and hydrolysis by phosphodiesterases (PDEs). Our earlier work shows that expression of cAMP-specific PDE4 is significantly increased in response to alcohol exposure in monocytes/macrophages including hepatic Kupffer cells. Notably our recent preliminary data suggest that ethanol exposure of primary mouse hepatocytes leads to a significant up-regulation of the PDE4 sub-family of enzymes PDEA B and D. Based on these findings we postulate that chronic ethanol feeding decreases cAMP levels in hepatocytes in a PDE4-dependent manner. There is no FDA-approved therapy for any stage of alcoholic liver disease (ALD). The most widely-used (off-label) drug therapies are glucocorticoids and pentoxifylline (PTX). Unfortunately an important subset of AH patients treated with glucocorticoids have "steroid resistance" and some patients have contraindications to steroid therapy. PTX is a broad spectrum PDE inhibitor with only a weak PDE4 inhibitor activity and the data available from the limited studies suggest a positive intervention effect. Hence a more directed intervention aimed at inhibiting PDE4 may be significantly more effective. In this regard our recent preliminary data show that treatment with PDE4 specific inhibitor rolipram markedly inhibits hepatic steatosis in ethanol-fed animals. Our central hypothesis is that alcohol exposure increases cAMP degrading PDE4 expression in hepatocytes lowering cAMP levels with a resultant increase in lipogenesis and a decrease in fatty acid beta oxidation leading to the development of steatosis and sensitization to TNF-induced toxicity. Importantly as a corollary lowering PDE4 activity may provide a significant therapeutic approach. The specific objectives of these mechanistic as well as translational studies are 1) to examine the effect of alcohol exposure on hepatocyte PDE4 expression cAMP metabolism and development of hepatic steatosis and injury and 2) to determine the role of PDE4 subclasses and effect of PDE4 inhibition on the development of alcohol induced hepatic steatosis and injury. Our future goal is to provide a conceptual basis for targeting PDE4 activity as a clinical treatment for alcoholic patients. !

project_terms:
ADD-1 protein;Acute;Adenylate Cyclase;Affect;Alcoholic Liver Diseases;Alcohols;Anabolism;Animal Feed;Apoptosis;Apoptotic;Cause of Death;Cell physiology;Cessation of life;Chronic;Cirrhosis;Clinical Treatment;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Cyclic AMP-Responsive DNA-Binding Protein;Data;Development;Endotoxins;Enzymes;Ethanol;FDA approved;Family;Fatty Acids;Fatty Liver;Fibrosis;Future;Genes;Glucocorticoids;Goals;Hepatic;Hepatocyte;Hepatorenal Syndrome;Hepatotoxicity;Homeostasis;Hydrolysis;In Vitro;Individual;Inflammatory;Injury;Injury to Liver;Intervention;Knock-out;Kupffer Cells;Label;Liver;Liver diseases;Metabolism;Mortality Vital Statistics;Mus;Patients;Pentoxifylline;Peroxisome Proliferator-Activated Receptors;Pharmacotherapy;Phosphodiesterase Inhibitors;Phosphorylation;Play;Predisposition;Prevention;Regulation;Role;Rolipram;Second Messenger Systems;Severities;Staging;Steroid Resistance;Steroid therapy;Stimulus;System;TNF gene;Therapeutic;Toxic effect;United States;Up-Regulation (Physiology);Work;alcohol effect;alcohol exposure;alcohol response;base;chronic alcohol ingestion;cytokine;fatty acid oxidation;feeding;in vivo;inhibitor/antagonist;intervention effect;lipid biosynthesis;lipid metabolism;liver injury;macrophage;monocyte;oxidation;phosphoric diester hydrolase;problem drinker;public health relevance;receptor;response;second messenger;translational study

public_health_relevance:
This project will determine the contributing role of dysregulated hepatocyte PDE4/cAMP homeostasis in thedevelopment of alcohol-induced hepatic steatosis and injury and examine the efficacy of PDE4 inhibition in theprevention and treatment of alcoholic liver disease.


application_id: 8638431
project_number: 1R21AG043721-01A1
project_title: Effect of Satellite Cell Ablation on the Aging Diaphragm
administering_ic: NIA
award_notice_date: 2013-09-25
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: AG
serial_number: 043721
suffix: A1
program_official: WILLIAMS, JOHN
project_start_date: 2013-09-30
project_end_date: 2015-06-30
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Motor dysfunction and skeletal muscle wasting are major causes of poor quality of life increased health carecosts and institutionalization in the elderly. However age-related dysfunction of the respiratory muscles hasan even greater impact on quality of life: impairment of the aging diaphragm disrupts a number of importantbehaviors such as breathing airway protective reflexes (coughing and sneezing) and voice. Since thediaphragm and accessory respiratory muscles must be active throughout life to sustain ventilation it is notsurprising that their response to aging diverges from that seen in other skeletal muscles. In contrast to limbmuscles atrophy does not explain the weakness and increased fatigability of the aging diaphragm; howeversince the diaphragm is constantly active it may have a need for constant remodeling. Indirect evidence for thisnotion stems from the fact that there is an apparent depletion of satellite cells in diaphragm muscle of mdxmice rendering it more susceptible to damage. Whether a similar situation exists for aging diaphragm muscleand whether satellite cell depletion and/or dysfunction play a role in decreased diaphragm function with ageare completely unexplored issues. We are in the unique position to test the role of satellite cells in diaphragmmuscle with aging using the Pax7-DTA mouse which allows for temporal and specific control of satellite cellablation; we showed previously that >90% of satellite cells are ablated in response to tamoxifen treatmentusing this genetic model. It is currently unknown what the role of satellite cells is in the maintenance ofdiaphragm function with aging by itself or when the muscle is functionally challenged. Therefore ourhypothesis is that satellite cells are necessary to sustain the structure and function of the aging diaphragmallowing it to withstand functional challenges. We will test the hypothesis using two specific aims. In Aim 1 wewill determine whether satellite cell ablation in Pax7-DTA mice alters structure and function of the diaphragmwith aging. Satellite cells will be ablated at 4 months of age and mice will be tested at 6 18 and 24 months ofage. The efficiency of satellite cell ablation will be measured and analyses will be performed to assessmorphological as well as functional changes in the diaphragm and in ventilation in vivo. In Aim 2 we willestablish whether satellite cell ablation impairs the ability of the aging diaphragm to adapt to functionalchallenges. Satellite cells will be ablated at 4 months of age and mice will be subjected to normobaric hypoxiafor 4 weeks or running activity for 8 weeks. Analyses will be performed as in Aim 1 and compared to measuresobtained from mice in Aim 1. We expect that satellite cell ablation causes detrimental functional and structuralchanges in the aged diaphragm and that the ability of the diaphragm to adapt to changes in functional demandis impaired particularly in the aged. With the studies proposed in this application we will provide insight intothe role of satellite cells in diaphragm muscle with advancing age which is an unexplored area; this knowledgewill enable us to develop effective intervention strategies for the loss of diaphragm function with age.

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

public_health_relevance:
Diaphragm muscle function is decreased with age but the role of muscle stem cells (satellitecells) in this process is unclear. We propose to study whether satellite cells are required tomaintain muscle structure and function of diaphragm with age and in response to a functionalchallenge. The knowledge from these studies will enable us to design therapies to combatdecreased ventilatory reserve with age.


application_id: 8638119
project_number: 1U01HL121807-01
project_title: The Impact of Oxidative Stress on HIV-induced Lung Disease
administering_ic: NHLBI
award_notice_date: 2013-09-26
opportunity_number: RFA-HL-13-026
application_type: 1
activity_code: U01
ic: HL
serial_number: 121807
program_official: CALER, ELISABET V
project_start_date: 2013-09-26
project_end_date: 2018-07-31
study_section: Special Emphasis Panel[ZHL1 CSR-S (S1)]
contact_pi_person_id: 8816315
contact_pi: RAMIREZ, JULIO ALBERTO
other_pis: ROMAN, JESSE
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Lung diseases are major causes of morbidity and mortality in patients infected with the Human Immunodeficiency Virus (HIV). Currently antiretroviral therapy (ART) has changed HIV into a chronic disease. In the pre-ART era pulmonary infections were very common. In patients with ART however pulmonary infections are less frequent and noninfectious lung disorders such as COPD pulmonary hypertension lung cancer and pulmonary fibrosis are emerging as important causes of illness. These are important cause of morbidity and mortality yet the mechanisms responsible for these disorders in HIV patients are unknown. All pulmonary disorders mentioned above are associated with among other things lung inflammation and tissue remodeling characterized by alterations in matrix expression deposition and degradation. Interestingly HIV infection is also associated with oxidant stress caused by oxidation of the thiol disulfide couple cysteine (Cys)/cysteine (CySS) redox potential (Eh); also termed Eh Cys/CySS. This is important because in vitro studies show that an oxidized Eh Cys/CySS stimulates lung cells to produce more fibronectin (a matrix glycoprotein implicated in tissue injury and repair) transforming growth factor b (a pro-fibrotic growth factor) and pro-inflammatory cytokines like interleukin-1b. It also stimulates the
proliferation and epithelial- mesenchymal transformation of lung fibroblasts processes implicated in tissue remodeling. These data suggest that HIV-related oxidation of Eh Cys/CySS may promote lung tissue remodeling. We have shown that one mechanism by which oxidation of Eh Cys/CySS stimulates tissue remodeling is through the activation of nicotinic acetylcholine receptors (nAChRs). This is intriguing considering that HIV-1 proteins like gp120 bind and increase the expression and signaling of nAChRs expressed in brain and this mechanism has been implicated in HIV-related dementia. We hypothesize that patients with HIV infection have oxidation of the Eh Cys/CySS which together with gp120 activates nAChR-mediated signaling in lung cells and leads to their expression of cellular products with pro-inflammatory and pro-fibrotic effects such as cytokines and growth factors matrix glycoproteins and tissue proteases. The persistent and exaggerated production of these factors activates lung tissue remodeling thereby promoting HIV-related lung disease. The type of disease developed (e.g. COPD versus pulmonary hypertension) however is dependent on both the genetic makeup of the subject and external factors such as smoking and infection. It is important that this hypothesis be tested considering that diet and other interventions have been shown to influence Eh Cys/CySS (9). If found to be causal Eh Cys/CySS and nAChRs can be targeted for intervention in the hope of reducing the incidence and/or severity of HIV-related non-infectious lung disease.

project_terms:
Address;Binding (Molecular Function);Blood;Brain;Bronchoalveolar Lavage Fluid;Cause of Death;Cells;Chronic Disease;Chronic Obstructive Airway Disease;Chronic lung disease;Clinical Research;Clinical Trials;Cysteine;Data;Data Analyses;Databases;Dementia;Deposition;Deterioration;Diet;Disease;Disulfides;Epidemiologic Studies;Epithelial;Fibroblasts;Fibronectins;Genetic;Glycoproteins;Goals;Growth Factor;HIV;HIV Envelope Protein gp120;HIV-1;Immunologist;In Vitro;Incidence;Individual;Infection;Inflammatory;Interleukins;Intervention;Lung;Lung Inflammation;Lung diseases;Malignant neoplasm of lung;Mediating;Mesenchymal;Morbidity - disease rate;Mortality Vital Statistics;Myofibroblast;Nicotinic Receptors;Oxidation-Reduction;Oxidative Stress;Patients;Peptide Hydrolases;Physicians;Process;Production;Proteins;Pulmonary Fibrosis;Pulmonary Hypertension;Research Personnel;Scientist;Severities;Signal Transduction;Smoking;Structure of parenchyma of lung;Sulfhydryl Compounds;Testing;Tissues;Transforming Growth Factors;Universities;Virus Diseases;antiretroviral therapy;base;cytokine;design;env Gene Products;follow-up;injury and repair;oxidant stress;oxidation;prevent;programs;public health relevance;pulmonary function;research and development;transdifferentiation


application_id: 8638093
project_number: 1R21ES022745-01A1
project_title: Mechanisms of atherogenic effects of bisphenol A
administering_ic: NIEHS
award_notice_date: 2014-03-27
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: ES
serial_number: 022745
suffix: A1
program_official: NADADUR, SRIKANTH
project_start_date: 2014-04-01
project_end_date: 2016-03-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project SummaryThis is an R21 application intended to investigate the mechanisms of atherogenic effects of bisphenol A (BPA).BPA is a base chemical used extensively in polycarbonate plastics in many consumer products and humanexposure to BPA is ubiquitous. Higher BPA exposure has recently been associated with an increased risk ofcardiovascular disease (CVD) in multiple human population-based studies. However the mechanismsresponsible for these associations remain unknown. Many environmental chemicals can activate the xenobioticreceptor pregnane X receptor (PXR) which in turn acts as a xenobiotic sensor to regulate xenobioticmetabolism and exhibits considerable differences in its pharmacology across species. Very recently werevealed PXR's pro-atherogenic effects in animal models and found that chronic activation of mouse PXRincreases atherosclerosis in atherosclerosis-prone apolipoprotein E deficient (ApoE-/-) mice. We alsodemonstrated that BPA is a potent activator of human but not mouse PXR consequently the choice of animalmodel is paramount in predicting the human risk assessment of BPA. Therefore we generated novel PXR-humanized ApoE-/- mice (huPXRApoE-/- i.e. ApoE knockout mice with the human PXR transgene in place ofmouse PXR) that can respond to human PXR ligands. Our central hypothesis is that chronic activation of PXRby exposure to BPA promotes foam cell formation and increases atherosclerotic lesion formation in PXR-humanized mice thereby increasing the risk of CVD in exposed individuals. Two specific aims are proposed totest this hypothesis: 1) Does chronic exposure to BPA at doses relevant to human exposure increaseatherosclerosis in PXR-humanized ApoE-/- mice? 2) What molecular pathway does BPA act through toinfluence atherogenesis? The proposed studies are the first to investigate the effects of BPA exposure onatherosclerosis in a suitable animal model and to explore the precise molecular mechanisms by which BPAinduces CVD at the molecular level.

project_terms:
Address;Adverse effects;Affect;Agonist;Animal Model;Animals;ApoE knockout mouse;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Biological;Biological Monitoring;Bone Marrow Transplantation;CD36 gene;Cardiovascular Diseases;Chemicals;Chronic;Development;Dietary Steroid;Dose;Environment;Etiology;Exhibits;Exposure to;Foam Cells;Future;Genes;Goals;Health;Hormones;Human;Individual;Ligands;Link;Lipids;Mediating;Molecular;Mus;Nuclear Receptors;Pathway interactions;Pharmacologic Substance;Pharmacology;Pilot Projects;Play;Population;Production;Receptor Activation;Risk;Risk Assessment;Role;Specificity;Testing;Transgenes;Transgenic Mice;Uncertainty;Variant;Xenobiotic Metabolism;Xenobiotics;atherogenesis;base;bisphenol A;blood lipid;cardiovascular disorder risk;consumer product;environmental chemical;exposed human population;gene environment interaction;human population study;in vivo;leukocyte activation;macrophage;novel;polycarbonate plastic;population based;pregnane X receptor;public health relevance;receptor;scavenger receptor;sensor;species difference

public_health_relevance:
Project NarrativeThe roles of environmental chemicals in the etiology of CVD are poorly understood. Although exposure toenvironmental chemicals such as bisphenol A (BPA) is suspected to increase the risk of CVD the lack ofevidence in suitable animal models has hampered progress. We will now remedy this impasse by employingunique "humanized" transgenic mice that will enable us to study the biological mechanisms by whichenvironmental chemicals induce CVD.


application_id: 8637115
project_number: 5KL2TR000116-04
project_title: Kentucky Center for Clinical and Translational Science
administering_ic: NCATS
award_notice_date: 2014-06-07
opportunity_number: RFA-RM-10-001
application_type: 5
activity_code: KL2
ic: TR
serial_number: 000116
program_official: BRAZHNIK, OLGA
project_start_date: 2011-06-01
project_end_date: 2016-02-29
study_section: ZRR1-CR-1(01)
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
At the University of Kentucky (UK) we have established the Center for Clinical and Translational Science (CCTS) as a home for clinical and translational research. UK is located in Lexington on the western edge of mid-Appalachia one ofthe poorest areas ofthe country where there are unprecedented disparities in disease and mortality. Many of these disparities stem from risky behaviors such as smoking drug abuse and obesity. In this proposal our overarching goal is to transform the pace effectiveness and quality of translational research at UK which will result in better health for the people of mid-Appalachia. Scientific discovery offers the potential for improved care with community-based research offering a faster impact on health through a better dissemination of optimal medical care. However scientific discoveries often do not reach the community due to the many difficulties with navigating the complex process of clinical and translational research. In this application we will capitalize on our strengths in education basic and clinical sciences as well as our outstanding programs in practice- and community- based participatory research. These efforts will result in scientific discovery that will impact the health ofthe Appalachian rural community in the near term and prime the pipeline for the future. To accomplish these goals UK will form a collaboration with Marshall University which is 2 hr away in Huntington WV. In addition we will form an Appalachian Translational Reseach Network involving not only Marshall but also the CTSAs at the Ohio State University University of Cinncinati Morehead University and Pikeville School of Osteopathic Medicine. This network will be especially important in the further development of our strong programs in community based participatory research. To help integrate our efforts we have developed an innovative group of faculty CATalysts who will build collaborative team science programs backed by generous pilot funding that will target novel ideas at all levels of science. New CCTS programs in "Drug Development" "Novel Methodologies" and "Risk-Related Behavior Research" will capitalize on our strengths engage investigators with diverse areas of expertise and will more quickly impact the health ofthe Appalachian community. We have recently recruited a new leader in Biomedical Informatics and have invested heavily in this program which will greatly improve our ability to transform data into knowledge throughout the CCTS. Through these initiatives UK will fulfill its mandate as Kentucky's flagship university to improve the health of Central Appalachia and thereby add unique value to improvements in the health ofthe nation.

project_terms:
Address;Administrator;Aging;Appalachian Region;Area;Attention;Back;Basic Science;Behavior;Businesses;Cardiovascular Diseases;Cardiovascular system;Caring;Censuses;Clinical;Clinical Research;Clinical Sciences;Collaborations;Communities;Complex;Country;County;Data;Dentistry;Development;Disease;Drug abuse;Economically Deprived Population;Educational aspects;Effectiveness;Environment;Faculty;Foundations;Funding;Future;Future Generations;Goals;Health;Health Sciences;Health education;Home environment;Huntington Disease;Institution;Instruction;Kentucky;Knowledge;Life;Malignant Neoplasms;Marshal;Medical;Medicine;Mentors;Methodology;Mortality Vital Statistics;Obesity;Ohio;Osteopathic Medicine;Pharmacy facility;Population;Positioning Attribute;Poverty;Process;Productivity;Professional Practice;Public Health Nurses;Public Health Nursing;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Research Training;Resources;Risk;Risk Behaviors;Rural;Rural Community;Rural Health;Rural Population;Schools;Science;Services;Smoking;Smoking Behavior;Solutions;Source;Students;Training;Training Programs;Training and Education;Translational Research;Underserved Population;Universities;base;biomedical informatics;career;career development;catalyst;college;community based participatory research;design;diabetes risk;drug development;improved;innovation;misuse of prescription only drugs;novel;practice-based research network;programs;stem

public_health_relevance:
RELEVANCE (See Instructions): The CCTS at UK has developed well-integrated relationships with University programs in Central Appalachia and with rural health programs. We routinely apply a foundation principal of community based participatory research where the lay community identifies the research issues and co-develops solutions. This proposal seeks to make research more relevant by breaking down barriers to research translation and greatly improving the pace by which science discoveries drive improvements in health in Kentucky and the nation.


application_id: 8637113
project_number: 5TL1TR000115-04
project_title: Kentucky Center for Clinical and Translational Science
administering_ic: NCATS
award_notice_date: 2014-06-07
opportunity_number: RFA-RM-10-001
application_type: 5
activity_code: TL1
ic: TR
serial_number: 000115
program_official: BRAZHNIK, OLGA
project_start_date: 2011-06-01
project_end_date: 2016-02-29
study_section: ZRR1-CR-1(01)
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
At the University of Kentucky (UK) we have established the Center for Clinical and Translational Science (CCTS) as a home for clinical and translational research. UK is located in Lexington on the western edge of mid-Appalachia one of the poorest areas of the country where there are unprecedented disparities in disease and mortality. Many of these disparities stem from risky behaviors such as smoking drug abuse and obesity. In this proposal our overarching goal is to transform the pace effectiveness and quality of translational research at UK which will result in better health for the people of mid-Appalachia. Scientific discovery offers the potential for improved care with community-based research offering a faster impact on health through a better dissemination of optimal medical care. However scientific discoveries often do not reach the community due to the many difficulties with navigating the complex process of clinical and translational research. In this application we will capitalize on our strengths in education basic and clinical sciences as well as our outstanding programs in practice- and community- based participatory research. These efforts will result in scientific discovery that will impact the health of the Appalachian rural community in the near term and prime the pipeline for the future. To accomplish these goals UK will form a collaboration with Marshall University which is 2 hr away in Huntington WV. In addition we will form an Appalachian Translational Reseach Network involving not only Marshall but also the CTSAs at the Ohio State University University of Cinncinati Morehead University and Pikeville School of Osteopathic Medicine. This network will be especially important in the further development of our strong programs in community based participatory research. To help integrate our efforts we have developed an innovative group of faculty CATalysts who will build collaborative team science programs backed by generous pilot funding that will target novel ideas at all levels of science. New CCTS programs in "Drug Development" 'Novel Methodologies" and "Risk-Related Behavior Research" will capitalize on our strengths engage investigators with diverse areas of expertise and will more quickly impact the health of the Appalachian community. We have recently recruited a new leader in Biomedical Informatics and have invested heavily in this program which will greatly improve our ability to transform data into knowledge throughout the CCTS. Through these initiatives UK will fulfill its mandate as Kentucky's flagship university to improve the health of Central Appalachia and thereby add unique value to improvements in the health of the nation.

project_terms:
Address;Administrator;Aging;Appalachian Region;Area;Attention;Back;Basic Science;Behavior;Businesses;Cardiovascular Diseases;Cardiovascular system;Caring;Censuses;Clinical;Clinical Research;Clinical Sciences;Collaborations;Communities;Complex;Country;County;Data;Dentistry;Development;Disease;Drug abuse;Economically Deprived Population;Educational aspects;Effectiveness;Environment;Faculty;Foundations;Funding;Future;Future Generations;Goals;Health;Health Sciences;Health education;Home environment;Huntington Disease;Institution;Instruction;Kentucky;Knowledge;Life;Malignant Neoplasms;Marshal;Medical;Medicine;Mentors;Methodology;Mortality Vital Statistics;Neurosciences;Obesity;Ohio;Osteopathic Medicine;Pharmacy facility;Population;Positioning Attribute;Poverty;Process;Productivity;Professional Practice;Public Health Nurses;Public Health Nursing;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Research Training;Resources;Risk;Risk Behaviors;Rural;Rural Community;Rural Health;Rural Population;Schools;Science;Services;Smoking;Smoking Behavior;Solutions;Source;Students;Training;Training Programs;Training and Education;Translational Research;Underserved Population;Universities;base;biomedical informatics;career;career development;catalyst;college;community based participatory research;design;diabetes risk;drug development;improved;innovation;misuse of prescription only drugs;novel;practice-based research network;programs;stem

public_health_relevance:
RELEVANCE (See instructions): The CCTS at UK has developed well-integrated relationships with University programs in Central Appalachia and with rural health programs. We routinely apply a foundation principal of community based participatory research where the lay community identifies the research issues and co-develops solutions. This proposal seeks to make research more relevant by breaking down barriers to research translation and greatly improving the pace by which science discoveries drive improvements in health in Kentucky and the nation.


application_id: 8636908
project_number: 5R01CA149438-04
project_title: Activation of Cyclin-Dependent Kinases by Fructose-26-Bisphosphate
administering_ic: NCI
award_notice_date: 2014-03-20
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: CA
serial_number: 149438
program_official: SPALHOLZ, BARBARA A
project_start_date: 2011-04-01
project_end_date: 2016-03-31
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 1923745
contact_pi: CHESNEY, JASON A.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The 6-phosphofructo-2-kinase/fructose-26-bisphosphatases (PFKFB) phosphorylate fructose-6-phosphate (F6P) to fructose-26-bisphosphate (F26BP) which is an allosteric activator of 6-phosphofructo-1-kinase a rate-limiting enzyme in the glycolytic pathway. Although there are four PFKFB enzymes PFKFB3 and PFKFB4 are of particular interest since these enzymes have been found to be activated in human cancers to be increased by hypoxic exposure via HIF-1? and in the case of PFKFB3 to be required for the growth of Ras-transformed tumors. In order to better understand the relative contributions of PFKFB2-4 to glycolysis we examined the subcellular localization of these enzymes and were surprised to find that whereas PFKFB2 and PFKFB4 localized to the cytoplasm (the site of glycolysis) PFKFB3 localized to the nucleus. We then over-expressed PFKFB3 in HeLa cells and observed no change in glucose uptake but rather an increase in proliferation. Eukaryotic cell division is controlled by cyclin dependent kinases (CDKs) that bind to regulatory cyclins and phosphorylate hundreds of substrates that control DNA replication transcription and mitosis. We found that over-expression of PFKFB3 stimulated CDK1 activity in HeLa cells and that purified F26BP stimulated recombinant monomeric CDK1 in vitro. We then confirmed the requirement of CDK1 for the pro-proliferative effects of PFKFB3 by demonstrating that CDK1 siRNA but not CDK2 CDK4 or CDK6 siRNA reversed the increased proliferation caused by over-expression of PFKFB3. Importantly transfection of HeLa cells with PFKFB3-specific siRNA decreased endogenous PFKFB3 which in turn reduced CDK1 activity increased p27 expression suppressed G1/S transition induced apoptosis but had no impact on glucose uptake. These data support a distinct role for PFKFB3 in the regulation of cell cycle progression and apoptosis and not glucose metabolism. We propose to test the hypothesis that nuclear F26BP generated by PFKFB3 activates CDKs and promotes cell cycle progression. We anticipate that nuclear F26BP may serve unique roles in regulating CDK1 and other CDKs and that inhibition of PFKFB3 will suppress CDK activities without significantly affecting glucose metabolism in transformed but not in normal cells.

project_terms:
6-Phosphofructo-2-kinase;6-Phosphofructokinase;Affect;Amino Acids;Apoptosis;Binding (Molecular Function);CDC2 Protein Kinase;CDK2 gene;CDK4 gene;Cancer cell line;Cell Cycle;Cell Cycle Progression;Cell Cycle Regulation;Cell Nucleus;Cell division;Cells;Cyclin-Dependent Kinases;Cyclins;Cytoplasm;Cytostatics;DNA biosynthesis;Data;Enzymes;Epithelial;Epithelial Cells;Eukaryotic Cell;Family;Family member;Fructose;G1/S Transition;Genes;Genetic Transcription;Genomics;Glycolysis;Growth;Hela Cells;Hematopoietic;Human;Human Development;Hypoxia;In Vitro;Liver;Malignant Neoplasms;Mitosis;Molecular Target;Mus;Mutation;Normal Cell;Normal tissue morphology;Nuclear;Oncogenes;Pathway interactions;Phosphoric Monoester Hydrolases;Phosphotransferases;Protein p53;Recombinants;Regulation;Relative (related person);Research;Role;Signal Pathway;Site;Small Interfering RNA;Testing;Tissues;Transfection;Transformed Cell Line;Transgenic Organisms;base;cancer cell;chemotherapeutic agent;clinically significant;fructose-6-phosphate;glucose metabolism;glucose uptake;in vitro activity;interest;mutant;neoplastic;novel;public health relevance;receptor;screening;small molecule;tumor;tumor growth;tumor progression;virtual

public_health_relevance:
The research proposed in this application may enable the identification of a novel molecular target - the CDK1 F26BP-binding domain - that is required for the regulation of the cell cycle and cancer progression. This binding pocket then can be used for receptor-based virtual screening to identify novel anti-neoplastic agents.


application_id: 8636423
project_number: 5R01DA035552-02
project_title: Long-lasting cocaine-metabolizing enzyme for cocaine addiction treatment
administering_ic: NIDA
award_notice_date: 2014-02-21
opportunity_number: RFA-DA-13-004
application_type: 5
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: ZDA1-GXM-A(11)S
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:
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: 8636275
project_number: 1R03CA176777-01A1
project_title: Modulation of colitis-associated cancer by cyclosporine A
administering_ic: NCI
award_notice_date: 2013-12-19
opportunity_number: PAR-12-144
application_type: 1
activity_code: R03
ic: CA
serial_number: 176777
suffix: A1
program_official: DASCHNER, PHILLIP J
project_start_date: 2014-01-01
project_end_date: 2015-12-31
study_section: Special Emphasis Panel[ZCA1 RTRB-Z (O1)]
contact_pi_person_id: 1878476
contact_pi: COHEN, DONALD A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Patients with inflammatory bowel disease (IBD) develop malignancies of the intestinal tract at an increasedfrequency compared to the normal population. This is thought to be due in part to the chronic inflammationassociated with this debilitating disease. Cyclosporine A (CsA) is an effective treatment for patients withsevere steroid-refractory IBD especially ulcerative colitis (UC). However the use of CsA in animal models hasbeen associated with enhanced spread of colorectal cancer cells. We have shown that treatment of bonemarrow transplanted (BMT) mice with CsA leads to a colitis-like disease similar to other models of IBD.Importantly recent studies have demonstrated a role for the inflammasome in intestinal homeostasis and thedevelopment of colitis-associated intestinal tumors. IBD patients have decreased inflammasome activity whichmay contribute to the development of clinical disease and animals with deficiencies in the inflammasomedevelop enhanced colitis and colon tumors. We have documented that CsA-treatment of BMT mice inhibitedthe activation of the inflammasome and may have participated in the development of colitis-like diseasemaking suspect the clinical use of CsA in refractory IBD. Given these findings two specific aims will beproposed to test the hypothesis that cyclosporine treatment will alter intestinal homeostasis via inhibition ofinflammasome function resulting in enhanced tumor growth in the azoxymethane (AOM)/dextran sulfatesodium (DSS) model of colitis-associated colon cancer (CAC). Aim 1 will determine if treatment of AOM/DSS-treated animals with a therapeutic dose of CsA will enhance the severity of colitis and the development ofCAC. Inflammasome expression and activity will be determined in CsA-treated mice after induction ofAOM/DSS CAC. Preliminary results show that CsA therapy inhibits intestinal barrier function in BMT mice.Thus we propose that intestinal damage which occurs during the induction of AOM/DSS also will be prolongedby CsA therapy. Aim 2 will test the hypothesis that CsA-induced alterations in intestinal epithelium will lead toincreased permeability and decreased barrier function via inhibition of inflammasome function which maycontribute to increased colitis and development of CAC. As patients with IBD have reduced inflammasomeactivity the potential exists that the use of CsA to treat refractory IBD may enhance development of thedisease by further reducing inflammasome function leading to and enhanced risk of CAC. It is imperative toanalyze the effects of immunosuppressive therapy on intestinal damage induction of colitis and CAC in modelanimal systems to understand the risk of CsA therapy in the treatment of IBD.

project_terms:
Acute;Affect;Allogenic;Animal Diseases;Animal Model;Animals;Azoxymethane;Biological Models;Bone Marrow Transplantation;Calcineurin;Characteristics;Chronic;Clinical;Colitis;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Crohn's disease;Cyclosporine;Development;Disease;Dose;Epithelial Physiology;Exhibits;Experimental Models;Frequencies (time pattern);General Population;Immune;Immunosuppressive Agents;Inflammation;Inflammatory Bowel Diseases;Inflammatory disease of the intestine;Intestinal Neoplasms;Intestines;Large Intestine;Lead;Malignant Neoplasms;Modeling;Mus;Neoplasm Metastasis;Patients;Permeability;Pharmaceutical Preparations;Population;Refractory;Risk;Role;Severities;Small Intestines;Sodium Dextran Sulfate;Steroids;Syndrome;System;Testing;Therapeutic;Therapeutic immunosuppression;Toxic effect;Ulcerative Colitis;cancer cell;cancer risk;colitis associated cancer;effective therapy;feeding;intestinal epithelium;intestinal homeostasis;member;microbiome;mouse model;pre-clinical;public health relevance;response;tumor;tumor growth;tumor progression

public_health_relevance:
The murine AOM/DSS model exhibits many of the characteristics of IBD-associated colon cancer and is usefulas a proof of concept model to examine the role of calcineurin inhibition in the integrity of the intestinalepithelium during chronic inflammation. This project will determine the effect of CsA/immunosuppressivetherapy on the development of inducible colon cancer.


application_id: 8635319
project_number: 5R01CA175105-02
project_title: Targeting Translation Dependence in Colorectal Cancer Progression
administering_ic: NCI
award_notice_date: 2014-04-02
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 175105
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2013-04-01
project_end_date: 2018-03-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 10534129
contact_pi: SHE, QING-BAI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Animal Model;Biochemical;Biological Markers;Biology;Biometry;Cancer Cell Growth;Cancer Patient;Cancer cell line;Clinic;Clinical;Colonic Neoplasms;Colorectal Cancer;Data;Dependence;Drug Targeting;Effectiveness;Exhibits;Feedback;Genes;Goals;Growth;Human;In Vitro;Knowledge;MEK inhibition;MEKs;Messenger RNA;Modeling;Molecular;Mus;Mutation;Neoplasm Metastasis;Oncogene Proteins;Operative Surgical Procedures;PI3K/AKT;PTEN gene;Pathogenesis;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Play;Polyribosomes;Proteomics;Proto-Oncogene Proteins c-akt;Recruitment Activity;Research Infrastructure;Resistance;Role;Signal Pathway;Signal Transduction;Solid;Specimen;Techniques;Testing;Therapeutic;Translating;Translation Initiation;Translational Activation;Translational Regulation;Translational Repression;Translations;Tumor-Derived;Tyrosine Kinase Receptor Inhibition;Xenograft Model;base;cancer therapy;cell motility;clinically relevant;human FRAP1 protein;in vivo;inhibitor/antagonist;insight;interdisciplinary collaboration;mTOR Inhibitor;mTOR inhibition;metastatic colorectal;novel;pre-clinical;prevent;public health relevance;response;survivin;therapeutic target;tumor;tumor growth;tumor progression;tumorigenesis

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


application_id: 8634180
project_number: 1K99AG044445-01A1
project_title: Involvement of myelin integrity in Alzheimer's disease pathogenesis
administering_ic: NIA
award_notice_date: 2013-11-29
opportunity_number: PA-11-197
application_type: 1
activity_code: K99
ic: AG
serial_number: 044445
suffix: A1
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2013-12-01
project_end_date: 2015-11-30
study_section: Basic Neuroscience of Aging Study Section[NIA-N]
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM D
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This K99/R00 application provides career development training and a research plan to further the understanding of glial responses in white matter in the context of Alzheimer's disease (AD). The hypothesis to be tested is that a progressive loss of myelin integrity occurs in AD activating microglia towards a proinflammatory feed-forward loop which mediates hyperphosphorylation of the microtubule-associated protein tau and traditional AD pathology: neuritic plaques (NP) and neurofibrillary tangles (NFTs). Conventionally considered a disease of the CNS gray matter AD also has pronounced and progressive deterioration of cerebral white matter. Recent evidence suggests that changes in myelin integrity could be an early factor driving AD pathology through stimulation of inflammatory microglia activation and subsequent axonal damage. Extensive work has been done to understand the glial response in AD gray matter yet very little is known about microglia activation in AD white matter despite the fact that we and others have found a more robust activation of microglia and inflammatory response in AD white matter compared to gray matter. No studies have systematically and quantitatively examined myelin changes and inflammatory profiles as a function of disease progression. Our project will fill this gap by using human autopsy tissue and a mouse model that exhibits loss of myelin integrity to test our hypothesis. Our specific aims are: 1) Quantify the relationship between myelin integrity microglia activation proinflammatory cytokine levels and traditional measures of AD burden (NPs and NFTs) in the white matter of autopsy samples; 2) Determine if loss of myelin integrity induced by mutation in PLP in hTau mice will accelerate hyper-phosphorylated tau pathology and if this pathology can be rescued by suppressing the chronic neuroinflammation using a glia cytokine inhibitor. This project takes advantage of a strong scientific environment and extensive resources at the University of Kentucky including the Alzheimer's Disease Center clinically well-characterized autopsy cases that span the disease pathology continuum and renowned scientific expertise of an enthusiastic and committed mentoring team. A comprehensive training and career development plan has been developed for the K99 phase that includes further scientific training in oligodendrocyte/myelin biology and human neuropathology; formal coursework and participation in local national and international scientific meetings; evaluative meetings with th mentoring team; and activities designed to improve communication writing teaching and management skills. Overall there is an outstanding intellectual environment and access to relevant expertise in the applicant's project area multiple opportunities for career growth and substantial institutional commitment. This rich and supportive environment will enable a highly promising young scientist to further develop his research expertise pursue his structured training and career development plan and launch his career as an independent academic investigator.

project_terms:
Alzheimer's Disease;Amyloid beta-Protein Precursor;Animal Model;Area;Automobile Driving;Autopsy;Biochemistry;Brain;Brodmann's area;Central Nervous System Diseases;Cerebrum;Cessation of life;Chronic;Clinical;Cognitive;Commit;Communication;Data;Deterioration;Development Plans;Diffusion Magnetic Resonance Imaging;Disease;Disease Progression;Educational process of instructing;Environment;Enzyme-Linked Immunosorbent Assay;Event;Exhibits;Genes;Genetic;Goals;Growth;Health;Human;Human Biology;Immunoblotting;Immunohistochemistry;Induced Mutation;Inflammation;Inflammatory;Inflammatory Response;Interleukin-1;International;Kentucky;Late Onset Alzheimer Disease;Measures;Medial;Mediating;Mental disorders;Mentors;Methods;Microglia;Mus;Mutation;Myelin;Myelin Proteins;Neocortex;Neuregulin 1;Neurodegenerative Disorders;Neurofibrillary Tangles;Neuroglia;Neurons;Oligodendroglia;Pathogenesis;Pathologic;Pathology;Pathway interactions;Phase;Phosphorylation;Research;Research Personnel;Research Project Grants;Resources;Role;Sampling;Scientist;Senile Plaques;Structure;Synapses;TNF gene;Temporal Lobe;Testing;Tissues;Training;Universities;Work;Writing;beta-site APP cleaving enzyme 1;brain tissue;burden of illness;career;career development;cytokine;design;digital;feeding;frontal lobe;genetic risk factor;gray matter;hTau Mice;human tissue;hyperphosphorylated tau;improved;inhibitor/antagonist;insight;lipid transport;meetings;mild cognitive impairment;mouse model;myelination;neuroinflammation;neuron loss;neuropathology;pre-clinical;response;skills;tau Proteins;white matter;white matter change;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This research project will provide fundamental insights regarding the role of microglia dysregulated neuroinflammation and white matter integrity in the temporal onset of Alzheimer's disease. Recent data suggest white matter involvement in a variety of neurodegenerative and psychiatric disease. Therefore the understanding of oligodendrocyte - microglia - neuron interaction in Alzheimer's disease could have a broad impact on our understanding of cognitive health and disease.


application_id: 8634120
project_number: 5K23GM095859-04
project_title: Adjunctive Peritoneal Resuscitation in Hemorrhagic Shock
administering_ic: NIGMS
award_notice_date: 2014-03-31
opportunity_number: PA-10-060
application_type: 5
activity_code: K23
ic: GM
serial_number: 095859
program_official: SOMERS, SCOTT D
project_start_date: 2011-04-01
project_end_date: 2015-03-31
study_section: Special Emphasis Panel[ZRG1-SBIB-E(02)M]
contact_pi_person_id: 9885498
contact_pi: SMITH, JASON WAYNE
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
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): This K23 proposal will enable Jason W. Smith MD to achieve his goal of becoming an independent investigator focusing on clinical and translational research in hemorrhagic shock and inflammation. Dr. Smith will conduct a prospective clinical study evaluating the effects of adjunctive direct peritoneal resuscitation (DPR) on patients undergoing damage control surgery and hemorrhagic shock. Highlights of Dr. Smith's career development plan include: (1) obtaining a PhD in Physiology and Biophysics focusing on microcirculation and hemorrhagic shock (2) experience running a prospective clinical trial at a large academic hospital and (3) technical laboratory training in experimental methods that can be applied across a wide range of future experiment subjects. These activities will occur in the setting of the University of Louisville and the University Of Louisville Hospital Trauma Institute and will be monitored quarterly by an advisory committee. An estimated 46 million Americans suffer a traumatic accident yearly. A number of those patients will suffer hemorrhagic shock and its sequelae as a result of their injury. Our preliminary data document (i) improvement in patient outcomes using adjunctive peritoneal resuscitation and (ii) improvement in liver blood flow after administration of DPR. Our hypothesis is that DPR therapy will result in improvement in mechanisms postulated to play a role in the development and progression of systemic inflammatory response due to hemorrhagic shock. To test this hypothesis we will perform a prospective randomized controlled mechanistic study of DPR administration in 100 patients undergoing damage control surgery for hemorrhagic shock over a 30 month period. The expected primary endpoints are an (i) increase in hepatic blood flow during resuscitation in patients treated with DPR  (ii) reduction in cellular edema and hepatocyte necrosis similar to our laboratory findings and (iii) a reduction inflammatory response and chemotactic mediators compared to the conventional resuscitation group. Additionally expected secondary clinical endpoints are (i) improved timeto abdominal closure (ii) decreased fluid resuscitation requirements with decreased vascular permeability and (iii) a reduction in post-operative complications following damage control surgery. These studies utilize state of-the art well validated techniques in a translational approach to develop an enhanced understanding of a potential innovativetherapy for hemorrhagic shock.    PUBLIC HEALTH RELEVANCE: This K23 proposal will enable Jason W. Smith MD to achieve his goal of becoming an independent investigator focusing on clinical and translational research in hemorrhagic shock and inflammation. We will perform a randomized controlled study of adjunctive peritoneal resuscitation in patient suffering from hemorrhagic shock secondary to traumatic injury during the 30 month study period.

project_terms:
Abdomen;Accidents;Advisory Committees;American;Attenuated;Biophysics;Blood Circulation;Blood capillaries;Blood flow;Cause of Death;Cells;Cessation of life;Clinical;Clinical Research;Clinical Trials;Complex;Data;Development;Development Plans;Dialysis Solutions;Diffusion;Doctor of Philosophy;Edema;Future;Glucose;Goals;HMGB1 Protein;Health Benefit;Hemorrhage;Hemorrhagic Shock;Hepatic;Hepatocyte;Hospitals;Human;Inflammation;Inflammatory Response;Injury;Institutes;Intensive Care Units;Interleukin-6;Intravenous;Laboratories;Laboratory Finding;Laboratory Research;Liquid substance;Liver;Mediator of activation protein;Methodology;Methods;Microcirculation;Microcirculatory Bed;Monitor;Mortality Vital Statistics;Necrosis;Operative Surgical Procedures;Organ;Outcome;Patients;Perfusion;Peritoneal;Peritoneal Dialysis;Physiology;Play;Postoperative Period;Production;Publishing;Randomized;Randomized Controlled Trials;Reporting;Research Personnel;Resuscitation;Role;Running;Safety;Secondary to;Shock;Sodium Channel;Solutions;Surgical Intensive Care;TNF gene;Techniques;Testing;Time;Tissues;Training;Translational Research;Trauma;United States;Universities;Vascular Permeabilities;Vasodilation;Visceral;Water;Work;animal data;arm;base;capillary;career development;chemokine;clinical practice;crystalloid;experience;human study;hyaluronate;hypoperfusion;improved;innovation;interstitial;intrahepatic;prospective;public health relevance;research study;socioeconomics;translational approach

public_health_relevance:
Project Narrative_________________________________________________________________________This K23 proposal will enable Jason W. Smith MD to achieve his goal of becoming an independentinvestigator focusing on clinical and translational research in hemorrhagic shock and inflammation. We willperform a randomized controlled study of adjunctive peritoneal resuscitation in patient suffering fromhemorrhagic shock secondary to traumatic injury during the 30 month study period.


application_id: 8633755
project_number: 1R01DA036827-01
project_title: Topiramate-Phentermine Combinations for Cocaine Dependence
administering_ic: NIDA
award_notice_date: 2014-09-09
opportunity_number: PA-10-268
application_type: 1
activity_code: R01
ic: DA
serial_number: 036827
program_official: HAMPSON, AIDAN
project_start_date: 2014-09-15
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1 RPIA-N (09)]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract Cocaine (COC) dependence is a significant public health concern. A widely effective pharmacotherapy hasnot yet been identified for COC dependence. Innovative strategies are needed to identify an effectivepharmacotherapy for COC dependence. Testing medications effective for disorders that share neurobiologicalsubstrates with drug dependence for example could yield treatments for managing COC dependence. Obesity is also a significant public health concern. While obesity and COC dependence aretypically considered distinct clinical entities both involve perturbations of central biogenic amine systems. Theobesity epidemic has spurred development of medications to promote weight loss. The Food and DrugAdministration (FDA) recently approved a combination of topiramate (TOP) and phentermine (PHEN) forobesity. The overarching goal of this application is to demonstrate the initial efficacy safety and tolerability ofTOP-PHEN combinations for COC dependence. A mixed-model experiment will be conducted in whichseparate cohorts of non-treatment-seeking COC-dependent participants will be randomized to different TOPmaintenance doses (i.e. TOP is a between-subject factor). Participants (N=12) in each TOP cohort will bemaintained concurrently on PHEN (i.e. PHEN is a within-subject factor). The reinforcing effects of COC will bedetermined after participants in each TOP cohort are maintained for 7 days on each PHEN dose (i.e. COC is awithin-subject factor). COC (4 [placebo] 40 80 mg) will be tested with each dose combination of TOP (0 100200 mg/day) and PHEN (0 15 30 mg/day). The proposed study will therefore identify the optimal TOP-PHENdose combination that most effectively attenuates the reinforcing effects of COC. This research will provide critical information regarding the initial efficacy and optimal doses of a novel drugcombination TOP and PHEN for COC dependence which will enhance the probability of success whenadvanced to a clinical trial. Innovations of the proposal include: 1) testing a drug combination effective for adisorder obesity that shares neurobiological and behavioral substrates with COC addiction; 2) the use of drugself-administration procedures; 3) providing the impetus for the conduct of a Phase II clinical trial to furtherdemonstrate the efficacy of TOP-PHEN combinations for COC addiction; 4) demonstrating the initial efficacy ofcommercially available drugs as opposed to waiting for novel molecules to be available for testing in humansthereby impacting clinical research and practice more quickly; 5) facilitating communications between scientistsstudying distinct clinical entities (e.g. obesity and COC addiction); and 6) spurring sponsor interest in addictionpharmacotherapy because demonstrating the efficacy of the TOP-PHEN combination would support a novelindication for this product in a new population and extend patent life. The proposed project will shift the currentresearch paradigm in pharmacotherapy development and have a significant impact on COC abuse treatment.

project_terms:
Abstinence;Adverse effects;Attenuated;Behavior Therapy;Behavioral;Biogenic Amines;Body Weight;Body Weight decreased;Clinical;Clinical Research;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Combination Drug Therapy;Communication;Development;Disease;Dose;Drug Addiction;Drug Combinations;Drug usage;Enrollment;Epidemic;Excitatory Amino Acid Antagonists;Food;GABA Agonists;Goals;Human;Inpatients;Investigation;Laboratory Study;Legal patent;Life;Maintenance;Modeling;Mono-S;Neurobiology;Obesity;Outcome Measure;Participant;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase II Clinical Trials;Phentermine;Physiological;Placebos;Population;Probability;Procedures;Questionnaires;Randomized;Relative (related person);Research;Research Design;Safety;Scientist;Self Administration;System;Testing;United States Food and Drug Administration;Work;addiction;clinical practice;cocaine use;cohort;double-blind placebo controlled trial;indexing;innovation;interest;monoamine;novel;programs;public health medicine (field);public health relevance;reinforcer;research study;secondary outcome;success;topiramate

public_health_relevance:
Project NarrativeThe research proposed in this application will determine the initial efficacy safety and tolerability of a noveldrug combination topiramate and phentermine as a pharmacotherapy for cocaine dependence. A rigorousinpatient human laboratory study will be conducted. The proposed study is innovative and important becauseit will provide the impetus for the conduct of double blind placebo-controlled trials to further demonstrate theefficacy of topiramate-phentermine combinations for managing cocaine dependence.


application_id: 8633724
project_number: 1R21DA035376-01A1
project_title: Motivation for Cocaine and Non-Drug Reinforcers: Targeting Glutamate Homeostasis
administering_ic: NIDA
award_notice_date: 2014-05-09
opportunity_number: PA-10-269
application_type: 1
activity_code: R21
ic: DA
serial_number: 035376
suffix: A1
program_official: GRANT, STEVEN J
project_start_date: 2014-06-01
project_end_date: 2016-05-31
study_section: Neurobiology of Motivated Behavior Study Section[NMB]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACTCocaine is the most commonly used illicit stimulant in the United States. Despite great strides in ourunderstanding of the neuropharmacological underpinnings of cocaine addiction in the preclinical arena thenumber of cocaine users in the United States has remained relatively stable in recent years indicating thatmore clinical research is necessary to translate these findings to humans in an attempt to develop moreeffective means of reducing cocaine use. Emerging data suggest that perturbations in glutamate transmissionfollowing cocaine use (i.e. disrupted glutamate homeostasis) contribute to the maladaptive pattern of drugtaking characterized by cocaine addiction. Specifically preclinical studies indicate that cocaine exposureresults in increased motivation to take cocaine and decreased drive for non-drug reinforcers. This change inreinforcer salience corresponds with complex neuropharmacological changes in the glutamate system.Whereas preclinical data suggest that targeting glutamate systems specifically restoring glutamatehomeostasis reduces drug reinforcer salience this research area remains relatively unexplored in humans.Some initial studies suggest that n-acetylcysteine pretreatment normalizes glutamate levels in cocaine usersand that n-acetylcysteine maintenance attenuates desire for cocaine and attention to cocaine cues in abstinentcocaine-dependent subjects. Whether restoration of glutamate homeostasis impacts motivation for drugrelative to non-drug reinforcers remains to be determined in humans. The research proposed here willdemonstrate that restoration of glutamate homeostasis reduces motivation to take cocaine and increasesmotivation to obtain a non-drug alternative reinforcer (i.e. money) in cocaine-dependent humans usingprogressive-ratio schedules of reinforcer availability which are an accepted means to measure motivation. Theuse of concurrent progressive-ratio schedules of drug and non-drug reinforcer availability will allow inferencesto be made about the influence of restored glutamate homeostasis on motivation to obtain these two types ofreinforcers. Cognitive tasks that assess domains relating to reinforcer choice also will be included tocomplement the self-administration outcomes. This study will translate findings from preclinical research andprovide the initial clinical evidence that restoration of glutamate homeostasis shifts reinforcer salience awayfrom drug reinforcers towards non-drug reinforcers in active cocaine users. Outcomes of the experiment willnot only contribute to our understanding of the clinical neuropharmacology of cocaine addiction they also canbe used to guide development of treatments for cocaine use disorders.

project_terms:
Abstinence;Acetylcysteine;Acute;American;Area;Attention;Attenuated;Automobile Driving;Basic Science;Behavior;Brain;Ceftriaxone;Chronic;Clinical;Clinical Research;Cocaine;Cocaine Dependences;Cocaine Users;Cognitive;Complement;Complex;Cues;Cystine;Data;Decision Making;Diagnostic;Disease;Dose;Drug Use Disorder;Glutamate Transporter;Glutamates;Goals;Homeostasis;Human;Laboratories;Left;Link;Maintenance;Measures;Motivation;Neuropharmacology;Neurosciences Research;Oral;Outcome;Pattern;Performance;Pharmaceutical Preparations;Pharmacodynamics;Physiological;Placebos;Population;Pre-Clinical Model;Prevalence;Relative (related person);Reporting;Research;Role;Safety;Sampling;Schedule;Self Administration;System;Testing;Translating;United States;cocaine exposure;cocaine use;flexibility;human subject;improved;insight;meetings;non-drug;pre-clinical;pre-clinical research;preclinical study;public health medicine (field);public health relevance;reinforcer;research study;restoration;therapy development;transmission process

public_health_relevance:
Project NarrativePreclinical data implicate disrupted glutamate homeostasis in the disordered motivation that characterizescocaine addiction. The goal of this project is to translate preclinical findings by determining how restoration ofglutamate homeostasis impacts motivation for cocaine and non-drug reinforcers in active cocaine users whichwill improve our understanding of the clinical neuropharmacology of cocaine addiction and provide insights intotreatment development.


application_id: 8631938
project_number: 1R01GM105977-01A1
project_title: Exploring Post-Type II PKS Frame Modifications
administering_ic: NIGMS
award_notice_date: 2014-09-09
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: GM
serial_number: 105977
suffix: A1
program_official: GERRATANA, BARBARA
project_start_date: 2014-09-10
project_end_date: 2018-07-31
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
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
project_abstract:
Natural products have a major impact on drug discovery. They have contributed toapproximately 50% of new chemical entities between 1940 and 2006 because they offer aunique richness in structural skeletons combined with a high degree of chirality that has thepotential to selectively match bio-receptors. Natural products have been particularly useful forthe treatment of cancer and infectious diseases nonetheless new drugs are urgently neededbecause current drug regimens inevitably lose their effectiveness due to resistancemechanisms. Many important natural product drugs are generated by polyketide synthases(PKS multiple enzyme complexes) and various frame-modifying reactions called post-PKStailoring steps. Type II PKSs assembling multicyclic aromatic intermediates together with therespective tailoring enzymes are responsible for the generation of important drugs such as theclinically used tetracycline antibiotics or anthracycline and aureolic acid anticancer drugs. Whiletype II PKSs are well studied the post-PKS steps are much less understood although the framemodifying enzymes typically render an inert scaffold into a bioactive drug. The primary goal ofthis proposal is to functionally and mechanistically characterize uniquely reacting and organizedframe modifying post-PKS enzymes involved in the biosynthesis of anticancer polyketide drugsof the angucycline and aureolic acid groups. It is our expectation that uncovering the moleculardetails of catalysis will help to evolve these critical enzymes so that they can be exploited tomodify type II PKS scaffolds. This could lead to novel second-generation 'unnatural' naturalproducts and/or derivatives of natural products via combinatorial biosynthesis mutasynthesis orchemo-enzymatic synthetic strategies. The studies also will help to generate new mithramycinand gilvocarcin analogues that will be useful to further study and steer the interactions of thesedrugs with their recently discovered specific targets.

project_terms:
Address;Anabolism;Anthracyclines;Antibiotics;Antineoplastic Agents;Biochemical;Biological;Biological Factors;Catalysis;Characteristics;Chemicals;Chemotherapy-Oncologic Procedure;Clinical;Collaborations;Communicable Diseases;Complex;DNA Sequence Rearrangement;Development;Drug Interactions;Effectiveness;Engineering;Enzyme Interaction;Enzymes;Epirubicin;Event;Evolution;Future;Generations;Goals;In Vitro;Investigation;Kentucky;Laboratories;Lead;Methods;Methylation;Michigan;Modeling;Modification;Molecular;Multienzyme Complexes;National Institute of Diabetes and Digestive and Kidney Diseases;Natural Product Drug;Nature;Oxidoreductase;Oxygenases;Parents;Pathway interactions;Pharmaceutical Preparations;Pharmacy facility;Plicamycin;Proteins;Reaction;Recombinant Proteins;Regimen;Resistance;Side;Skeleton;System;Tetracyclines;United States National Institutes of Health;Universities;Vertebral column;Work;analog;antineoplastic antibiotics;base;cancer therapy;catalyst;chemotherapy;college;combinatorial;cost;drug discovery;drug synthesis;expectation;glycosylation;glycosyltransferase;improved;interest;member;novel;overexpression;polyketide synthase;protein structure;public health relevance;receptor;resistance mechanism;scaffold;screening;tigecycline;tool;transamination

public_health_relevance:
NarrativeThe proposed work aims to study key enzymes and enzyme complexes of the type II post-polyketide synthase(PKS) machinery found in the biosynthesis of natural product anticancer drugs which are essential to turnprimary polyketide scaffolds into bioactive drugs. Uncovering the molecular details of catalysis will help toevolve these critical enzymes so that they can be exploited to modify primary PKS scaffolds. This could leadto novel second-generation 'unnatural' natural products and/or derivatives of natural products viacombinatorial biosynthesis mutasynthesis or chemo-enzymatic synthetic strategies. The studies also will helpto generate new mithramycin and gilvocarcin analogues that will be useful to further study and steer theinteractions of these drugs with their recently discovered specific targets.


application_id: 8631859
project_number: 1R01AI103053-01A1
project_title: Evolutonary Mechanisms of RNA Virus Host Switching
administering_ic: NIAID
award_notice_date: 2014-03-28
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: AI
serial_number: 103053
suffix: A1
program_official: CASSETTI, CRISTINA
project_start_date: 2014-04-01
project_end_date: 2015-03-31
study_section: Virology - B Study Section[VIRB]
contact_pi_person_id: 1871909
contact_pi: JONSSON, COLLEEN 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:
7. Project SummaryBroad long-term objectives: The research objectives stated herein and in future studies thatwould build upon these findings seek to reveal general scientific principles in the mechanismsthat drive "spillover" and adaption of zoonotic RNA viruses.Significance: RNA viruses contribute to more than half of all human infectious diseases thathave originated as zoonoses. Wildlife studies to form a complete understanding of RNA viral-host interactions especially those that directly test the impact of ecological pressures on viralspread during contact and the first adaptive steps of the virus during spillover can provideimportant insights. Specifically the study of the emergence and adaption of hantaviruses canprovide critical data for: (1) models for prediction of RNA viral emergence and mitigation; (2)identification of viral and host targets for therapeutic intervention; and (3) a basic understandingof the selective pressures that modulate viral-host interactions and viral genetic variation.Specific aims: We propose field and laboratory studies using South American hantaviruses asa model system to test specific selective pressures to reveal evolutionary mechanisms of RNAvirus adaption in reservoir (HR) and spillover host (HS) host systems. The three Aims proposedwill: (1) define viral emergence within host reservoirs and sympatric rodent species duringextrinsic (environmental) pressure; (2) reveal the relationship of extrinsic (environment &ecological) pressures on preexisting intrahost genetic variation in wild rodent populations; and(3) define viral fitness virulence and genotype during adaptation to new host species in vitro.Research design and methods: The proposed field site for Aim 1 lies in eastern Paraguaywhere two hantaviruses co-circulate and where elevated seroprevalence levels of hantavirusesare associated with anthropogenic alteration of land use. We propose to assess effects of: (1)increased food resources and (2) reduced predation on virus prevalence (Aim 1) and intra- andinterhost genetic variation in rodents within native and disturbed forest areas (Aim 2). In Aim 3we focus on the fitness and virulence of these viruses and the genetic changes that lead toadaptation. Using primary endothelial cell culture-based approaches we will define the impactof intrinsic (host) selective pressures occurring when a new host species HS interacts with virusas it replicates adapts to a new host host.

project_terms:
Area;Automobile Driving;Biological Models;Cell Culture Techniques;Climate;Communicable Diseases;Communities;Cotton Rats;Coupled;Data;Disease Outbreaks;Endothelial Cells;Environment;Environmental Impact;Environmental Risk Factor;Event;Evolution;Food;Future;Genetic;Genetic Determinism;Genome;Genotype;Habitats;Hantavirus;Health;Human;In Vitro;Infection;Infectious Agent;Intrinsic factor;Laboratories;Laboratory Study;Lead;Longitudinal Studies;Lung;Modeling;Mutation;Paraguay;Personal Satisfaction;Play;Population;Population Density;Predatory Behavior;Prevalence;Primary Cell Cultures;Process;RNA Viruses;Research;Research Design;Research Methodology;Resources;Rodent;Role;Seroprevalences;Site;Source;South American;Staging;Structure;Study models;System;Testing;Therapeutic Intervention;Variant;Variation (Genetics);Viral;Viral Genome;Virulence;Virus;Water;Zoonoses;Zoonotic Infection;aging nutrition;anthropogenesis;base;demographics;experience;field study;fitness;food resource;forest;human disease;in vitro Model;insight;land use;mouse model;pressure;public health relevance;sex;transmission process;viral RNA;virus genetics

public_health_relevance:
8. Project NarrativeGreater than half of all human infectious diseases begin through the cross-species transmissionof RNA viruses from wildlife to humans. Hantaviruses provide an exceptional model system forthe study of RNA virus spillover as significant source of outbreaks zoonotic infections andhuman disease. This study examines genetic determinants which facilitate spread in its rodentreservoir and its adaptation in vitro to new rodents which will in turn provide understanding andprediction of human-environmental interactions.


application_id: 8631058
project_number: 5R00CA149144-04
project_title: The Role of Sulfiredoxin in Tumorigenesis and Cancer Progression.
administering_ic: NCI
award_notice_date: 2014-03-26
application_type: 5
activity_code: R00
ic: CA
serial_number: 149144
program_official: WOODHOUSE, ELIZABETH
project_start_date: 2012-04-01
project_end_date: 2016-03-31
study_section: NSS
contact_pi_person_id: 10043947
contact_pi: WEI, QIOU
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-04-01
project_abstract:
Sulfiredoxin (Srx) is a novel gene that has been found to be highly expressed in several types of humancancers including cancers of skin and lung. However the function of Srx in cancer development has not beenwell studied. The primary hypothesis of this study is that Srx has an oncogenic function that may contribute totumorigenesis and cancer progression in mouse and human. The long-term object of this study is tounderstand the function and molecular mechanisms of Srx in human cancer development and progressionwhich will be valuable for future development of novel strategies for cancer prevention and treatment. The firstaim of the study is to test whether the genomic loss of Srx will cause mice more resistant to tumorigenesisusing a chemical induced mouse skin carcinogenesis model. The second aim is to study the function andmolecular basis of Srx in human lung cancer cell migration invasion and metastasis. The third aim is tocharacterize the proteins that interact with Srx and to determine how they contribute to the oncogenic functionof Srx in human lung cancer cells. The function of Srx will be examined using cell culture and mouse model ofskin carcinogenesis and mouse models of human cancer cell tumorigenesis and metastasis. The mechanisticstudy will be focused on the cell signaling change and protein-protein interactions using biochemistry andmolecular biology techniques. The successful completion of the proposed research will further theunderstanding of the role of Srx in human cancer will broaden the knowledge of antioxidant proteins intumorigenesis and cancer progression and will facilitate the development of novel strategies for cancerprevention and treatment.

project_terms:
910-Dimethyl-12-benzanthracene;A549;Adenocarcinoma;Affect;Affinity;Anchorage-Independent Growth;Antioxidants;Binding (Molecular Function);Biochemistry;Cell Culture Techniques;Cells;Chemicals;Data;Development;Down-Regulation;Enzymes;Epithelial Cells;Future;Gelatinase B;Genes;Genomics;Goals;Human;Knockout Mice;Knowledge;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Mediating;Modeling;Molecular;Molecular Biology Techniques;Molecular Target;Mus;Neoplasm Metastasis;Neoplastic Cell Transformation;Normal tissue morphology;Oncogenic;Oxidative Stress;Peroxidases;Phenotype;Protein Family;Proteins;Research;Resistance;Role;Signal Transduction;Skin;Skin Cancer;Skin Carcinogenesis;Squamous Cell Lung Carcinoma;Staging;Testing;Tetradecanoylphorbol Acetate;Transcription Factor AP-1;Tumor Promoters;Tumorigenicity;base;cancer cell;cancer prevention;cancer therapy;cell motility;in vivo;migration;mouse model;novel;novel strategies;protein protein interaction;tissue culture;tumor progression;tumorigenesis

public_health_relevance:
The project is to study the function of a novel gene Sulfiredoxin in cancer development using mousemodels and human cancer cells. Understanding the function and molecular mechanisms of Srx in caner isimportant for future development of novel strategies for cancer prevention and treatment.


application_id: 8630871
project_number: 5F31DA033728-02
project_title: Individual Differences in Escalation of Tobacco Use: Impulsivity and Alcohol Use
administering_ic: NIDA
award_notice_date: 2013-04-18
opportunity_number: PA-11-111
application_type: 5
activity_code: F31
ic: DA
serial_number: 033728
program_official: BJORK, JAMES M
project_start_date: 2012-04-22
project_end_date: 2013-08-24
study_section: Special Emphasis Panel[ZRG1-F16-B(20)L]
contact_pi_person_id: 11038716
contact_pi: LEE, DUSTIN CLARK
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): Like adolescents young adults are at risk of initiating tobacco use and escalating to daily use and tobacco dependence. However not every young adult who uses cigarettes intermittently becomes tobacco dependent and the time-course of those who transition to daily use varies widely. Individual differences likely contribute to the variability observed in patterns of tobacco use. This project will use a multi-modal research approach to examine dimensions of impulsivity and characteristics of alcohol that are associated with vulnerability for escalation of cigarette smoking and how alcohol interacts with behavioral inhibition to increase cigarette consumption. Furthermore this project will support the
applicant's career goal of becoming an independent investigator in the field of behavioral pharmacology capable of identifying and understanding risk factors associated with vulnerability to drug use and dependence. Impulsivity is a multidimensional construct that can be assessed using trait measures and tasks of behavioral inhibition and it is likely that these assessments inform drug use vulnerability. Dimensions of impulsivity are differentially associated with tobacco
initiation escalation and dependence. Moreover behavioral inhibition is altered as a consequence of acute and chronic drug exposure. Alcohol is also closely associated with vulnerability to escalating tobacco use and acute alcohol exposure is associated with decrements in behavioral inhibition. Thus it is likely that impulsivity and alcohol use have separate and combined influences on vulnerability to tobacco use. The first study will utilize data
from a longitudinal study to identify trajectories of tobacco use in young adults in order to determine 1) which dimensions of impulsivity and alcohol use inform vulnerability to escalating tobacco use and 2) if measures of behavioral inhibition are altered as a consequence of escalating cigarette use. The second study will utilize a laboratory design to examine whether alcohol-induced impairments in behavioral inhibition mediate the relationship between acute alcohol administration and increases in ad-libitum cigarette consumption. Results from these studies will improve scientific knowledge by elucidating the relationship between individual differences in both impulsivity and characteristics of alcohol use and escalation of cigarette smoking and identifying the mechanism(s) responsible for alcohol-induced escalation of tobacco use. This knowledge will help inform screening and prevention efforts aimed at reducing the amount of young adults who escalate to daily smoking.

project_terms:
Acute;Adolescent;Alcohol consumption;Alcohols;Behavior;Behavioral;Behavioral inhibition;Cessation of life;Characteristics;Chronic;Cigarette;Cigarette Smoker;Consumption;Cues;Data;Dependence;Development;Dimensions;Drug Addiction;Drug Exposure;Drug usage;Early Intervention;Goals;Impairment;Impulsivity;Individual Differences;Knowledge;Laboratories;Longitudinal Studies;Measures;Mediating;Modeling;Monitor;Non-smoker;Patient Self-Report;Pattern;Personality;Placebos;Population;Prevalence;Prevention;Preventive Intervention;Relative (related person);Reporting;Research;Research Personnel;Risk;Risk Factors;Self Administration;Smoker;Smoking;Smoking Behavior;Time;Tobacco;Tobacco Dependence;Tobacco smoking;Tobacco use;United States;alcohol effect;alcohol exposure;base;behavior measurement;behavioral pharmacology;career;cigarette smoking;design;improved;non-smoking;public health research;screening;trait;university student;young adult

public_health_relevance:
Young adults are at risk for escalating patterns of tobacco use and individual differences in impulsivity and alcohol use likely are associated with vulnerability of smoking escalation. This multi-modal project will examine dimensions of impulsivity and characteristics of alcohol use to determine which factors alone or in combination are associated with the escalation of tobacco smoking and how alcohol interacts with behavioral inhibition to increase cigarette consumption. This research will help inform screening treatment and prevention efforts aimed at reducing the number of young adults who become daily smokers.


application_id: 8628874
project_number: 5UM1HL113530-03
project_title: University of Louisville Regional Clinical Center for the CCTRN
administering_ic: NHLBI
award_notice_date: 2014-02-21
opportunity_number: RFA-HL-12-026
application_type: 5
activity_code: UM1
ic: HL
serial_number: 113530
program_official: EBERT, RAY F
project_start_date: 2012-03-22
project_end_date: 2019-02-28
study_section: ZHL1-CSR-O(F2)
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Activities of Daily Living;Address;Affect;Area;Basic Science;CD34 gene;Cardiac;Cardiac Surgery procedures;Cardiomyopathies;Cardiovascular Surgical Procedures;Cardiovascular system;Cell Therapy;Cell physiology;Cells;Cellular biology;Characteristics;Clinical;Clinical Research;Collaborations;Commit;Coupled;Effectiveness;Embryo;Enrollment;Environment;Event;Faculty;Goals;Heart failure;Hospitals;Human;Human Resources;Implant;In Vitro;Infarction;Institution;Left;Letters;Life;Medicine;Motivation;Multicenter Trials;Myocardial;Myocardial Ischemia;Myocardium;Names;Natural regeneration;Patients;Performance;Personnel Staffing;Phase;Population;Positioning Attribute;Postdoctoral Fellow;Proto-Oncogene Protein c-kit;Quality of life;Recovery;Reporting;Research;Research Infrastructure;Research Personnel;Resources;Safety;Staging;Stem cells;Testing;Therapeutic;Thoracic Surgical Procedures;Time;Universities;Work;base;clinical infrastructure;control trial;follower of religion Jewish;human study;implantation;improved;in vivo;injured;insight;member;novel;outcome forecast;phase 1 study;phase 2 study;phase 3 study;pre-clinical research;preclinical study;programs;repaired;stem cell population;stem cell therapy;success;ventricular assist device


application_id: 8628142
project_number: 5R01HD070792-03
project_title: Indomethacin and delayed umbilical cord clamp for preterm infant IVH
administering_ic: NICHD
award_notice_date: 2014-06-03
opportunity_number: PAR-11-246
application_type: 5
activity_code: R01
ic: HD
serial_number: 070792
program_official: REN, ZHAOXIA
project_start_date: 2013-04-01
project_end_date: 2018-03-31
study_section: Special Emphasis Panel[ZRG1-EMNR-R(55)R]
contact_pi_person_id: 6654912
contact_pi: GIANNONE, PETER J
other_pis: BAUER, JOHN ANTHONY
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abbreviations;Address;Adverse effects;Affect;Apoptotic;Biological Markers;Birth;Birth Weight;Blinded;Blood;Blood Volume;Brain;Brain Injuries;Brain imaging;Caring;Case Study;Cephalic;Cerebral Palsy;Child;Clinical;Cognitive;Communities;Costs and Benefits;Data;Developmental Delay Disorders;Developmental Disabilities;Effectiveness;Evaluation;Extremely Low Birth Weight Infant;FDA approved;Frequencies (time pattern);Gestational Age;Goals;Head;Health Care Costs;Hemorrhage;Incidence;Indomethacin;Infant;Inflammatory;Intervention;Intestinal Perforation;Investigation;Kidney;Lesion;Life;Link;Magnetic Resonance Imaging;Measurement;Medical;Medical center;Mental Retardation;Mothers;Neonatology;Neurocognitive;Neurologic;Neurons;Newborn Infant;Organ failure;Outcome;Outcome Measure;Patient Care;Pediatric Hospitals;Performance;Periventricular Leukomalacia;Phenotype;Premature Infant;Prevalence;Prevention;Prevention therapy;Protocols documentation;Randomized;Research;Risk;Safety;Severities;Site;Stem cells;Stress;Surveys;Survivors;Testing;Toxic effect;Ultrasonography;Umbilical cord structure;clinical care;comparative efficacy;cost;design;disability;follow-up;hemodynamics;high risk;improved;intraventricular hemorrhage;patient population;premature;prevent;primary outcome;prophylactic;public health relevance;social;vascular inflammation


application_id: 8628110
project_number: 5R01DK074720-07
project_title: Novel hematopoietic effects of C5 cleavage fragment
administering_ic: NIDDK
award_notice_date: 2014-04-30
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DK
serial_number: 074720
program_official: BISHOP, TERRY ROGERS
project_start_date: 2007-03-01
project_end_date: 2017-02-28
study_section: Special Emphasis Panel[ZRG1-VH-C(02)]
contact_pi_person_id: 2265592
contact_pi: RATAJCZAK, MARIUSZ Z
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): Both pharmacological mobilization of hematopoietic stem progenitor cells (HSPCs) and myeloablative conditioning for transplantation activate the complement cascade (CC) in bone marrow (BM) and in the previous funding period we focused on the role of the third complement component (C3) in mobilization and homing of HSPCs. In this competing renewal we will focus on the fifth complement component (C5) which is located downstream from C3. C5 cleavage leads to generation of the potent anaphylatoxins C5a and desArgC5a and generation of non-lytic and lytic C5b-C9 known as the membrane attack complex (MAC). Our recently published data support a crucial role for C5a/C5b-C9 in trafficking of HSPCs. In particular C5-deficient mice are poor mobilizers in response to granulocyte colony stimulating factor (G-CSF) and exhibit delayed hematopoietic reconstitution after transplantation with wild type (WT) BM cells. Based on these findings the central hypothesis of this competing renewal is that the activation of distal steps of the complement cascade and release of C5a and C5b-C9 (MAC) are important regulators of mobilization and homing of HSPCs. To address this hypothesis we propose: Specific Aim 1. The molecular basis of the mobilization defect in C5-deficient mice. Based on our observation that C5-deficient mice are poor G-CSF mobilizers we will address whether C5 cleavage is i) required for circadian HSPC mobilization ii) mobilization of HSPC induced by other agents and iii) whether C5 activation and S1P plasma level correlates with mobilization efficacy in patients. We will also focus on the role of erythrocyte-released S1P in mobilization by performing mobilization studies in CD55/CD59-deficient mice that are highly sensitive to C5b-C9 (MAC) lysis. Finally we will focus on the role of C5b-C9-induced release of S1P in mobilization observed in patients with hemolytic syndromes. Specific Aim 2. The molecular basis of the homing defect in C5-deficient mice. We found that the CC is activated in lethally irradiated mice and that C5-deficient mice engraft poorly with WT BM cells. To shed more light on the role of the distal part of the CC (C5a/C5b-C9) in homing/engraftment we will study whether conditioning for transplantation by chemotherapy also activates the CC in BM and study the effect of C5a/C5b-C9 on expression of i) HSPC chemoattractants in BM ii) adhesion/tethering molecules for HSPCs on BM endothelium and ii) on secretion of factors facilitating homing. Specific Aim 3. The C5a/C5b-C9-induced BM stroma-derived cathelicidin (LL-37) as a potent homing sensitizing factor. We found that LL-37 like C3a is a very strong priming factor for SDF-1 that becomes upregulated in BM stroma after conditioning for transplantation in a C5a/C5b-C9-dependent manner. In an immunodeficient mouse model we will test whether short exposure of HSPCs to LL-37 before transplantation increases homing of human BM- and umbilical cord blood (UCB)-derived HSPCs. We will also address whether LL-37 also primes the responsiveness of HSPCs to other homing factors and focus on the molecular mechanism of these phenomena.

project_terms:
Address;Adhesions;Adult;Anaphylatoxins;Blood Vessels;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;CXCR4 Receptors;CXCR4 gene;Cell Adhesion Molecules;Cells;Chemotactic Factors;Circadian Rhythms;Collaborations;Complement;Complement 3a;Complement 5a;Complement Activation;Complement Membrane Attack Complex;Complement component C5;Cytolysis;Data;Defect;Development;Dinoprostone;Distal;Endothelium;Engraftment;Erythrocytes;Exhibits;Fibroblasts;Funding;Generations;Granulocyte Colony-Stimulating Factor;Growth Factor;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Mobilization;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Homing;Human;Integrin alpha4beta1;Integrins;Investigation;Lead;Life;Ligands;Light;Link;Lipids;Lytic;Molecular;Mus;Natural Immunity;Nucleotides;Osteoblasts;Patients;Physiological;Plasma;Polysaccharides;Process;Publishing;Role;Stem cells;Syndrome;Testing;Transplantation;Transplantation Conditioning;Umbilical Cord Blood;Vascular Cell Adhesion Molecule-1;Work;base;cathelicidin;ceramide 1-phosphate;chemotherapy;complement C3 precursor;complement C5b;immunodeficient mouse model;leukemia;novel;novel therapeutics;peripheral blood;public health relevance;reconstitution;response;sphingosine 1-phosphate;stem;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Section In this competing renewal we will focus on the role of a major component of innate immunity namely activation of the complement cascade in trafficking of hematopoietic stem/progenitor cells. This application will allow us to better understand this process as well as lead to the development of novel therapeutic strategies to treat patients with leukemias and inborn defects of hematopoiesis by transplantation of hematopoietic stem cells.


application_id: 8627598
project_number: 5R01DE017680-07
project_title: Role of GSK3 in host inflammation
administering_ic: NIDCR
award_notice_date: 2014-03-31
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DE
serial_number: 017680
program_official: MELILLO, AMANDA A
project_start_date: 2007-04-25
project_end_date: 2018-02-28
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
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_terms:
Alveolar Bone Loss;Amplifiers;Anti-Bacterial Agents;Anti-Inflammatory Agents;Anti-inflammatory;Attention;Bacteria;Bacterial Infections;Cardiovascular system;Cells;Cessation of life;Chronic;Communicable Diseases;Complex;Cutaneous;Data;Dental Plaque;Development;Disease;Disease Progression;Event;Glycogen Synthase Kinases;Goals;Health Care Costs;Host Defense;Human;Immune;Immune response;Immune system;In Vitro;Infection;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Interferon-beta;Interleukin-10;Invaded;Lead;Leukocytes;Life Cycle Stages;Lung diseases;Matrix Metalloproteinases;Mediating;Microbe;Modeling;Molecular;Mus;Natural Immunity;Nature;Nicotinic Receptors;PI3K/AKT;Pathology;Pathway interactions;Pattern;Pattern recognition receptor;Periodontal Diseases;Periodontitis;Pharmacologic Substance;Play;Porphyromonas gingivalis;Production;Regulation;Role;Seminal;Signal Pathway;Signal Transduction;Site;T-Cell Development;TLR2 gene;TLR4 gene;Testing;Therapeutic;Therapeutic Intervention;Tissues;Toll-like receptors;anakinra;cholinergic;controlled release;cytokine;driving force;in vivo;microbial;novel;novel strategies;oral pathogen;pathogen;pathogenic bacteria;public health relevance;receptor;response;therapeutic target;tool

public_health_relevance:
It is the host response to dental plaque that leads to the development of periodontitis one of the most common infectious diseases in humans that consumes   >$14 billion dollars in health costs in the U.S. per annum. We will identify overlapping events between several endogenous mechanisms of inflammatory suppression (the PI3K/AKT/GSK3b; cholinergic; and Wnt3a anti-inflammatory pathways); elucidate specific mechanisms that suppress pro-inflammatory cytokine production in response to bacterial infection; determine anti-inflammatory events that control the release of tissue degrading matrix metalloproteinases; and establish if we can exploit these anti-inflammatory pathways to reduce inflammation and periodontal disease progression in murine models. These data will identify novel potential therapeutic approaches to the control of destructive inflammation.


application_id: 8626878
project_number: 1R15ES023693-01
project_title: The role of microRNA miR-21 in nickel nanoparticles-induced MMPs production
administering_ic: NIEHS
award_notice_date: 2014-09-17
opportunity_number: PA-12-006
application_type: 1
activity_code: R15
ic: ES
serial_number: 023693
program_official: NADADUR, SRIKANTH
project_start_date: 2014-09-17
project_end_date: 2019-06-30
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 8567542
contact_pi: ZHANG, QUNWEI
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
With the development of nanotechnology a large number of metal nanoparticles are being developed andproduced with new formulations and surface properties to meet novel demands. For example as an importanttransition metal nickel nanoparticles (Nano-Ni) have wide ranging applications in the fields of batterieselectrical conductors permanent magnets magnetic fluids magnetic recording media solar energyabsorption fuel cell electrodes and catalysts. In addition due to structural and inherent chemical and physicalproperties nickel alloy nanomaterials have received special interest in biomedical applications. As the use ofnanomaterials continues to grow the risk of environmental contamination by nanoparticles is increases. Theterm 'Nanotoxicology' has been used to put forward the concept that nanoparticles might represent a uniqueclass of particulate toxins that differ from conventional pathogenic particles. In this proposal we selectedNano-Ni as a model metal nanoparticles because of its wide industrial interest and biological and medicalapplications. Based on our preliminary data we hypothesize that Nano-Ni will activatemonocytes/macrophages altering the expression and activity of matrix metalloproteinases (MMPs)through hypoxia inducible factor 1a (HIF-1a) and microRNA miR-21. It is possible that structurally-tailored Ni-containing nanoparticles such as nickel alloy nanoparticles could have fewer or even noeffects. This would be very important to know. This project will use both in vitro and in vivo systems toaddress the following objectives. (1). Determine the alteration of MMPs and TIMPs expression and activityin monocytes/macrophages exposed to Nano-Ni or nickel alloy nanoparticles in vitro and in vivo. Wewill examine whether exposure to Nano-Ni will alter MMP-2 MMP-9 TIMP-1 and TIMP-2 production in bothU937 cells (human leukemic monocyte lymphoma cell line) and monocytes isolated from mice by usingquantitative real-time PCR gelatin zymography or reverse zymography assay in vitro. We will also determinethe alteration of MMPs and TIMPs expression and activity in monocytes isolated from Nano-Ni-exposed mice.We will investigate whether nickel alloy nanoparticles Nano-Ni core and silica or carbon shell and silica orcarbon supported Nano-Ni will reduce the Nano-Ni-induced activation of MMPs and toxic effect in vitro and invivo settings. (2). Examine HIF-1a accumulation in monocytes/macrophages with exposure to Nano-Niand the role of HIF-1a on the Nano-Ni-induced alteration of MMPs expression and activity. We willmeasure the HIF-1a level in U937 cells with exposure to Nano-Ni. To investigate the role of HIF-1a in Nano-Ni-induced MMPs expression and activity we will employ the following strategies: (1) use of HIF-1a inhibitorssuch as heat-shock protein 90 (Hsp90); (2) use of HIF-1a-specific siRNA to knock-down HIF-1a expression;and (3) use of HIF-1a knock-out cells. (3). Investigate whether Nano-Ni-induced alteration of MMPsexpression and activity through up-regulation of microRNA miR-21 by activation of HIF-1a. We will firstidentify whether exposure to Nano-Ni will cause up-regulation of miR-21 by quantitative real-time PCR. We willthen investigate whether miR-21 modulates MMPs expression and activity by activation HIF-1a by using: (1)pre-miR-21 transfection to increase the abundance of miR-21 in the cells; (2) anti-miR-21 transfection to lowerthe level of miR-21 in the cells; and (3) use HIF decoy to block the activity of endogenous HIF transcriptionfactor in the cells.

project_terms:
17-(Allylamino)-17-demethoxygeldanamycin;Address;Adverse effects;Alloys;Area;Biological;Biosensor;Blood Cells;Blood Circulation;Bone Marrow;Breathing;Carbon;Cell Line;Cells;Data;Development;Diagnostic;Drug Formulations;Electrical battery;Electrodes;Engineering;Environmental Pollution;Exposure to;Gastrointestinal tract structure;Gelatin Zymography;Gelatinase A;Gelatinase B;Growth;Health;Heat-Shock Proteins 90;Hematopoietic stem cells;Home environment;Human;Hyperthermia;Hypoxia Inducible Factor;Immune response;In Vitro;Inflammatory;Inflammatory Response;Information Technology;Knock-out;Knowledge;Lead;Leukocytes;Liquid substance;Location;Lung;Lymphoma;Magnetic Resonance Imaging;Magnetism;Matrix Metalloproteinases;Measures;Medical;Messenger RNA;Metal exposure;Metals;MicroRNAs;Modeling;Molecular;Mus;Nanotechnology;Nickel;Particulate;Play;ProMMP-9;Production;Rattus;Reporting;Risk;Role;Silicon Dioxide;Site;Skin;Small Interfering RNA;Solar Energy;Surface Properties;System;Testing;Time;Tissue Inhibitor of Metalloproteinase-1;Toxic effect;Toxin;Transfection;Transition Elements;U937 Cells;Up-Regulation (Physiology);Work;absorption;base;catalyst;chemical property;cytokine;improved;in vitro Assay;in vivo;inhibitor/antagonist;interest;knock-down;macrophage;meetings;monoblast;monocyte;nano;nanomaterials;nanoparticle;nanosized;nanotoxicology;new technology;novel;particle;peripheral blood;physical property;public health relevance;titanium dioxide;tool;transcription factor

public_health_relevance:
Nanotechnology is considered to be one of the world's most promising new technologies. It directly improvesour lives in areas as diverse as materials engineering information technology and medical diagnostics. Thisproject will provide important scientific information regarding the potential for metal nanoparticles to causeadverse health effects in humans. We expect that our results will provide tools for evaluating othernanomaterials. Successful completion of this project will also lead to a better understanding of the mechanismsby which metal nanoparticles induce pulmonary and systemic effects.


application_id: 8625708
project_number: 5K23AR060275-03
project_title: Clinical and Biochemical Predictors of Outcome after Knee Injury in Young Patient
administering_ic: NIAMS
award_notice_date: 2014-05-08
opportunity_number: PA-10-060
application_type: 5
activity_code: K23
ic: AR
serial_number: 060275
program_official: PANAGIS, JAMES S
project_start_date: 2012-03-05
project_end_date: 2017-02-28
study_section: Arthritis and Musculoskeletal and Skin Diseases Special Grants Study Section[AMS]
contact_pi_person_id: 9042382
contact_pi: LATTERMANN, CHRISTIAN
other_pis: Not Applicable
congressional_district: 06
department: ORTHOPEDICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Posttraumatic osteoarthritis is an acknowledged outcome of contact-related sports injuries but is an underestimated and understudied problem occurring after non-contact rupture of the anterior cruciate ligament (ACL).  It is estimated that approximately 40-50% of young athletes are at significant risk for developing progressive osteoarthritis (OA) 10-20 years after ACL injury suffered during high school sports participation. Unfortunately reliable predictors of which athletes are at highest risk for developing OA after ACL injury do not exist.   We propose to establish for the first time baseline serum measures of specific biomarkers in 350 injury- free adolescent high school athletes before during and after their competitive season (Aim 1). We will follow this cohort of subjects prospectively for 4 years. Simultaneously we will study a second age- matched cohort of young high school athletes with documented ACL tears. Biomarkers will be measured in these subjects post-injury until biomarker values normalize.  These subjects will be followed for two years post-operatively using patient reported outcome (PRO) instruments. We hypothesize that biomarker levels will increase after ACL injury relative to a normative population. In addition we hypothesize that biomarkers will be highest in subjects with more severe bone bruising after ACL injury (Aim 2).  Finally we will determine outcomes of subjects with severe bone bruises following ACL injury (Aim 3). The presence of bone bruise is not known to be a predictor of posttraumatic OA and lower clinical outcomes scores however bone bruises have been implicated in the progression of osteoarthritis after ACL injury. We will examine if any correlation exists between the magnitude distribution or severity of bone bruise lower patient reported outcomes and evidence of posttraumatic OA initiation at 2 year follow-up. We will also re-examine pre-operative MRI scans pre and post-operative standardized  x-ray and patient reported outcomes followed over 2 years (with a follow-up rate of 85%) in a  prospective longitudinal cohort of 112 isolated ACL injured patients with no additional comorbidities.   Typically 90-100% of these patients may be expected to have a bone bruise after ACL injury.   The impact of these studies is expected to be significant. The identification and validation of biomarkers with and without supporting correlating data from the extent of bone bruise associated with ACL rupture  will provide clinicians with the means to identify adolescents at high risk for the development of  disabling and crippling posttraumatic osteoarthritis and tailor treatment and rehabilitation protocols  that may prevent or delay early onset osteoarthritis in this vulnerable population.

project_terms:
Adolescent;Age;Anterior Cruciate Ligament;Arthritis;Athletic Injuries;Biochemical;Biological Markers;Bone Injury;Cartilage;Cartilage injury;Characteristics;Clinical;Comorbidity;Contusions;Data;Degenerative polyarthritis;Development;Elderly;Employee Strikes;Enrollment;Film;Goals;Image Analysis;Individual;Injury;Knee;Knee Injuries;Lead;Lesion;Location;Lower Extremity;Magnetic Resonance Imaging;Measures;Operative Surgical Procedures;Outcome;Patient Outcomes Assessments;Patients;Pattern;Physiologic pulse;Population;Postoperative Period;Protocols documentation;Recommendation;Regimen;Rehabilitation therapy;Relative (related person);Reporting;Risk;Seasons;Serum;Severities;Sports;Testing;Time;Universities;Validation;Visual;Vulnerable Populations;Work;anterior cruciate ligament rupture;articular cartilage;bone;cohort;design;disability;early onset;follow-up;high risk;high school;injured;instrument;ligament injury;mammalian COMP;prevent;prospective;young adult

public_health_relevance:
Non-contact injuries to the knee in the young are becoming prevalent at an alarming rate as participation in high school sports increases. Anterior cruciate ligament (ACL) injuries with bone bruises may hasten cartilage loss predisposing some individuals to early onset osteoarthritis. This study investigates the ability of a serum biomarkerand magnetic resonance imaging to predict (separately or in combination) progressive unremitting cartilage loss in high school athletes at the time of ACL injury. The result of this study may significantly impact the design and implementation of new better treatment and rehabilitation protocols in these young athletes.


application_id: 8625606
project_number: 1R03CA172954-01A1
project_title: Evaluation of T Cell Response to Cisplatin Resistant NSCLC
administering_ic: NCI
award_notice_date: 2013-12-30
opportunity_number: PAR-11-079
application_type: 1
activity_code: R03
ic: CA
serial_number: 172954
suffix: A1
program_official: PERLOFF, MARJORIE
project_start_date: 2014-01-01
project_end_date: 2015-12-31
study_section: Special Emphasis Panel[ZCA1 SRLB-J (O1)]
contact_pi_person_id: 1870178
contact_pi: YANNELLI, JOHN R.
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
project_abstract:
Abstract: Non small cell lung cancer (NSCLC) is a leading killer of men and women around the world. Mostpatients present in the clinic with advanced stage disease at a point where surgery is not an option andconventional chemotherapy and radiation therapy are limited in their effectiveness. Novel therapies are neededfor this patient population. Continued failure to significantly impact NSCLC patients with conventional therapywill tax the health care system and remain a financial burden for families and society. Interestingly whileNSCLC is responsive to chemotherapeutic agents such as cisplatin tumor is often observed to recur orprogress in additional anatomic sites. It is known that NSCLC as well as other solid tumors developmechanisms of drug resistance. Thus continued exposure to cisplatin remains ineffective. In the current studywe propose to investigate whether Immunotherapy which exploits the patient's immune system to recognizeand eliminate cancer should be considered to address the issue of chemo-resistance. We are asking thequestion that following cisplatin therapy in NSCLC patients what role can immunotherapy play in preventingthe growth of chemo-resistant tumor cell clones which likely result in tumor recurrence and progression? Ourhypothesis is that proteins which characterize cisplatin chemo-resistance can be targeted by vaccinetherapy. To address this hypothesis we will build on the expertise of our group in developing and deliveringvaccines in lung cancer. The current proposal is a proof of principle study which will investigate the existenceof novel shared tumor associated antigens which are immunogenic and define the chemo-resistant phenotype.A unique methodology is proposed to identify HLA-A2 restricted cisplatin resistant CTL in normal donors basedon specific antigen stimulation and TCR-Vbeta analysis. Understanding preferential usage of Vbetas in normaldonors will be applied to the analysis of archived PBMC derived from -A2+ patients with NSCLC. Using thismethodology we will determine if the precursor frequency for CTL specific for peptides characteristic of thecisplatin resistant state will be higher in patients previously exposed to cisplatin. If true in a future clinicalstudy we hypothesize that NSCLC patients can be immunized against these peptides before cisplatin therapy.Following an appropriate period of rest NSCLC patients given boost vaccine injections with the peptidesderived from the chemo-resistant proteins are expected to generate a potent immune response allowing therecognition and destruction of chemo-resistant tumor cells; thus preventing recurrence and progression. Allrequired reagents for this proof of principle analysis are available to the applicant.

project_terms:
Accounting;Address;Adjuvant;Advocate;Allogenic;Anatomic Sites;Antigens;Apoptotic;Archives;Autologous Dendritic Cells;Brain;Breast;CD8B1 gene;Cancer Patient;Cancer cell line;Cell Line;Cell Survival;Cells;Centers for Disease Control and Prevention (U.S.);Cessation of life;Characteristics;Cisplatin;Clinic;Clinical Research;Colon;Colon Carcinoma;Cytotoxic T-Lymphocytes;Data;Disease;Drug Targeting;Drug resistance;Drug toxicity;Effectiveness;Evaluation;Exposure to;Failure (biologic function);Family;Flow Cytometry;Frequencies (time pattern);Funding;Future;Growth;HLA-A2 Antigen;Habits;Healthcare Systems;Household;Immune response;Immune system;Immunity;Immunotherapeutic agent;Immunotherapy;In Vitro;Injection of therapeutic agent;Investigation;Kentucky;Laboratories;Lead;Link;Literature;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Methodology;Necrosis;Non-Small-Cell Lung Carcinoma;Oncologist;Operative Surgical Procedures;Outcome;Patients;Peptides;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phenotype;Play;Population;Primary Health Care;Prostate;Proteins;Quality of life;Radiation;Radiation therapy;Reagent;Recurrence;Resistance;Rest;Role;Site;Smoke;Smoking;Societies;Solid Neoplasm;Source;Specificity;Staging;Supportive care;Survival Rate;Symptoms;T cell response;T-Lymphocyte;Taxes;Therapeutic;Tumor Antigens;Universities;Vaccine Therapy;Vaccines;Variant;Woman;base;beta-Glucans;bone;chemotherapeutic agent;chemotherapy;conventional therapy;design;disease diagnosis;immunogenic;immunogenicity;improved;lymph nodes;malignant breast neoplasm;men;neoplastic cell;never smoker;novel;novel vaccines;outcome forecast;patient population;prevent;public health relevance;research clinical testing;tumor;vaccine development;vaccine evaluation

public_health_relevance:
Narrative: Prognosis of advanced stage NSCLC is grim. While some oncologists advocate therapeuticnihilism for advanced NSCLC based on excessive drug toxicity and universally poor outcomes chemotherapycan reduce symptoms improve quality of life and result in small improvement in survival when compared tobest supportive care. This application describes Proof of Principle studies for the improvement of an alreadyproven cellular vaccine for NSCLC.


application_id: 8624215
project_number: 1R21AI109529-01
project_title: Mechanism of inhibition of RNA virus replication by host WW-domain proteins
administering_ic: NIAID
award_notice_date: 2014-03-31
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: AI
serial_number: 109529
program_official: PARK, EUN-CHUNG
project_start_date: 2014-04-01
project_end_date: 2016-03-31
study_section: Virology - A Study Section[VIRA]
contact_pi_person_id: 7353039
contact_pi: NAGY, PETER
other_pis: Not Applicable
congressional_district: 06
department: OTHER BASIC SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Recent genome-wide screens with multiple viruses have identified several host proteins which inhibit RNA virus accumulation and act as restriction factors against viruses. Unfortunately the restriction functions of these host factors are not yet
defined for important human viruses. Among the identified inhibitory host proteins are the family of WW-domain proteins which are effective against several viruses. WW-domain proteins are abundant proteins participating in protein interactions and they are involved in several diseases such as human cancers inherited diseases and viral infections. Progress in our understanding of the mechanisms of host factors is slow due to functional redundancy or lack of knowledge about their functions. However easily tractable virus - host systems such as Tomato bushy stunt virus (TBSV) and yeast as a model host can contribute to our understanding of the functions of these host proteins. This project will likely advance our understanding of the role of
host WW-domain proteins in virus-host interactions. This advance could immensely help other scientists working with less tractable but devastating viral pathogens for which similar studies are currently not yet feasible. The following are the major strengths of the proposal: (i) Host restriction factors have clear negative impact on viruses. (ii) The restriction function of WW-domain proteins will be explored against tombusviruses and insect nodaviruses. (iii) The combination of yeast and authentic cell-free assay developed by the PI is currently the most potent for studying the mechanism of host factors involvement in viral RNA replication and viral pathogenesis. (iv) The research holds promise of benefiting society by leading to groundbreaking results in the area of virus replication host-virus interactions and the viral pathogenesis.

project_terms:
Affect;Animals;Antiviral Agents;Area;Biochemical;Biological Assay;Cataloging;Catalogs;Cells;Dengue Virus;Development;Disease;Evolution;Flavivirus;Genes;Hepatitis C virus;Human;Human Virus;Inherited;Insecta;Integration Host Factors;Knowledge;Lead;Malignant Neoplasms;Modeling;Pathology;Pestivirus;Plants;Play;Protein Family;Proteins;Proteomics;RNA Viruses;RNA replication;Research;Role;Scientist;Societies;System;Tertiary Protein Structure;Tombusvirus;Viral;Viral Pathogenesis;Virus;Virus Diseases;Virus Replication;West Nile virus;Work;Yeast Model System;Yeasts;base;genome wide association study;high throughput screening;insight;novel;novel strategies;pathogen;protein protein interaction;public health relevance;replicase;tomato bushy stunt virus;viral RNA;virus host interaction;yeast genetics

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Viruses which are important and emerging human animal and plant pathogens are greatly affected by host restriction factors. We find in high throughput screens that inactivation of selected host WW-domain proteins facilitated robust RNA virus replication. The proposed work will explore the inhibitory roles of host WW-domain proteins in virus infection that could facilitate the development of novel antiviral approaches.


application_id: 8623116
project_number: 5R01DA027981-05
project_title: Victimization and Women in the Criminal Justice System
administering_ic: NIDA
award_notice_date: 2014-02-14
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DA
serial_number: 027981
program_official: HARTSOCK, PETER
project_start_date: 2010-04-01
project_end_date: 2016-02-29
study_section: Community Influences on Health Behavior Study Section[CIHB]
contact_pi_person_id: 6472821
contact_pi: GOLDER, SEANA
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 SOCIAL WELFARE/WORK
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposed study (R01; PA-07-070) will examine the heterogeneity of victimization its' relationship with substance use and psychological distress as well as the combined affect of these factors on the health seeking process among victimized women in the criminal justice (CJ) system. Study aims are to 1) identify and characterize latent class trajectories based on victimization substance use and psychological distress among 400 victimized women on probation and parole; 2) determine the extent to which women in the identified trajectory classes vary over a two year time period in levels of risk and protection in the health seeking process; and 3) examine the theory based components of the health seeking process among 400 victimized women on probation and parole. Findings from this research will be used to identify those groups of women that are most at risk for engagement in high risk behaviors (current drug use; psychological distress; HIV risk behavior; lawbreaking and continued CJ involvement) and to identify and characterize their associated levels of risk and protection in the health seeking process across a two year time period. Study findings will provide a theoretically guided understanding of the relationship among the component parts of the health seeking process that affect engagement in high risk behavior over time among this population. These data are necessary prerequisites to the development of tailored intervention strategies that target specific groups of women within the CJ system; these data can provide practitioners administrators and policy makers with direct information about which groups of women will be most amenable to which intervention/prevention approaches. Study findings have the potential to have broad relevance within the CJ system and other care systems (e.g. substance abuse and mental health treatment systems) that provide services to this marginalized and growing population.

project_terms:
Address;Administrator;Adult;Affect;Age;Alcohol or Other Drugs use;Area;Behavior;Child;Child Welfare;Childhood;Cognitive;Color;Communicable Diseases;Communities;Crime;Criminal Justice;Data;Development;Drug usage;Emotions;Employment;Ethnicity aspects;Family;Goals;Growth;HIV risk;Health;Heterogeneity;Housing;Imprisonment;Individual;Intervention;Justice;Longevity;Mental Health;Methodology;Nature;Pathway interactions;Pattern;Personal Satisfaction;Policy Maker;Population;Prevention approach;Preventive Intervention;Process;Race;Research;Resources;Rewards;Risk;Risk Behaviors;Security;Services;Social support;Stress;Subgroup;Substance abuse problem;System;Testing;Time;Victimization;Woman;Women's Group;base;care systems;cohesion;coping;high risk;high risk behavior;men;parole;peer;person centered;physical conditioning;probation;psychological distress;psychosocial;public health medicine (field);public health relevance;response;self esteem;social;theories;therapy development;virtual

public_health_relevance:
The confluence of race and class among women in the CJ system means that increases in this population disproportionately affect the health and well-being of women of color particularly poor women of color; the increased involvement of women in the CJ system has perpetuated and fueled racial disparities and biases in the areas of child well-being and the child welfare system infectious diseases and other markers of public health and other domains of psychosocial functioning such as employment and educational attainment. Results of this study will contribute directly to the development of targeted intervention strategies to address the needs of this population; study results will allow for the identification of those groups of victimized women in the CJ system that are most at risk for engagement in high risk behaviors (current drug use; psychological distress; HIV risk behavior; lawbreaking and continued CJ involvement) and to characterize their associated levels of risk and protection in the health seeking process across time. Results will also provide a theoretically guided understanding of the health seeking process by which these women come to engage in high risk behavior.


application_id: 8622285
project_number: 1R21EB017902-01
project_title: Biodegradable Polymerized Simvastatin
administering_ic: NIBIB
award_notice_date: 2014-09-22
opportunity_number: PA-12-284
application_type: 1
activity_code: R21
ic: EB
serial_number: 017902
program_official: RAMPULLA, DAVID
project_start_date: 2014-09-22
project_end_date: 2016-06-30
study_section: Biomaterials and Biointerfaces Study Section[BMBI]
contact_pi_person_id: 1874927
contact_pi: PULEO, DAVID A.
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION:  Synthetic degradable polymers are commonly used for drug delivery and to aid in tissue regeneration. Drugs are routinely encapsulated in the material for subsequent diffusion- and/or degradation-mediated release. Limitations with encapsulation however include limited payload and the potential for premature exhaustion of the delivery system. To prolong release drugs have been conjugated to polymers. Drug can be attached to the polymer via a linker that subsequently releases the molecule following cleavage or it can be incorporated into the polymeric backbone during synthesis.  The overarching goal of this project is to develop and characterize a polymer synthesized using drug molecules in the present case simvastatin as monomers. The working hypothesis is that the structure of simvastatin with a lactone moiety in the prodrug is amenable to ring-opening polymerization. As such polymerized simvastatin could then be processed into films that degrade by hydrolysis to release bioactive simvastatin molecules which have osteogenic anti-inflammatory and angiogenic properties in addition to their well-known known hypolipidemic effects.  Aim 1 will develop and characterize a degradable polymerized form of simvastatin. With respect to this objective it is hypothesized that the polymer can be processed into biodegradable films that release simvastatin. Aim 2 will investigate whether polymerized films of simvastatin degrade in vivo to stimulate osteogenesis in a rodent supracalvarial implantation model. It is hypothesized that as the polymer degrades bioactive simvastatin is released to enhance local bone formation.  If the proof-of-principle studies proposed for this Exploratory/Developmental Award are successful the polymer may be fabricated into a variety of physical forms (e.g. microspheres and tissue engineering scaffolds) to exploit the pleiotropic effects of simvastatin for bone and other tissue applications as well as the methods potentially being applicable to other members of the statin family.

project_terms:
Adverse effects;Anti-Inflammatory Agents;Anti-inflammatory;Award;Biocompatible Materials;Biological;Biomedical Engineering;Cells;Data;Defect;Development;Diffusion;Drug Delivery Systems;Drug usage;Encapsulated;Ethylene Glycols;Family;Film;Glycolates;Goals;Hydrolysis;Implant;Lactones;Local Anti-Infective Agents;Mediating;Methods;Microspheres;Modeling;Molecular Weight;Nanosphere;Nylons;Osteogenesis;Pharmaceutical Preparations;Polyanhydrides;Polyesters;Polymers;Process;Prodrugs;Property;Reaction;Research Project Grants;Rodent;Simvastatin;Site;Structure;System;Systemic Therapy;Testing;Tissue Engineering;Tissues;Trauma;Ursidae Family;Vertebral column;Work;biodegradable polymer;biomaterial compatibility;bone;cancer therapy;caprolactone;controlled release;copolymer;design;direct application;ethylene glycol;exhaustion;implantation;in vivo;member;monomer;multidisciplinary;osteogenic;particle;poly(lactic acid);polycarbonate;polymerization;premature;public health relevance;response;scaffold;tissue regeneration;tumor;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Synthetic degradable polymers are commonly employed for drug delivery and to aid in tissue regeneration. Although current materials are useful limitations
include limited payload and instability of drug. This project will develop a polymer directly composed of the drug simvastatin which has several important biological activities including osteogenic anti-inflammatory and angiogenic effects.


application_id: 8622195
project_number: 5R01EY012716-15
project_title: Functional State of Developing Retinogeniculate Synapse
administering_ic: NEI
award_notice_date: 2014-02-27
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: EY
serial_number: 012716
program_official: GREENWELL, THOMAS
project_start_date: 2001-05-01
project_end_date: 2018-02-28
study_section: Special Emphasis Panel[ZRG1-IFCN-Q(02)M]
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_terms:
3-Dimensional;Address;Adopted;Age;Architecture;Axon;Behavioral;Biological Models;Brain;Brain Stem;Cell Nucleus;Cells;Cholera Toxin Protomer B;Deafferentation procedure;Development;Disease;Dorsal;Event;Exhibits;Eye;Felis catus;Genetic;Goals;Imagery;In Vitro;Injection of therapeutic agent;Injury;Interneurons;Knowledge;Label;Lateral Geniculate Body;Life;Light;Mus;Neurons;Optic Nerve;Pathway interactions;Pattern;Preparation;Retina;Retinal;Retinal Ganglion Cells;Rhodopsin;Signal Transduction;Slice;Source;Specificity;Synapses;Testing;Thalamic structure;Time;Transgenic Mice;Transgenic Organisms;Trees;Variant;Viral;Visual;Visual Cortex;base;biocytin;cell type;cholinergic;developmental disease/disorder;insight;loss of function;monocular;mouse model;mutant;nerve supply;nervous system disorder;optogenetics;postnatal;preference;public health relevance;reconstruction;research study;response;retinal axon;retinal progenitor cell;retinogeniculate;synaptogenesis;transcription factor;transmission process

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. Knowledge gained from these studies will also have important implications for understanding and predicting how thalamic circuits involving retinal and nonretinal projections respond to disease or injury.


application_id: 8620620
project_number: 5R01CA167181-02
project_title: Novel Mechanism of Genome Instability in Colorectal Cancer
administering_ic: NCI
award_notice_date: 2014-01-16
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 167181
program_official: OKANO, PAUL
project_start_date: 2013-02-15
project_end_date: 2018-01-31
study_section: Molecular Genetics B Study Section[MGB]
contact_pi_person_id: 7875365
contact_pi: LI, GUO-MIN
other_pis: GU, LIYA
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this project is to study how post-translational modifications of DNA mismatch repair (MMR) proteins impact genome integrity and cancer development. MMR maintains genome stability by removing mismatches in the newly synthesized strand during DNA replication. The MMR reaction involves mismatch recognition by the initiation factors (MutS MutL and PCNA) mismatch removal by nucleases and DNA gap-filling by DNA polymerases. The importance of MMR is under- scored by the fact that MMR defects lead to hypermutations and susceptibility to both hereditary and sporadic colorectal cancers (CRCs). Exhibiting elevated instability in simple repeats called microsatellite instability (MSI) is a hallmark of MMR-deficient CRCs. However only ~70% of hereditary and sporadic CRC cases that display MSI have identifiable mutations in MMR genes suggesting that other mechanism(s) are responsible for the MSI phenotype in the remaining 30% of the cases. We recently showed that CRC cells containing high levels of PCNA tyrosine phosphorylation are defective in MMR in vitro. We therefore hypothesize that PCNA phosphorylation inhibits MMR leading to genome instability and CRC development. To test this hypothesis three Specific Aims are proposed. Aim 1 is to determine how phosphorylated PCNA inhibits MMR. A well-defined in vitro MMR reaction will be conducted in both a nuclear extract system and a reconstituted system in the presence or absence of phosphorylated PCNA and analysis of the repair products will allow determination of the specific step(s) of the reaction tht is blocked. Aim 2 is to determine hypermutability and MMR proficiency in cells stably expressing phosphorylated PCNA mimics while suppressed for endogenous PCNA expression. Aim 3 is to analyze tumorigenesis in transgenic mice expressing phosphorylated PCNA. A successful completion of the proposed work will establish PCNA tyrosine phosphorylation as a novel biomarker for cancer etiology and progression.

project_terms:
Adult;American;Biological Assay;Biological Markers;Cancer Etiology;Cancer cell line;Cell Line;Cell Proliferation;Cells;Cessation of life;Colorectal Cancer;DNA;DNA biosynthesis;DNA-Directed DNA Polymerase;Defect;Deoxyribonucleases;Development;Disease;EGFR Protein Overexpression;Epidermal Growth Factor Receptor;Excision;Exhibits;Family;Gene Mutation;Gene Proteins;Genes;Genetic;Genome;Genome Stability;Genomic Instability;Goals;Health;In Vitro;Inherited;Laboratories;Lead;Link;Maintenance;Malignant Neoplasms;Measures;Mediating;Microsatellite Instability;Mismatch Repair;Molecular;Monitor;Mutation;Nuclear Antigens;Nuclear Extract;Nucleotides;Peptide Initiation Factors;Phenotype;Phosphorylation;Play;Polymers;Post-Translational Protein Processing;Predisposition;Proliferating;Proteins;Reaction;Receptor Protein-Tyrosine Kinases;Role;Surgical incisions;System;Testing;Transgenic Animals;Transgenic Mice;Tyrosine;Tyrosine Phosphorylation;United States;Work;cancer cell;cancer therapy;colorectal cancer screening;improved;in vivo;member;novel;nuclease;overexpression;public health relevance;reconstitution;repaired;stable cell line;tumor progression;tumorigenesis

public_health_relevance:
Despite that great progress has been made in colorectal cancer (CRC) therapy the disease is still the second leading cause of cancer deaths among adults in the United States. A major reason for this is that the factors that cause a significant fraction of CRC are not fully understood. To improve the health of Americans this application aims to identify these factors which will improve both CRC screening and treatment.


application_id: 8618902
project_number: 5R01ES021375-03
project_title: PCBs worsen obesity/metabolic syndrome through 'toxic metabolic endotoxemia'
administering_ic: NIEHS
award_notice_date: 2014-02-25
opportunity_number: PAR-11-170
application_type: 5
activity_code: R01
ic: ES
serial_number: 021375
program_official: HEINDEL, JERROLD
project_start_date: 2012-05-08
project_end_date: 2017-02-28
study_section: Special Emphasis Panel[ZRG1-EMNR-D(55)R]
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): 68% of US adults are either overweight or obese and more than 100 million Americans have diabetes or pre- diabetes. These conditions may lead to cardiovascular disease and cancer. Recent research indicates a potential role for polychlorinated biphenyls (PCBs) which are persistent organic pollutants in obesity and diabetes. PCBs were previously used in electrical transformers. Although they were banned over 30 years ago PCBs are still present in the US food supply and in all adult Americans. Preliminary research performed by our group and others suggests that PCBs cause a "leaky gut" to disrupt the gut:liver:adipose axis. Subsequently intestinal-derived bacterial products enter the bloodstream causing inflammation liver disease and contribute to obesity and diabetes. We call this problem "toxic-metabolic endotoxemia". We hypothesize that PCBs interact with high fat or high carbohydrate diets through toxic metabolic endotoxemia to worsen obesity and diabetes; and studying this hypothesis is the overall objective of this grant. The specific aims of this novel nutrient:toxin interaction translational project are to:!! 1) Determine in mice mechanisms by which PCBs disrupt the gut:liver:adipose axis to increase metabolic endotoxemia and worsen diet-induced obesity/insulin resistance. 2) Determine the potential role of cellular receptors in PCBs-associated toxic-metabolic endotoxemia in mice and cell culture models. 3) Study mechanisms of toxic metabolic endotoxemia in stored blood samples from a large group of highly PCB-exposed humans. We expect to find that PCBs activate receptors perturb the gut:liver:adipose axis and worsen obesity/diabetes via toxic metabolic endotoxemia in mice and in humans. This innovative project is the first to study PCB- related endotoxemia in obesity/diabetes and is expected to lead to a new understanding of these conditions. The proposal is relevant to all overweight/obese people exposed to environmental pollution.

project_terms:
Adipose tissue;Adult;Alabama;American;Animal Model;Antioxidants;Archives;Attenuated;Binding (Molecular Function);Biological Assay;Biological Markers;Blood Circulation;Blood specimen;Body fat;C57BL/6 Mouse;Carbohydrates;Cardiovascular Diseases;Cell Culture Techniques;Cells;Chemicals;Cytokeratin 18;Data;Diabetes Mellitus;Diet;Dose;Endotoxemia;Endotoxins;Environmental Pollution;Epidemiology;Exposure to;Fatty Liver;Fatty acid glycerol esters;Food Supply;Fructose;General Population;Genetic;Glutathione;Grant;Hepatocarcinogenesis;Hormones;Human;Inflammation;Inflammatory;Insulin Resistance;Intestines;Lead;Ligands;Liver;Liver diseases;Malignant Neoplasms;Measures;Metabolic;Metabolic syndrome;Modeling;Mus;Nutrient;Obesity;Occupational Exposure;Organ;Overweight;Oxidative Stress;Pathogenesis;Permeability;Plants;Polychlorinated Biphenyls;Prediabetes syndrome;Production;Proteins;Research;Role;Sampling;Serum;Site;Steatohepatitis;TLR4 gene;Tight Junctions;Toll-like receptors;Toxin;Wild Type Mouse;aroclor 1260;base;clinically relevant;cohort;cost;cytokine;driving force;feeding;gut microflora;innovation;macrophage;member;mutant;non-alcoholic fatty liver;nonalcoholic steatohepatitis;novel;pollutant;receptor;receptor expression;research study;toxicant

public_health_relevance:
We expect to find that PCBs worsen obesity/diabetes via toxic metabolic endotoxemia in mice and in humans. This innovative project is the first to study PCB-related endotoxemia in obesity/diabetes and is expected to lead to a new understanding of these conditions. The proposal is relevant to all overweight/obese people exposed to environmental pollution.


application_id: 8618419
project_number: 1R03HD078491-01
project_title: Biomechanical Assessment of Femur Fracture in Pediatric Falls
administering_ic: NICHD
award_notice_date: 2014-04-14
opportunity_number: PA-11-262
application_type: 1
activity_code: R03
ic: HD
serial_number: 078491
program_official: MAHOLMES, VALERIE
project_start_date: 2014-04-14
project_end_date: 2016-03-31
study_section: Function, Integration, and Rehabilitation Sciences Study Section[CHHD-K]
contact_pi_person_id: 9540778
contact_pi: THOMPSON, ANGELA KNIGHT
other_pis: BERTOCCI, GINA E.
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Child abuse is the leading cause of trauma-related fatalities in children less than four years of age. Children one year of age and younger are particularly at risk; approximately 1 out of every 48 children in this age group is a victim of abue or neglect. Cases of physical child abuse are commonly mistaken for accidental trauma. If the abuse goes unrecognized the child is at risk for further escalating injuries. An abused child returned to an unsafe home environment has up to an 80% risk for additional injury and up to a 30% risk of death. These repeat occurrences may be preventable through early detection of abuse. Fractures are early indicators of child abuse but are also a common result of accidental trauma such as household falls. Clinicians are often faced with the task of determining whether a child's injuries are the result of accidental causes or whether abuse should be suspected. Since household falls are a common false history given by caretakers to conceal abusive trauma information regarding fracture potential in short-distance falls and specifically what type
of fracture could result from different fall scenarios may aid clinicians in distinguishing abusiv from accidental injuries thus improving the accuracy of child abuse diagnoses.  The purpose of this study is to provide objective biomechanically-based information regarding femur fracture potential in short-distance falls. Three specific aims have been established to address this goal: (1) Describe femur loading (type and magnitude) associated with short-distance falls in young children (2) Describe the likelihood of femur fractures in short-distance falls (3) Develop an improved understanding of the influence of child-specific bone characteristics on fracture potential.  This study will involve three primary methodological components. First a CRABI 12-month-old anthropomorphic test device (ATD) will be modified to improve biofidelity of the lower extremities and instrumented to measure femur loads. Then fall simulations will be conducted using the improved surrogate to determine femur loading characteristics. The final component involves development of a finite element model of a 12-month-old human child's femur. Femur loads from the ATD experiments will be reproduced in the finite element model. This will provide insight into fracture potential for the combined loading scenarios measured experimentally. Additionally key parameters will be varied in the model as part of a sensitivity analysis to determine their effect on fracture potential. This will elucidate the effect of child-specific characteristics (such as bone density) on femur fracture potential. The outcomes from this study will provide an improved understanding of femur fracture potential in short-distance pediatric falls and lay the foundation for future work that will improve clinical assessments of injury and history compatibility. Additionally though this study focuses on femur fracture potential the approach used may serve as a model for future investigation of fracture potential in other bones.

project_terms:
Accidental Injury;Address;Adult;Age-Years;Alcoholism;Biomechanics;Bone Density;Cessation of life;Characteristics;Child;Child Abuse;Childhood;Clinical assessments;Computer Simulation;Consult;Cover-up;Data;Depression and Suicide;Development;Devices;Diagnosis;Drug abuse;Early Diagnosis;Early identification;Elements;Family;Femoral Fractures;Femur;Foundations;Fracture;Future;Goals;Hip region structure;Home environment;Household;Injury;Investigation;Lead;Location;Lower Extremity;Measures;Mechanics;Modeling;Morbidity - disease rate;Outcome Study;Property;Publishing;Recording of previous events;Risk;Services;Stress;Testing;Trauma;Work;abuse victim;age group;base;bone;bone strength;child physical abuse;experience;falls;improved;insight;instrument;neglect;physical abuse;prevent;psychologic;public health relevance;research study;simulation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Clinicians are often challenged with determining whether a child's injuries are the result of accidental causes or whether abuse should be suspected. Since this decision often depends on the clinician's experience objective information about fracture potential in short-distance falls (a common excuse provided to conceal abuse) such as the location and type of fractures possible under various loading conditions will improve accuracy in child abuses diagnoses and the likelihood of earlier identification of child abuse.


application_id: 8617197
project_number: 5R01AA015407-10
project_title: GSK3beta a mediator of ethanol neurotoxicity
administering_ic: NIAAA
award_notice_date: 2014-02-26
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AA
serial_number: 015407
program_official: REGUNATHAN, SOUNDAR
project_start_date: 2005-08-01
project_end_date: 2016-02-29
study_section: Special Emphasis Panel[ZRG1-IFCN-C(02)M]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: SHI, XIANGLIN
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Alcohol is a neuroteratogen; alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD) among which fetal alcohol syndrome (FAS) is the most severe form. The depletion of neurons in the developing CNS is the most deteriorating effect of ethanol. The loss of CNS neurons may underlie many of the behavioral deficits observed in FASD. Glycogen synthase kinase 3 (GSK3) a serine/threonine kinase is an important mediator of neuron degeneration. We have demonstrated that ethanol activates GSK3 and the activation of GSK3 leads to neuronal death. Oxidative stress is also considered an important contributor to ethanol-induced neurotoxicity. We have purified a potent antioxidant from blackberries cyanidin-3-glucoside (C3G). Our study indicates that C3G inhibits GSK3 activity and alleviates oxidative stress in cultured neuronal cells. In addition C3G protects neuronal cells against ethanol-induced cell death. C3G-mediated neuroprotection is much more potent than other antioxidants and GSK3 inhibitors. C3G can cross the blood brain barrier (BBB) and distribute in the brain. C3G diminishes ethanol-induced activation of caspase-3 and Bax in the developing brain. Pharmacologically relevant concentrations of C3G are achievable through oral administration or intravenous (iv) injection in animals and no adverse effect is observed. These findings suggest that C3G is a promising neuroprotective agent that may ameliorate/prevent ethanol-induced neuronal damage. We hypothesize that C3G's potent protection against ethanol-induced neuronal loss is mediated by the combined action of its antioxidant property and inhibition of pro-apoptotic signaling GSK3/Bax pathways. To test the hypothesis we will (1) investigate the antioxidant property of C3G and its metabolites and their effects on GSK3 activity; (2) determine whether C3G protection against ethanol- induced neuronal loss is mediated by the combined action of its antioxidant property and the inhibition of GSK3; (3) determine whether C3G ameliorates ethanol-induced behavioral deficits.  C3G is a potent natural antioxidant and has diverse potential benefits for human health. It is a promising neuroprotective agent against ethanol toxicity due to its dual functions as an antioxidant and a GSK3 inhibitor. As a unit the proposed experiments will elucidate the novel role of C3G and provide an important basis for future clinical trials to evaluate the feasibility of C3G to treat ethanol neurotoxicity. Our study will potentially offer a new therapeutic strategy.

project_terms:
Acids;Acute;Adverse effects;Alcohol-Induced Disorders;Alcohol-Induced Neurotoxicity;Alcohols;Animals;Anthocyanins;Antioxidants;Apoptotic;Behavior;Behavioral;Blood - brain barrier anatomy;Brain;C57BL/6 Mouse;Cell Death;Cells;Cerebellum;Cerebral cortex;Cessation of life;Clinical Trials;Drug Kinetics;Electron Spin Resonance Spectroscopy;Episodic memory;Equilibrium;Ethanol;Ethanol toxicity;Exposure to;Family;Fetal Alcohol Spectrum Disorder;Fetal Alcohol Syndrome;Funding;Future;Generations;Glucosides;Glycogen Synthase Kinase 3;Glycogen Synthase Kinases;Health;Hippocampus (Brain);Human;Hydrogen Peroxide;Hydroxyl Radical;Hyperactive behavior;In Vitro;Learning;Life;Mediating;Mediator of activation protein;Memory;Mental Retardation;Microglia;Modeling;Motor;Mus;Neonatal Alcohol Exposure;Nerve Degeneration;Neuraxis;Neurons;Neuroprotective Agents;North America;Oral;Oral Administration;Oxidative Stress;Pathway interactions;Production;Property;Protein-Serine-Threonine Kinases;RAPGEF1 gene;Role;Signal Transduction;Superoxides;Testing;Therapeutic;Third Pregnancy Trimester;alcohol behavior;alcohol consumption during pregnancy;alcohol effect;alcohol exposure;base;caspase-3;free radical oxygen;in vivo;in vivo Model;inhibitor/antagonist;intravenous administration;intravenous injection;member;neuroblastoma cell;neuron apoptosis;neuron loss;neuroprotection;neurotoxicity;novel;novel therapeutics;postnatal;prenatal;prevent;public health relevance;research study

public_health_relevance:
Alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD) among which fetal alcohol syndrome (FAS) is the most severe form. The developing central nervous system (CNS) is particularly sensitive to ethanol. The loss of CNS neurons may underlie many of the behavioral deficits observed in FASD. Both glycogen synthase kinase 3 (GSK3) and oxidative stress contributes to ethanol neurotoxicity. We have purified a potent antioxidant from blackberries cyanidin-3-glucoside (C3G) which can also inhibit GSK3 and reduce oxidative stress. The current study is to determine whether C3G ameliorates ethanol-induced neuronal loss as well as behavioral deficits. The proposal will potentially develop a new therapeutic strategy.


application_id: 8616359
project_number: 5R01CA165469-02
project_title: Role of Tcl1 and Par-4 in regulation of chronic lymphocytic leukemia
administering_ic: NCI
award_notice_date: 2014-01-16
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 165469
program_official: HOWCROFT, THOMAS K
project_start_date: 2013-02-07
project_end_date: 2018-01-31
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 7739669
contact_pi: BONDADA, SUBBARAO
other_pis: RANGNEKAR, VIVEK M
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):  Chronic lymphocytic leukemia (CLL) also known as small cell lymphoma constitutes almost 30% of all cases of non-Hodgkin's lymphoma. It is the most common adult leukemia. Despite advances in chemotherapy treatment options for CLL patients are limited with only a modest efficacy especially for patients with unmutated types of B cell receptors (BCR) del (17p13.1) and p53 mutations. Tcl-1 an oncogene initially found to be translocated in T-cell leukemias has been found to be expressed at higher levels in CLL phenotypes that are classified as aggressive. A mouse model for CLL has been generated by expressing the Tcl-1 oncogene in B cells using immunoglobulin promoter and the E enhancer. These mice reproducibly develop CLL in 13-18 months and have been shown to be excellent models for human CLL. Par-4 is a pro-apoptotic tumor suppressor discovered by us that induces apoptosis in cancer but not normal cells using both the Fas pathway and by inhibiting NF-?B. We made four novel observations. First the B-cell receptor signaling pathway is active both in the human CLL cells and in the E-Tcl-1 mouse model of CLL as reflected by constitutive activation of Src family protein tyrosine kinases (SFK). Second we discovered that expression of Tcl1 is down regulated upon inhibition of SFK suggesting a role for BCR signaling in Tcl1 expression. Third we found that expression of Par-4 is down-regulated in E-Tcl1 CLL cells compared to normal mice while its expression has been found to be variable in human CLL cells. Fourth we discovered that E-Tcl1 cells are killed by soluble Par-4 and SAC a specific domain of Par-4 that is cytotoxic only to tumor cells. Based on these observations we hypothesize that a balance between Tcl1 and Par-4 regulated by BCR signaling decides the fate of CLL cells between survival and death. We have three specific aims. Aim 1 will determine the importance of BCR signaling and the role of specific SFKs in the regulation of Tcl-1 and Par-4 expression using the E-Tcl-1 mouse model of CLL. Aim 2 will investigate the importance of Par-4 overexpression for CLL development using a newly generated inducible Par-4 transgenic mice mouse model and the E-Tcl-1 mice. Aim 2 will involve preclinical studies to test the efficacy of extracellular Par-4 and SAC to inhibit CLL growth in the E-Tcl-1 mouse model. The relative importance of Tcl-1 and Par-4 will be studied in Aim 3 with primary CLL cells from patients thus translating the basic research findings in Aims 1 and 2 to clinical samples. The collaboration between UK and OSU provides us an opportunity to integrate the basic science and pre-clinical findings from the first two Aims with studies in Aim 3 using patient derived CLL cells. The exciting aspect of these studies is the possibility that soluble Par-4 or SAC can be developed into a treatment strategy for CLL cells either in isolation or in combination with SFK inhibitors or other targets that are currently being investigated in our laboratories.

project_terms:
17p13.1;A Mouse;Affect;Animal Model;Apoptosis;Apoptotic;B lymphoid malignancy;B-Cell Lymphomas;B-Lymphocytes;Basic Science;Biology;Bone Marrow;Cell Aging;Cell Survival;Cells;Cessation of life;Chromosomal translocation;Chronic Lymphocytic Leukemia;Clinical;Clinical Data;Clinical Investigator;Clinical Trials;Collaborations;Development;Disease;Down-Regulation;Elderly;Enhancers;Equilibrium;Family;Family member;GRP gene;GRP78;Genes;Genetic;Goals;Grant;Growth;Human;Immunoglobulins;In Vitro;Induction of Apoptosis;Killings;Laboratories;Leukemic Cell;Lymphoid;Malignant Neoplasms;Mediating;Modality;Modeling;Mus;Mutation;Nature;Non-Hodgkin's Lymphoma;Normal Cell;Oncogenes;Organ;PAWR gene;Pathway interactions;Patients;Peptides;Phenotype;Play;Predisposition;Promotor (Genetics);Protein Tyrosine Kinase;Proteins;Receptor Signaling;Receptors Antigen B-Cell;Regulation;Relative (related person);Resistance;Role;Sampling;Signal Pathway;Signaling Molecule;Small Interfering RNA;Small-Cell Lymphoma;Surface;T-Cell Leukemia;T-Cell Receptor;T-Lymphocyte;Testing;Therapeutic;Therapeutic Effect;Transcription Factor AP-1;Transgenic Mice;Transgenic Organisms;Translating;Tumor Suppressor Proteins;Western World;Whole Blood;adult leukemia;base;cancer cell;cell age;cell killing;chemotherapy;clinically relevant;cytotoxic;efficacy testing;extracellular;in vivo;inhibitor/antagonist;member;molecular marker;mouse model;neoplastic cell;novel;outcome forecast;overexpression;peripheral blood;pre-clinical;preclinical study;pro-apoptotic protein;public health relevance;receptor;response;therapy development;transcription factor;treatment strategy;tumor

public_health_relevance:
The efficacy of existing therapeutic modalities for Chronic lymphocytic leukemias which affect mainly older adults is not high and new therapies for this disease are not yet available. The proposed studies will focus on two novel molecules Tcl-1 and Par-4 that have antagonistic roles in survival of CLL cells and may provide new avenues that can be developed into therapeutic strategies.


application_id: 8616043
project_number: 5R01CA133429-07
project_title: The Role of PHLPP in Colon Cancer
administering_ic: NCI
award_notice_date: 2014-03-03
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 133429
program_official: YASSIN, RIHAB R
project_start_date: 2009-04-01
project_end_date: 2014-11-30
study_section: Molecular Oncogenesis Study Section[MONC]
contact_pi_person_id: 7353657
contact_pi: GAO, TIANYAN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Colorectal cancer is the second leading cause of cancer-related deaths in the United States with 112000 new cases diagnosed per year and approximately 52000 deaths estimated in 2007. Dysregulation of Akt and protein kinase C (PKC) contributes to tumorigenesis by promoting cell proliferation and inhibiting apoptosis. The signaling activation process of Akt and PKC has been studied in great detail. However little is known about how the signals are turned off once activated. Recently we have identified a family of novel protein phosphatases PHLPP (PH domain Leucine-rich-repeats Protein Phosphatase) that directly dephosphorylates Akt and PKC. However the role of PHLPP in cancer has not been defined. In the preliminary studies we found that loss of PHLPP expression occurs with high frequency in human colorectal cancer specimens. Furthermore our studies have suggested that PHLPP plays a role in regulating cell polarity. In light of our findings the central hypothesis driving this proposal is that PHLPP serves as a tumor suppressor by regulating cell polarity in addition to its ability of turning off the growth signaling activated by Akt and PKC. The long-term goal of our studies is to better understand the physiological role of PHLPP and its contribution to colon cancer development and progression in vivo. The Specific Aims are: Aim 1: To define the molecular mechanism of PHLPP downregulation. The goal of this aim is to investigate the potential mechanism leading to PHLPP downregulation in cancer. We will test the hypothesis that the expression level of PHLPP is controlled by the ubiquitin proteasome pathway in cells and preventing PHLPP degradation leads to upregulation of the protein. Aim 2: To determine the role PHLPP in maintaining cell polarity. We hypothesize that PHLPP exerts its function as a tumor suppressor by regulating cell polarity and cell growth. The functional effect of PHLPP on establishing epithelial cell polarity will be determined. To elucidate the underlying mechanism we will test the hypothesis that PHLPP is required for epithelial junction formation by modulating PKC activity via binding to the polarity protein Scribble. Aim 3: To delineate the role of PHLPP in tumorigenesis in vivo. The hypothesis driving this aim is that loss of PHLPP expression contributes to the initiation and progression of colorectal tumors. We will address the question whether there is an increase of tumor incidence when PHLPP is knocked out both basally and in combination with other carcinogenic factors. Furthermore we will assess the contribution of altered cell polarity in normal development of gut epithelium and tumor initiation using the knockout mice.

project_terms:
Address;Agreement;Apoptosis;Automobile Driving;Binding (Molecular Function);Biological Models;Cancer Center;Cancer Etiology;Cell Polarity;Cell Proliferation;Cells;Cellular biology;Cessation of life;Colon Carcinoma;Colorectal Cancer;Colorectal Neoplasms;Development;Diagnosis;Down-Regulation;Epithelial;Epithelial Cells;Failure (biologic function);Family;Frequencies (time pattern);Goals;Growth;Health;Howard Temin Award;Human;Human Development;Incidence;Intercellular Junctions;Intestines;Isoenzymes;Knock-out;Knockout Mice;Light;Malignant Neoplasms;Mediating;Mentored Research Scientist Development Award;Molecular;Names;Non-Small-Cell Lung Carcinoma;Oncogenic;PH Domain;Pathway interactions;Pharmacology and Toxicology;Phosphatidylinositols;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Physiological;Play;Process;Protein Dephosphorylation;Protein Kinase;Protein Kinase C;Protein phosphatase;Proteins;Proto-Oncogene Proteins c-akt;Publishing;Regulation;Research;Research Personnel;Role;Scheme;Signal Pathway;Signal Transduction;Specimen;Testing;Tumor Suppressor Proteins;Ubiquitin;United States;Up-Regulation (Physiology);base;cancer cell;cancer therapy;cell growth;citrate carrier;design;falls;gastrointestinal epithelium;in vivo;insight;intestinal homeostasis;leucine-rich repeat protein;multicatalytic endopeptidase complex;novel;overexpression;prevent;professor;research study;tumor;tumor growth;tumor initiation;tumorigenesis

public_health_relevance:
Colorectal cancer is the second leading cause of cancer-related deaths in the United States with 148000 new cases diagnosed per year and approximately 50000 deaths estimated in 2007 and among many contributing factors aberrant protein phosphorylation resulting from hyperactivation of oncogenic signaling mediated by protein kinases such as Akt and PKC is a key cause of colorectal cancer. We recently identified a novel protein phosphatase PHLPP that directly dephosphorylates Akt and PKC and terminates the growth signals activated by these kinases. We propose to determine the functional importance of PHLPP as a tumor suppressor in colorectal cancer and the results from this study will provide significant insights into the development of potential cancer therapy using PHLPP as a novel target.


application_id: 8613990
project_number: 1R01DK100892-01
project_title: The role of hepatic insulin resistance on SR-BI dependant HDL cholesterol uptake
administering_ic: NIDDK
award_notice_date: 2013-09-19
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: DK
serial_number: 100892
program_official: LAUGHLIN, MAREN R
project_start_date: 2013-09-20
project_end_date: 2017-08-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8553632
contact_pi: GRAF, GREGORY A
other_pis: VAN DER WESTHUYZEN, DENEYS REM
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall objective of this proposal is to examine the extent to which impaired insulin signaling alters HDL- mediated reverse cholesterol transport (RCT). A key cardioprotective function of HDL is the delivery of excess cholesterol from plasma and tissues to the liver for elimination from the body via RCT. SR-BI is the major hepatic HDL receptor and mediates the selective uptake of HDL cholesterol esters (HDL-CE). Compared to other circulating lipoproteins cholesterol carried on HDL particles is preferentially secreted int bile in an SR-BI dependent manner. In addition to SR-BI's role in trans-hepatic sterol transport both gain and loss-of-function studies have established that SR-BI is a determinant of hepatic cholesterol metabolism including cholesterol synthesis biliary cholesterol secretion rates and the incorporation of cholesterol into VLDL. Both HDL-CE uptake and biliary cholesterol secretion have been shown to be negatively affected by impaired insulin signaling a key contributing element to the Metabolic Syndrome (MetS) and the increased risk for cardiovascular disease. Our published and preliminary data indicate that insulin signaling regulates SR-BI by a novel post-translational mechanism that promotes SR-BI expression on the plasma membrane. We hypothesize that insulin resistance reduces HDL-CE uptake and alters SR-BI-dependent delivery of cholesterol to hepatic regulatory and secretory pools through mechanisms that include the redistribution of SR-BI to an intracellular compartment. Specific Aim 1 will determine the effect of hepatic insulin signaling and insulin resistance on SR-BI mediated sterol trafficking
to secretory and regulatory hepatic cholesterol pools. Hepatic insulin signaling will be disrupted by selective depletion of insulin receptors or by expression of a dominant negative phosphatidylinositol-3 kinase (AdnilPI3K) and the extent to which hepatic insulin resistance reduces SR-BI mediated HDL-C selective cholesterol ester uptake determined. Studies will also determine how reduced SR-BI function alters steady-state hepatic cholesterol synthesis and secretion in the setting of impaired insulin signaling? Specific Aim 2 will test the hypothesis tha transhepatic (THCE) elimination of HDL cholesterol in bile is reduced in the setting of hepatic insulin resistance and hypertriglyceridemia. This will be accomplished by a) determining whether reduced SR-BI function diminishes THCE of HDL-C b) determining whether hepatic IR decreases macrophage to feces RCT in an SR-BI dependent manner and c) examining whether changes in HDL particle composition disrupt THCE of HDL-C and synergize with SR-BI dysfunction to reduce HDL RCT function. Specific Aim 3 will determine the molecular mechanisms by which insulin signaling regulates SR-BI cell surface localization in hepatocytes. The effect of insulin-dependent PI3K signaling on SR- BI subcellular distribution will be examined in cultured hepatocytes together with the identity of the intracellular compartment(s) in which SR-BI accumulates as a result of impaired insulin signaling. The responsible insulin- dependent signaling pathways will be defined and studies will be performed to identify the determinants on SR- BI necessary for its regulation by insulin signaling.

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

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


application_id: 8613600
project_number: 1R01ES023470-01
project_title: Endocrine disruptor mediated activation of PXR causes dyslipidemia
administering_ic: NIEHS
award_notice_date: 2013-09-26
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: ES
serial_number: 023470
program_official: COLLINS, JENNIFER B
project_start_date: 2013-09-26
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1 DKUS-C (90)]
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Adverse effects;Affect;Agonist;Animal Model;Animals;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;CD36 Antigens;Cardiovascular Diseases;Cause of Death;Cells;Chemical Exposure;Chemicals;Chlorinated Hydrocarbons;Cholesterol;Chronic;Citrates;Cosmetics;Development;Diabetes Mellitus;Diet;Disease;Dose;Dyslipidemias;Endocrine Disruptors;Environment;Environmental Risk Factor;Etiology;Exposure to;FDA approved;Food Packaging;Future;Gene Expression;Genetic;Genetic Transcription;Goals;Health;Homeostasis;Human;Hyperlipidemia;In Vitro;Individual;Intestines;Knowledge;Lead;Link;Lipids;Liver;Mediating;Medical Device;Modeling;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Mus;Nuclear Receptors;Obesity;Organophosphates;Pesticides;Pharmaceutical Preparations;Pharmacologic Substance;Pilot Projects;Plasma;Plasticizers;Play;Polychlorinated Biphenyls;Receptor Activation;Regulation;Research;Risk Assessment;Role;Testing;Variation (Genetics);Wild Type Mouse;Xenobiotic Metabolism;Xenobiotics;absorption;analog;bisphenol A;cardiovascular disorder risk;cholesterol transporters;environmental chemical;gene environment interaction;human disease;in vivo;interest;mouse model;novel;packaging material;phthalates;pregnane X receptor;public health relevance;receptor function;research study;sensor;tool;uptake

public_health_relevance:
PROJECT NARRATIVECardiovascular disease is the leading cause of death worldwide and can be caused by genetic andenvironmental factors. The proposed studies will investigate the mechanisms through which exposure tocertain environmental chemicals leads to hyperlipidemia and cardiovascular disease. These studies willprovide important new information about underlying causes of cardiovascular disease and strong evidence toinform future risk assessment for environmental chemicals.


application_id: 8610955
project_number: 5R01NS073584-04
project_title: ER stress and oligodendrocyte survival after spinal cord injury
administering_ic: NINDS
award_notice_date: 2014-01-07
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: NS
serial_number: 073584
program_official: JAKEMAN, LYN B
project_start_date: 2011-02-01
project_end_date: 2016-01-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: HETMAN, MICHAL
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The endoplasmic reticulum (ER) is the intracellular organelle in which secretory and membrane proteins are synthesized and folded by resident chaperone proteins. The ER stress response (ERSR) is an evolutionarily conserved cell defense mechanism that protects against excessive accumulation of malfolded proteins in the ER. These malfolded proteins are translocated to the cytoplasm by the machinery of the ER- associated degredation (ERAD) where they are degraded. The ERSR is initiated after multiple cellular stresses including hypoxia inflammation trauma excitotoxicity and oxidative damage. The ERSR is initially protective but if malfolded proteins cannot be cleared apoptotic cell death initiates. The 3 pathways involved in the ERSR involve PERK IRE1/XBP-1 and ATF6 signaling. Preliminary data demonstrate upregulation of all 3 ERSR pathways following SCI. Mice null for CHOP a pro-apoptotic transcription factor that is downstream of PERK and activated during ERSR showed enhanced functional recovery after SCI and we identified oligodendrocytes as highly vulnerable to ER stress. We hypothesize that enhancing the protective or inhibiting the apoptotic aspects of the ERSR will enhance functional recovery after SCI. In Aim 1 we will potentiate the protective effectors of ERSR and in Aim 2 suppress those that initiate oligodendrocyte apoptosis. We will use a combination of pharmacological agents constitutive and conditional null mice as well as cell culture studies using wild type (WT) and available null oligodendrocyte precursor cells (OPCs) and/or siRNAs to address these questions.

project_terms:
Acute;Address;Apoptosis;Apoptotic;Cell Culture Techniques;Cell Death;Cell Survival;Cells;Cellular Stress;Cessation of life;Chemicals;Chemosensitization;Chronic;Coculture Techniques;Commit;Cytoplasm;Cytoprotection;Data;Defense Mechanisms;Disease;Endoplasmic Reticulum;Family;Functional disorder;Genes;Genetic;Grant;Hand;Hypoxia;In Vitro;Inflammation;Injury;Knockout Mice;Locomotor Recovery;Mediating;Mediator of activation protein;Membrane Proteins;Methods;Modeling;Molecular Chaperones;Mus;Neurons;Oligodendroglia;Organelles;Pathology;Pathway interactions;Patients;Phosphorylation;Protein Dephosphorylation;Proteins;Recovery of Function;Role;Signal Transduction;Small Interfering RNA;Spinal Cord;Spinal Ganglia;Spinal cord injury;TNFRSF10B gene;Translational Repression;Translations;Trauma;Traumatic CNS injury;Tunicamycin;Up-Regulation (Physiology);arm;biological adaptation to stress;cytotoxic;effective therapy;endoplasmic reticulum stress;excitotoxicity;improved;in vitro Assay;in vivo;inhibitor/antagonist;insight;loss of function;nervous system disorder;new therapeutic target;novel;oligodendrocyte precursor;oxidative damage;precursor cell;protective effect;public health relevance;research study;response;secretory protein;tauroursodeoxycholic acid;therapeutic target;transcription factor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Spinal cord injury (SCI) is a devastating injury for both patients and their families and at present there is no effective treatment either acutely or for chronic patients. This grant examines the role of the endoplasmic reticulum stress response a cellular defense mechanism induced in every spinal cord cell after SCI in mediating survival or death of myelinating oligodendrocytes after SCI. We expect to identify new acute therapeutic targets that will hopefully extend beyond SCI to other CNS trauma and neurological disease treatment.


application_id: 8610946
project_number: 5R24MD008018-02
project_title: Appalachians Together Restoring the Eating Environment (APPAL-TREE)
administering_ic: NIMHD
award_notice_date: 2014-05-02
opportunity_number: RFA-MD-12-006
application_type: 5
activity_code: R24
ic: MD
serial_number: 008018
program_official: DANKWA-MULLAN, IRENE
project_start_date: 2013-05-01
project_end_date: 2016-04-30
study_section: ZMD1-RN(07)
contact_pi_person_id: 8931964
contact_pi: SWANSON, MARK
other_pis: SCHOENBERG, NANCY E.
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): identified as a key priority population by the NIMHD the Appalachian counties of Kentucky suffer from some of the nation's highest rates of obesity and overweight lowest rates of produce consumption and high rates of premature mortality and diet-related diseases such as diabetes heart disease and various cancers. With the main partnership of three community-based organizations - the Community Farm Alliance (a community development organization designed to improve food production systems). Faith Moves Mountains (a community-based research team with ten years of culturally-based intervention experience) and the Big Sandy Area Development District (a well-respected network that plans promotes and coordinates programs for regional economic health and social development of Appalachia) - and with extensive input from the Community Advisory Board (CAB) faith partners and Cooperative Extension this community-academic partnership proposes to address the most modifiable risk factor for these main causes of morbidity and mortality: suboptimal diet. In this three-year planning grant the community-academic collaboration will undertake three specific aims and associated activities. In Aim 1 the project team will conduct a community needs assessment and assets inventory hold community forums to present this information and meet regularly with the community partners and CAB. The nutrition and agricultural economic co-investigators will partner with the community research team to use innovative and established methods including GIS mapping focus groups and nutritional and economic assessment techniques. In Aim 2 community forums CAB meetings and collaborative engagement sessions among project partners will facilitate the selection and initiation of an evidence-based pilot intervention to promote better nutrition emphasizing food access particularly fruits and vegetables. In Aim 3 the community-academic collaborative will implement and evaluate this pilot intervention tracking nutritional outcomes participant satisfaction and costs and reporting results to Appalachian community members.    
   
RELEVANCE: By addressing one of the nation's leading public health challenges - poor diet leading to overweight/obesity and subsequent health impacts - in a region (Appalachian Kentucky) suffering extreme disparities in diet and diet-related disease this project will develop implement and evaluate a comprehensive approach to dietary change by increasing access to healthy foods.

project_terms:
Address;Advocate;Agriculture;Americas;Appalachian Region;Area;Behavior;Benefits and Risks;Cause of Death;Chronic;Collaborations;Commit;Communities;Community Developments;Complex;Consumption;County;Development;Diabetes Mellitus;Diet;Dietary intake;Disease;Eating;Economics;Educational aspects;Effectiveness;Environment;Equipment and supply inventories;Evaluation;Evidence based intervention;Experimental Designs;Farming environment;Focus Groups;Food;Food Access;Food Safety;Frequencies (time pattern);Grant;Health;Health Food;Health Status;Health care facility;Heart Diseases;Improve Access;Individual;Institute of Medicine (U.S.);Institution;Intervention;Kentucky;Link;Malignant Neoplasms;Maps;Measures;Methods;Minority Groups;Mission;Morbidity - disease rate;Mortality Vital Statistics;Needs Assessment;Nutritional;Obesity;Outcome;Overweight;Participant;Pattern;Population;Premature Mortality;Principal Investigator;Process;Production;Publications;Reporting;Research;Research Personnel;Resources;Risk Factors;Social Development;Socioeconomic Status;System;Techniques;Testing;United States;base;community intervention;community organizations;cost;design;evidence base;experience;farmer;food environment;fruits and vegetables;health disparity;health economics;improved;innovation;meetings;member;modifiable risk;nutrition;programs;public health medicine (field);risk perception;safety net;satisfaction;therapy design


application_id: 8610914
project_number: 5R01DE022597-02
project_title: Bacterial peptidylarginine deiminase a link between gums and joint disease
administering_ic: NIDCR
award_notice_date: 2014-01-29
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DE
serial_number: 022597
program_official: LUNSFORD, DWAYNE
project_start_date: 2013-02-01
project_end_date: 2018-01-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
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
arra_indicator: N
project_terms:
Affect;Anaphylatoxins;Antibodies;Arginine;Atherosclerosis;Autoantibodies;Autoimmune Responses;Autoimmunity;Bacteria;Bioinformatics;Biological;Bone Resorption;Bradykinin;C-terminal;CAP18 lipopolysaccharide-binding protein;Chronic;Cigarette Smoker;Citrulline;Clinical;Collagen Arthritis;Complement;Complement 3a;Complement 5a;Complex;Connective Tissue;Cysteine Protease;Data;Dental Plaque;Development;Disease;Environment;Enzymes;Epidemiology;Epitopes;Exposure to;Forsythia;Generations;Gingiva;Gingival Crevicular Fluid;Homeostasis;Homologous Gene;Human;Immune;Immune Tolerance;Immune response;Immune system;Individual;Infection;Inflammation;Inflammatory;Intervention;Joints;Kinins;Knowledge;Lesion;Light;Link;Lung;Microbial Genome Sequencing;Molecular;Natural Immunity;Organism;Pathogenesis;Pathogenicity;Pathology;Patients;Peptides;Peptidoglycan;Periodontal Diseases;Periodontitis;Physiological;Population;Porphyromonas gingivalis;Post-Translational Protein Processing;Predisposition;Prevention;Process;Properdin;Protein-arginine deiminase;Proteins;Reaction;Reporting;Research;Research Proposals;Resistance;Rheumatoid Arthritis;Role;Serum;Signal Transduction;Site;Source;Substrate Specificity;Synovial Fluid;System;TNFRSF10A gene;Tissues;Tooth Loss;Tooth structure;Transgenic Mice;Treponema denticola;Validation;Virulence Factors;alveolar bone;arthropathies;bactericide;base;complement pathway;fimbria;gingipain;in vivo;innovation;interest;microbial;novel strategies;pathogen;pathogenic bacteria;polypeptide;preference;protein structure function;public health relevance;three dimensional structure;tool

public_health_relevance:
Rheumatoid arthritis is characterized by the development of autoantibodies against citrullinated proteins within the joints in susceptible individuals. Porphyromonas gingivalis a known periodontal pathogen is the only known bacterium which produces an enzyme (PPAD) that is capable of converting arginine residues in proteins into citrullin. It is hypothesized that PPAD activity in inflamed infected periodontal tissues not onlycontributes to the pathology of periodontitis but also may promote breakdown of immunotolerance and initiates the development of rheumatoid arthritis.


application_id: 8610884
project_number: 5K23AR062069-02
project_title: Prolonged alterations to muscle following knee surgery and physical therapy
administering_ic: NIAMS
award_notice_date: 2014-01-28
opportunity_number: PA-11-194
application_type: 5
activity_code: K23
ic: AR
serial_number: 062069
program_official: BOYCE, AMANDA T
project_start_date: 2013-02-01
project_end_date: 2018-01-31
study_section: ZAR1-CHW(M1)
contact_pi_person_id: 10137938
contact_pi: NOEHREN, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Anterior;Architecture;Area;Award;Biology;Biomechanics;Biophysics;Biopsy;Clinical;Clinical Research;Clinical Trials;Coupled;Data;Data Analyses;Degenerative polyarthritis;Development;Diffusion;Disease;Effectiveness;Fascicle;Fiber;Fibrosis;Future;Goals;Growth;Head;Health;Health Sciences;Individual;Intervention;Joints;Kentucky;Knee;Laboratories;Left;Leg;Length;Ligaments;Link;Magnetic Resonance Imaging;Measurement;Measures;Mechanics;Mentored Patient-Oriented Research Career Development Award;Mentors;Mentorship;Methods;Microscopic;Molecular;Morphology;Muscle;Muscle Fibers;Muscle Weakness;Muscle function;Operative Surgical Procedures;Outcome;Patient Outcomes Assessments;Patients;Physical therapy;Physiological;Physiology;Positioning Attribute;Process;Production;Property;Protocols documentation;Quadriceps Muscle of the Thigh;Recovery;Rehabilitation therapy;Research;Research Design;Research Personnel;Scientist;Senior Scientist;Structure;Testing;Time;Tissues;Training;Translating;United States National Institutes of Health;Universities;anterior cruciate ligament reconstruction;base;clinically significant;cohort;college;evidence base;experience;follow-up;functional outcomes;improved;innovation;interest;joint loading;muscular structure;non-invasive imaging;novel;professor;public health relevance;reconstruction;rehabilitation strategy;response to injury;skills;strength training;vastus lateralis

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


application_id: 8610273
project_number: 5R01DA033364-02
project_title: Medications Development for Cocaine: A Translational Approach in Monkey and Human
administering_ic: NIDA
award_notice_date: 2013-12-11
opportunity_number: PA-10-268
application_type: 5
activity_code: R01
ic: DA
serial_number: 033364
program_official: KAUTZ, MARY A
project_start_date: 2013-02-01
project_end_date: 2016-12-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cocaine-use disorders continue to be a significant public health concern yet no effective pharmacological treatments have been identified. This application is founded on the proposition that translational research on development of cocaine pharmacotherapies will benefit from the use of coordinated and homologous procedures in animals and humans to study effects of Candidate medications on choice between cocaine and a non-drug reinforcer. Self-administration procedures will be used in this project because the reinforcing effects of drugs are central to their abuse and the development of dependence. An alternative reinforcer to cocaine will be offered because the choice to use cocaine to the exclusion of other behaviors is a hallmark of dependence and an effective medication should assist patients in reducing drug use and reallocating behavior from drug use to more responsible and productive activities. Advantages of including preclinical research in the medications development process include strict control over environment and subject history and testing novel compounds and/or extensive dose ranges not feasible in humans. Rhesus monkeys were selected as the animal subjects because they are phylogenetically more closely related to humans than rodents and can be instrumented with chronically indwelling IV catheters which facilitates implementation of drug vs. food choice procedures. Human laboratory research permits the testing of putative pharmacotherapy effects on challenges with the abused drug in a clinically relevant subject population. Another advantage of pairing rhesus monkey and human laboratory models is that powerful within-subjects designs can be used with both species. Despite the relative strengths of human and non-human primate approaches translational research has been hampered by the use of widely different self-administration procedures and medication treatment regimens. The proposed project seeks to harmonize rhesus monkey and human procedures used to screen medications by first establishing parallel self-administration methods that will employ the same cocaine doses route of cocaine administration and schedule of reinforcement as well as a species-specific alternative reinforcer that effectively reduces drug taking. Cocaine doses schedule parameters and alternative reinforcer magnitude will then be adjusted to obtain equivalent functional effects prior to d-amphetamine maintenance testing. The use of d-amphetamine will permit equilibration of cross-species sensitivity and provide a comparator for effects of other non-dopaminergic Candidate medications examined in future studies. Achieving the aims of this project will exert a sustained and powerful impact by establishing a research platform for cocaine medication screening that will tightly link animal and human approaches thereby accelerating translational research on medications development. The proposed project is highly innovative in that it will develop coordinated and homologous procedures in nonhuman primates and humans using sophisticated cocaine choice procedures aimed towards medications development for cocaine-use disorders.

project_terms:
Address;Animals;Behavior;Catheters;Clinical;Clinical Research;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Dependence;Development;Dextroamphetamine;Disease;Dopamine;Dopamine Agonists;Dose;Drug Use Disorder;Drug usage;Effectiveness;Ensure;Environment;Evaluation;Exclusion;Food;Future;Goals;Gold;Human;Intravenous;Laboratories;Laboratory Research;Laboratory Study;Link;Macaca mulatta;Maintenance;Methods;Modeling;Monkeys;Patients;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacotherapy;Population;Prevalence;Prevention;Procedures;Process;Recording of previous events;Reinforcement Schedule;Relative (related person);Research;Rodent;Route;Safety;Schedule;Self Administration;Standardization;Testing;Translational Research;Treatment Protocols;base;clinically relevant;cocaine use;design;innovation;instrument;non-drug;nonhuman primate;novel;pre-clinical research;public health medicine (field);public health relevance;reinforcer;research study;screening;stimulant abuse;translational approach;uptake

public_health_relevance:
Cocaine-use disorders continue to be a significant public health concern yet no effective medications have been identified. This application is founded on the proposition that research to develop medications for cocaine addiction will benefit from the use of highly coordinated and homologous animal and human procedures to study effects of promising drugs on choice between cocaine and a non-drug alternative. The ultimate goal of this project is to establish a research platform that facilitates animal-to-human translational research on the development of medications for treatment of cocaine abuse and dependence.


application_id: 8610016
project_number: 1R21ES024030-01
project_title: Novel Treatments of Acrolein-induced Cardiotoxicity
administering_ic: NIEHS
award_notice_date: 2013-09-24
opportunity_number: PAR-13-005
application_type: 1
activity_code: R21
ic: ES
serial_number: 024030
program_official: NADADUR, SRIKANTH
project_start_date: 2013-09-24
project_end_date: 2015-08-31
study_section: Special Emphasis Panel[ZRG1 MDCN-B (55)]
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Novel Treatments of Acrolein-induced CardiotoxicityThe overall goal of this project is to develop new and improved countermeasures and therapeutics forpreventing human mortality and morbidity associated with chemical threats. Such threats might be imposed bya terrorist attack accidental leakage of chemicals used in industrial production or those released duringnatural disasters and fires. The most common and abundant reactive chemicals relevant to all these situationsare reactive carbonyl compounds (RCCs). A prototypical member of this class is acrolein. Acrolein and relatedRCCs are the most abundant and toxic constituents generated in lethal amounts (600 ppm) during forest andstructural fires. Profound respiratory and cardiovascular effects of exogenous and endogenous RCCs havealso been described; however neither the toxicological effects of RCCs nor their mechanisms of toxicity havebeen systematically delineated. Similarly the specific vulnerability of young old and women to RCC exposurehas not been assessed. Most importantly no effective countermeasures or therapeutic interventions arecurrently available. Possible therapeutic interventions include treatment with inhibitors of RCC receptors knownas transient receptor potential (TRP) channels. These antagonists including TRPV1 and TRPA1 inhibitors holdpromise to diminish the pain and inflammation in the cardiovascular and pulmonary systems associated withhigh dose exposure to RCC. Evaluation of mitigation therapies following high level RCC exposure will providethe first step in judging their relative efficacy for use in the case of a chemical emergency threat in humans.

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

public_health_relevance:
Novel Treatments of Acrolein-induced CardiotoxicityProject NarrativeProfound respiratory and cardiovascular effects of exogenous and endogenous reactive carbonyl compounds(RCCs) such as acrolein have been described; yet neither the toxicological effects of RCCs nor theirmechanisms of toxicity have been systematically delineated. Moreover the specific vulnerability of the youngold and females to inhaled RCCs including acrolein has not been assessed. Possible therapeuticinterventions include treatment with known transient receptor potential (TRP) channel inhibitors includingTRPA1 and TRPV1 antagonists and evaluation of mitigation therapy following high level RCC exposure willprovide the first step in judging their efficacy in the case of a chemical emergency threat in humans.


application_id: 8609430
project_number: 1P01HD071875-01A1
project_title: CIPAR1 A Novel Modulator of Progesterone Accumulation in Periovulatory Follicle
administering_ic: NICHD
award_notice_date: 2014-09-18
opportunity_number: PAR-10-245
application_type: 1
activity_code: P01
ic: HD
serial_number: 071875
suffix: A1
study_section: Special Emphasis Panel[ZHD1 DRG-D (41)]
subproject_number: 7820
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-09-19
project_terms:
Affect;Antibodies;Apoptosis;Castration;Cell Culture Techniques;Cell Differentiation process;Cell physiology;Cells;Collaborations;Cytoprotection;Data;Development;Enzymes;Experimental Models;Female;Fertility;Future;Gene Proteins;Genes;Goals;Gonadotropins;Hormones;Human;Immunoprecipitation;In Vitro;Instruction;Link;Location;Luteinization;Macaca;Mediating;Mediator of activation protein;Molecular;Monkeys;Ovary;Ovulation;Physiological;Play;Primates;Production;Progesterone;Prostaglandins;Prostate;Prostatic;Proteins;Proteomics;Rattus;Reproduction;Rodent;Role;Steroid biosynthesis;Testing;Tissues;Woman;base;corpus luteum;critical period;granulosa cell;hormone regulation;human tissue;improved;in vitro Model;in vivo;novel;research study;response


application_id: 8606402
project_number: 5R21AI103980-02
project_title: Identification of diagnostic markers for lupus nephritis
administering_ic: NIAID
award_notice_date: 2013-12-13
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: AI
serial_number: 103980
program_official: JOHNSON, DAVID R
project_start_date: 2013-01-18
project_end_date: 2015-12-31
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
contact_pi_person_id: 8638278
contact_pi: POWELL, DAVID W.
other_pis: MCLEISH, KENNETH R
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): Renal involvement in systemic lupus erythematosus (SLE) termed lupus nephritis (LN) occurs in about 60% of patients and is a leading cause of morbidity and mortality. Membranous lupus nephritis (MLN) (class V) is described in 15% to 40% of renal biopsies in these patients. The proposed pathogenesis of all classes LN is the glomerular deposition of immune complexes containing auto-antibodies. Three hypotheses describing how immune complexes containing  nephritigenic antibodies are deposited in glomeruli have been proposed deposition of  circulating immune complexes binding of anti-nuclear antibodies to antigens "planted" in the  glomerulus and cross reactivity of anti-nuclear antibodies with glomerular constituents. A proteomic approach similar to that proposed in this application was used to determine that an auto-antibody to the M-type phospholipase A2 receptor (PLA2R) is responsible for immune complex deposition in idiopathic membranous nephropathy. This antibody is present in 70% to 80% of patients with idiopathic membranous nephropathy but it is not present in patients with MLN. This suggests a new hypothesis that patients with MLN develop unique auto-antibodies against an endogenous component of the glomerular capillary. The current proposal will use proteomic approaches that were successfully employed by our group in idiopathic membranous nephropathy to identify and verify specific glomerular proteins to which autoantibodies that cause MLN are directed.

project_terms:
Actinin;Address;Adrenal Cortex Hormones;African American;Antibodies;Antigen Targeting;Antigen-Antibody Complex;Antineutrophil Cytoplasmic Antibodies;Autoantibodies;Binding (Molecular Function);Biological Markers;Biopsy;Cerebritis;Classification;Collaborations;Collagen Type IV;Deposition;Development;Diagnostic;Disease;Early Diagnosis;Epitopes;Functional disorder;Glomerular Capillary;Heparitin Sulfate;Hepatitis C;Idiopathic Membranous Nephropathy;Immunosuppressive Agents;Kidney;Kidney Diseases;Kidney Failure;Laminin;Lupus;Lupus Nephritis;Membranoproliferative Glomerulonephritis;Membranous Glomerulonephritis;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Neurons;Nuclear;Nucleosomes;Outcome;Pathogenesis;Patients;Phospholipase A2;Plant Antigens;Plants;Prevalence;Proteins;Proteomics;Recombinant Proteins;Reporting;Serum;Systemic Lupus Erythematosus;Tissues;base;cross reactivity;mouse model;novel therapeutics;podocyte;public health relevance;receptor;therapy development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The expected outcomes of the proposed studies will be the identification of specific target proteins for nephritigenic autoantibodies that induce membranous lupus nephritis (MLN). The impact of the proposed studies will be confirmation of a common pathophysiology for idiopathic and lupus membranous nephropathy identification of a biomarker for Class V MLN that allows early diagnosis definition of a biomarker for MLN that can be used to follow efficacy of treatment and development of new therapeutic strategies based on identification of the epitope to which nephritigenic autoantibodies are directed. Additionally definition of the target for nephritigenic autoantibodies and comparison with autoantibodies found in murine models of LN will allow development of a mouse model of MLN.


application_id: 8606092
project_number: 1R01HL120746-01
project_title: Tobacco Products and Atherosclerotic Disease
administering_ic: NHLBI
award_notice_date: 2013-09-19
opportunity_number: PAR-12-267
application_type: 1
activity_code: R01
ic: HL
serial_number: 120746
program_official: PUNTURIERI, ANTONELLO
project_start_date: 2013-09-19
project_end_date: 2018-08-31
study_section: Special Emphasis Panel[ZRG1 HDM-Q (54)]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION: Smoking is the leading cause of preventable deaths. Although cigarette smoking increases the risk of several chronic diseases nearly half of smoking related mortality could be linked to cardiovascular deaths. Therefore regulation of cigarettes and other tobacco products could significant lower the global burden of cardiovascular disease (CVD). The Family Smoking Prevention and Tobacco Control Act gives the FDA the authority to regulate the manufacturing marketing and distribution of tobacco products to protect public health. However to set standards for tobacco products it is important to know how cardiovascular effects of new and emerging tobacco products could be measured and which components of tobacco products induce cardiovascular injury. Because CVD is a chronic disease that develops over several years biomarkers of tobacco-induced cardiovascular injury are urgently needed to assess CVD risk in a time-frame sufficient for product evaluation. Moreover to relate biomarkers of injury with exposure to specific harmful and potentially harmful (HPHC) tobacco constituents it is essential to identify biomarkers that reflect exposure to specific constituents of tobacco products. Elucidation of the relationship between biomarker of exposure and biomarkers of injury will enable comparisons between the toxicities of different tobacco products and inform the design of future human studies for evaluating the cardiovascular effects of tobacco product use. Accordingly the overall goal of our project is to identify biomarkers of exposure to tobacco products and to relate them to atherosclerosis the underlying cause of several cardiovascular diseases. To accomplish this goal we will examine tobacco-induced injury in apoE-null mice and apoE-null rats. We will expose animals to varying intensities of tobacco smoke and smokeless tobacco we will identify urinary metabolites of exposure-derived aldehydes and determine how they relate to the extent and duration of exposure as well as to atherosclerotic lesion formation and lesion stability and how the relationship between the biomarkers of injury and biomarkers of exposure is affected by gender and the species and duration of exposure. In these experiments we will identify specific indices of atherosclerosis and thrombosis and how these biomarkers of injury are related to the biomarkers of exposure. To delineate the contribution of HPHCs we will identify which constituents of tobacco and tobacco smoke contribute to atherogenesis we will examine atherogenesis in mice exposed to individual constituents of exposure - nicotine acrolein and crotonaldehyde and determine how removal of these constituents affects atherosclerosis due to tobacco smoke and whether increases in the extent of exposure to these aldehydes and related reactive chemicals exacerbate atherosclerosis. Successful completion of this project will lead to the development of validated animal models to establish standard toxicity
changes and the discovery of novel biomarkers of cardiovascular injury that can be associated with measures of tobacco exposure. The findings of this project will provide new information regarding the contribution of reactive aldehydes such as acrolein and crotonaldehyde to the cardiovascular toxicity of cigarette smoke and smokeless tobacco. These findings will be useful in evaluating the contribution of HPHCs to tobacco product toxicity in humans; assessing the extent of harm reduction in PREPs and in developing policies for regulating HPHCs in smokeless tobacco cigarettes and emerging tobacco products. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

project_terms:
2-butenal;Acrolein;Affect;Aldehydes;Animal Model;Animals;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Biological Markers;Blood Platelets;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Chemicals;Cholesterol Homeostasis;Chronic Disease;Cigarette;Development;Disease;Doctor of Philosophy;Evaluation;Excision;Exposure to;Family Smoking Prevention and Tobacco Control Act;Future;Gender;Goals;Harm Reduction;Health;Heart Diseases;Heart failure;Human;Individual;Injury;Ischemia;Knockout Mice;Lead;Lesion;Link;Marketing;Measures;Mediating;Mortality Vital Statistics;Mus;Nature;Nicotine;Policies;Principal Investigator;Rattus;Regulation;Reperfusion Therapy;Risk;Risk Factors;Smoke;Smokeless Tobacco;Smoking;Surrogate Markers;Thrombosis;Time;Tobacco;Tobacco smoke;Tobacco use;Toxic effect;atherogenesis;authority;cardiovascular disorder risk;cardiovascular injury;cigarette smoke;cigarette smoking;design;indexing;novel;programs;public health medicine (field);research study;stroke;tobacco exposure;urinary


application_id: 8605864
project_number: 5R01DA022451-05
project_title: Enhancement of Sexual Motivation
administering_ic: NIDA
award_notice_date: 2014-02-10
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DA
serial_number: 022451
program_official: LYNCH, MINDA
project_start_date: 2010-02-01
project_end_date: 2016-01-31
study_section: Special Emphasis Panel[ZRG1-BBBP-T(03)M]
contact_pi_person_id: 7876913
contact_pi: AKINS, CHANA K.
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): There is considerable evidence for a co-morbid relationship between cocaine abuse and risky sexual behavior. Clinical studies have shown a correlation between cocaine use and risky sexual practices such as increased frequency an increased number of partners and unprotected sex. These sexual practices have been linked to adverse health consequences including high prevalence rates for sexually-transmitted diseases. Controlled preclinical studies that utilize animal models have demonstrated that prior repeated exposure to cocaine enhances sexual motivation and behavior. However no parametric or systematic studies further investigating the basic mechanisms underlying this relationship have been conducted. The goal of the proposed experiments is to utilize an animal model whose sexual behavior system has been well-studied Japanese quail. In addition to the benefits of using quail to study sexual behavior the use of a visually-oriented species in studying drug effects may be of additional relevance to studying human drug addiction. We currently have preliminary evidence in male Japanese quail that preexposure to cocaine enhances sexual motivation. This finding ties in well with clinical observations that indicate that cocaine use in humans may increase sexual motivation thereby increasing the likelihood of the occurrence of high-risk sexual behavior. The overall working hypothesis of this proposal is that the magnitude of the sexual response depends on several cocaine preexposure parameters including dose amount of exposure time between exposures and the withdrawal period before sexual behavior testing. Additionally we hypothesize that cocaine preexposure increases the resistance to extinction (harder to eliminate) and facilitates the reacquisition of a sexual response that has been extinguished. The proposed research has the potential to contribute to our understanding of cocaine preexposure effects on sexual motivation using a visually-oriented animal model. For example in males sexual motivation may be enhanced by prior cocaine exposure. Such an enhancement might translate in humans as high risk or compulsive sexual behaviors such as increased frequency of sexual activity sex with multiple partners and unprotected sex. These risky sexual behaviors have been linked with considerable health consequences such as the transmission of HIV and hepatitis C. The goal of the proposed project is to contribute to understanding underlying mechanisms of cocaine's effects on sexual motivation.

project_terms:
Acute;Animal Model;Animals;Association Learning;Behavior;Brain region;Breeding;Chronic;Clinical;Clinical Research;Cocaine;Cocaine Abuse;Conditioned Stimulus;Coturnix japonica;Cues;Dependence;Dose;Drug Addiction;Drug abuse;Drug usage;Empirical Research;Ethics;Event;Extinction (Psychology);Female;Food;Frequencies (time pattern);Goals;HIV;Health;Hepatitis C;High Prevalence;Human;Investigation;Learning;Length;Light;Link;Long-Term Effects;Measures;Memory;Mentored Research Scientist Development Award;Methods;Modeling;Motivation;Multiple Partners;Partner in relationship;Performance;Pharmaceutical Preparations;Phase;Physiological Effects of Drugs;Pre-Clinical Model;Procedures;Property;Publishing;Quail;Recovery;Research;Research Training;Resistance;Rewards;Rodent;Saline;Seasons;Sensory;Sex Behavior;Sexually Transmitted Diseases;Signal Transduction;Simulate;Stimulus;System;Testing;Time;Translating;United States;Unsafe Sex;Visual;Withdrawal;Work;addiction;approach behavior;behavior test;clinically relevant;cocaine exposure;cocaine use;conditioning;drug of abuse;drug testing;experience;high risk;high risk sexual behavior;indexing;learned behavior;male;neural circuit;preclinical study;public health medicine (field);research study;response;sex;transmission process

public_health_relevance:
Clinical studies have shown a correlation between cocaine use and risky sexual practices such as increased frequency an increased number of partners and unprotected sex. These sexual practices have been linked to adverse health consequences including high prevalence rates for sexually-transmitted diseases. The current application is a preclinical model used to investigate how drugs of abuse alter sexual motivation.


application_id: 8605834
project_number: 5R21AI099509-02
project_title: Host glycosyltransferases in the glycosylation of Toxoplasma proteins
administering_ic: NIAID
award_notice_date: 2013-12-16
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: AI
serial_number: 099509
program_official: MCGUGAN, GLEN C
project_start_date: 2013-01-18
project_end_date: 2015-12-31
study_section: Pathogenic Eukaryotes Study Section[PTHE]
contact_pi_person_id: 6624897
contact_pi: SINAI, ANTHONY 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 protozoan parasite Toxoplasma gondii is an important infection causing life threatening disease in patients with HIV-AIDs and other immune suppressive conditions. Despite the activation of a robust immune response including high antibody titers in infected individuals sterile cure is not achieved. Rather the parasite differentiates into a relatively metabolically quiescent tissue cyst form. Tissue cysts which establish within muscle and the CNS are characterized by having a highly glycosylated cyst wall and matrix. A given cyst may contain several hundred individual parasites. Our studies using lectin reactivity have identified the presence of sialic acid containing glycans in the tissu cyst wall and matrix of both brain derived and tissue culture induced cysts. This finding is remarkable in light of the absence of any of the machinery for the synthesis activation and transfer of sialic acid being found in the parasite genome. The implication of this finding is that
host activities may be responsible for the sialylation of the tissue cyst associated glycans. In ths study we explore this radical hypothesis by using established host cell mutants with defects in distinct steps of the sialylation pathway to confirm the contribution of the host cell. In addition specific host activities will also be targeted using siRNA knockdowns to establish the classes of sialyltransferases involved. Finally we will develop as split GFP/Luc based system to address whether fusion of the parasitophorous vacuole membrane and the associated ER as well as the redirection of Golgi associated vesicles is involved in the delivery of cyst modifying glycosylatin enzymes from the host cell. We believe that by hijacking the host's own glycosylation machinery the parasite may avoid detection by the immune system by effectively "sugar coating" potentially antigenic determinants with "self" sugars rendering them functionally invisible.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Affinity;Agglutinins;Animals;Antibodies;Antigens;Binding (Molecular Function);Biogenesis;Bioinformatics;Biological Assay;Biology;Blood;Brain;Cells;Chinese Hamster Ovary Cell;Competence;Cross Presentation;Cultured Cells;Cyst;Defect;Detection;Disease;Dolichos;Elements;Endoplasmic Reticulum;Enzymes;Epitopes;Event;Exhibits;Felis catus;Funding Mechanisms;Genes;Genome;Glycoproteins;Golgi Apparatus;Growth;HIV;Immune;Immune response;Immune system;Individual;Infection;Ingestion;Integration Host Factors;Label;Lectin;Life;Light;Link;Maintenance;Measures;Mediating;Membrane;Modification;Molecular Cloning;Monoclonal Antibodies;Muscle;Natural immunosuppression;Oocysts;Organelles;Parasites;Pathogenesis;Pathway interactions;Patients;Pattern;Peanut Agglutinin;Polysaccharides;Protein Glycosylation;Proteins;Recruitment Activity;Reporter;Research Design;Risk;Role;Sambucus nigra;Sialic Acids;Sialyltransferases;Small Interfering RNA;Spatial Distribution;Specificity;Staining method;Stains;Sterility;System;Testing;Tissues;Toxoplasma;Toxoplasma gondii;Toxoplasmosis;Vacuole;Vesicle;Viral Tumor Antigens;Work;base;clinically relevant;glycosylation;glycosyltransferase;innovation;jacalin;microbial;mutant;novel;parasite genome;pathogen;prevent;public health relevance;sialylation;success;sugar;tissue culture;transmission process

public_health_relevance:
Toxoplasma gondii causes serious illness in immune compromised individuals including patients with HIV- AIDS. Our understanding of the role of glycosylation in parasite biology is very limited. With this application we investigate a novel paradigm and address a potential mechanism by which host activities may glycosylated parasite proteins in the vacuolar space and the tissue cyst.


application_id: 8602825
project_number: 5R01AI095032-03
project_title: Cooperation of CD8+ T cells and phagocytes to eliminate Toxoplasma cysts
administering_ic: NIAID
award_notice_date: 2013-11-29
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AI
serial_number: 095032
program_official: WALI, TONU M
project_start_date: 2012-01-01
project_end_date: 2016-12-31
study_section: AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC]
contact_pi_person_id: 1882071
contact_pi: SUZUKI, YASUHIRO
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Toxoplasma gondii establishes an important chronic infection capable of causing life-threatening toxoplasmic encephalitis in AIDS patients and other immunocompromised individuals. The basis of persistence of the infection is the tissue cyst which remains largely quiescent for the life of the host but can reactivate and cause disease. This stage of the parasite is not affected by any of the current drug treatments and it has been generally regarded as untouchable. However our recent studies revealed that the immune T cells are able to eliminate T. gondii cysts from the brains of infected hosts when the T cells are transferred into infected immunodeficient animals that have already developed large numbers of the cysts. This T cell-mediated immune process is associated with accumulation of mononuclear cells primarily microglia and macrophages morphologically around tissue cysts. Since the accumulated phagocytes penetrate within the cyst these cells appear to be the main effector cells that destroy the cysts and eliminate them from the brain after initiation of this process by immune T cells. CD8+ immune T cells possess a potent activity to initiate this anti-cyst immune process and the protective activity of the T cells requires perforin. The overall goalof this research project is to determine the molecular mechanisms by which perforin-mediated activity of CD8+ immune T cells cooperates with the phagocytes to remove T. gondii cysts from the brain. In the first aim we will determine if CD8+ immune T cells accumulate and attach to the cyst-containing cells in the brain. We will also determine if the CD8+ T cells lyse cyst-containing cells in a perforin-dependent manner in vitro and whether the perforin- mediated activity of CD8+ T cells induces the accumulation of phagocytes around the cysts in the brain. In the second aim we will determine the MHC class I molecule(s) critical for recognition of cyst-containing cells by CD8+ T cells. We will then determine the T. gondii cyst epitope(s) presented by the identified MHC class I molecule for recognition by the CD8+ T cells by screening predicted bradyzoite epitope peptides and/or bradyzoite cDNA library. The third aim is to determine the mechanisms by which phagocytes eliminate T. gondii cysts after initiation of the immune process by CD8+ T cells. We will examine the roles of inducible nitric oxide synthase and autophagy in killing of bradyzoites and elimination of cysts using mice lacking a molecule required for each mechanism. The information generated from the studies in these three specific aims all together will provide the essential basis for developing a novel method(s) to activate CD8+ T cells and phagocytes to eliminate T. gondii cysts that can reactivate and cause toxoplasmic encephalitis.

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

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


application_id: 8602633
project_number: 1R01NS083405-01A1
project_title: Multi-Mechanism Inhibition of Lipid Peroxidation in TBI
administering_ic: NINDS
award_notice_date: 2013-05-06
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: NS
serial_number: 083405
suffix: A1
program_official: HICKS, RAMONA R
project_start_date: 2013-07-01
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1 BDCN-L (02)]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): We have previously documented that generation of the potent reactive nitrogen species (RNS) peroxynitrite (PN) is responsible for oxidative damage by lipid peroxidation (LP) and protein modification (carbonylation and tyrosine nitration) to mitochondrial and other cellular elements during the first 72 hrs after traumatic brain injury (TBI). The PN-mediated oxidative damage leads to brain mitochondrial dysfunction and ultimately failure. As a consequence of oxidative compromise of mitochondrial function including calcium (Ca++) buffering) posttraumatic intracellular Ca++ overload is exacerbated leading to calpain-mediated cytoskeletal degradation neurodegeneration and neurological impairment. We have preliminarily shown that treatment with the potent LP inhibitor U-83836E with the LP-derived lipid aldehyde 4-hydroxynonenal (4-HNE) scavenger phenelzine or with the mitochondrial permeability transition inhibitor cyclosporine (CsA) can partially attenuate posttraumatic brain LP damage mitochondrial dysfunction and calpain-mediated cytoskeletal damage in a mouse TBI model. Most importantly the window for this effect is at least 12 hrs post-injury. However our preliminary results show only a partial attenuation of post-injury LP-related neural damage' even when any of these antioxidant compounds is individually administered after injury. This partial neuroprotective effect strongly points to the logic of an antioxidant neuroprotective strategy that combines either two or all three of these mechanistically complimentary antioxidant compounds to achieve a greater degree of neuroprotection. Therefore the overall goal of the proposed experiments is to explore the hypothesis that interrupting post-traumatic secondary LP oxidative damage at multiple points will produce a quantitatively greater neuroprotective effect with less variability that will have a
greater chance of translational success in future TBI clinical trials. The combination approach should not only increase the maximal neuroprotective effect but may also prolong the therapeutic window for inhibition of secondary brain injury after TBI.

project_terms:
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole;3-nitrotyrosine;4 hydroxynonenal;Aldehydes;Antioxidants;Attenuated;Brain;Brain Injuries;Buffers;Calcium;Calpain;Clinical Trials;Complex;Cyclosporine;Dose;Effectiveness;Elements;Extravasation;Failure (biologic function);Free Radicals;Functional disorder;Future;Generations;Goals;Human;Impairment;Injury;Intervention;Lesion;Lipid Peroxidation;Lipids;Logic;Mediating;Membrane Lipids;Mitochondria;Modeling;Molecular;Mortality Vital Statistics;Motor;Mus;Nerve Degeneration;Nervous System Trauma;Neurologic;Neurons;Patients;Permeability;Peroxonitrite;Pharmaceutical Preparations;Phase III Clinical Trials;Phenelzine;Post-Translational Protein Processing;Production;Rattus;Reactive Nitrogen Species;Reactive Oxygen Species;Recovery of Function;Regimen;Reporting;Subarachnoid Hemorrhage;Testing;Therapeutic;Tissues;Translating;Traumatic Brain Injury;Traumatic Subarachnoid Hemorrhage;Treatment Efficacy;Treatment Protocols;Tyrosine;attenuation;base;cognitive function;controlled cortical impact;design;improved;inhibitor/antagonist;injured;lipid peroxidation inhibitor;mitochondrial dysfunction;neuroprotection;neurotoxic;nitration;oxidative damage;protective effect;public health relevance;relating to nervous system;research study;respiratory;response;success;treatment strategy

public_health_relevance:
This project will examine the potentially greater benefits that might be obtained in the rat controlled cortical impact traumatic brain injury model when multiple neuroprotective compounds that target oxidative secondary injury mechanisms are administered together. Specifically we will test a combination multi-mechanistic antioxidant treatment strategy combining two or three of the following mechanistically complimentary antioxidant compounds: 1) the lipid peroxidation-inhibiting drug U-83836E 2) the commercially available compound phenelzine that scavenges the neurotoxic lipid peroxidation-derived lipid aldehyde 4- hydroxynonenal (4-HNE) and 3) the extensively demonstrated mitochondrial protective compound cyclosporine A(CsA) which reduces post-TBI mitochondrial permeability transition and free radical leakage. After determining the best neuroprotective dose optimal treatment regimen and therapeutic efficacy window of each compound pharmacologically-optimized dosing regimens of each of the compounds will be compared in a single experiment. This will be followed by the testing of the combination effectiveness of two (U-83836E + phenelzine U-83836E + CsA phenelzine + CsA) or all three (U-83836E + phenelzine + CsA).


application_id: 8601974
project_number: 2P20GM103492-06
project_title: Project 3 - Regulation of Metabolism by Nitric Oxide
administering_ic: NIGMS
award_notice_date: 2013-08-01
opportunity_number: PAR-12-224
application_type: 2
activity_code: P20
ic: GM
serial_number: 103492
study_section: Special Emphasis Panel[ZGM1 TWD-Y (C2)]
subproject_number: 5008
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
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: 2013-08-01
budget_end_date: 2014-06-30
project_terms:
Adipocytes;Adipose tissue;Adult;Affect;Bile Acid Biosynthesis Pathway;Bile Acids;Biogenesis;Body fat;Branched-Chain Amino Acids;Burn injury;Cardiovascular system;Cell Differentiation process;Centers for Disease Control and Prevention (U.S.);Cyclic GMP;Development;Diabetes Mellitus;Diet;Endothelium;Epidemic;Europe;Fatty acid glycerol esters;Functional disorder;Human;In Vitro;Individual;Insulin;Insulin Resistance;Lead;Link;Lipids;Measures;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Mus;Nitric Oxide;Nitric Oxide Donors;Nitric Oxide Synthase;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Obesity;Overweight;Phenotype;Population;Predisposition;Production;Regulation;Reporting;Research;Resistance;Risk;Risk Factors;Role;Secondary to;Signal Transduction;Stem cells;Testing;Tissues;Transplantation;Weight Gain;absorption;adipocyte differentiation;cofactor;diabetic;enzyme activity;feeding;human NOS3 protein;in vivo;metabolomics;novel;novel therapeutic intervention;overexpression;prevent;stem


application_id: 8601973
project_number: 2P20GM103492-06
project_title: Project 2 - Effects of Particulate Matter on Insulin Resistance and Endothelial
administering_ic: NIGMS
award_notice_date: 2013-08-01
opportunity_number: PAR-12-224
application_type: 2
activity_code: P20
ic: GM
serial_number: 103492
study_section: Special Emphasis Panel[ZGM1 TWD-Y (C2)]
subproject_number: 5007
contact_pi_person_id: 11375489
contact_pi: HABERZETTL, PETRA
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: 2013-08-01
budget_end_date: 2014-06-30
project_terms:
Accounting;Aerosols;Affect;Air;Air Pollution;Arrhythmia;Biological;Biological Markers;Blood Vessels;Body Composition;Breathing;Cardiovascular Diseases;Centers of Research Excellence;Cessation of life;Chemicals;Chronic;Data;Deposition;Developing Countries;Development;Diabetes Mellitus;Diet;Dose;Environmental Pollutants;Environmental Risk Factor;Epidemic;Epidemiologic Studies;Epidemiology;Exposure to;Fatty acid glycerol esters;Functional disorder;Funding;Future;Health;Human;IL18 gene;Incidence;Inflammation;Inflammatory;Injury;Insulin;Insulin Resistance;Interruption;Intervention;Knockout Mice;Laboratories;Lead;Link;Longevity;Maintenance;Measures;Mediating;Metabolic Diseases;Metabolic syndrome;Modeling;Molecular;Mortality Vital Statistics;Mus;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Organ;Particulate Matter;Pathway interactions;Patients;Policies;Prevalence;Prevention;Process;Property;Prospective Studies;Regulation;Research;Risk;Risk Factors;Role;Stem cells;System;Testing;Tissues;Vascular Endothelium;air filter;ambient particle;base;cardiovascular disorder risk;chemical property;diabetes risk;dosimetry;feeding;improved;indexing;insight;insulin sensitivity;mouse model;novel;particle;physical property;prevent;repaired;research study;response;stroke


application_id: 8600989
project_number: 5R01HL108621-04
project_title: Mitophagic and anti-angiogenic mechanism of heart failure
administering_ic: NHLBI
award_notice_date: 2013-12-10
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 108621
program_official: ADHIKARI, BISHOW B
project_start_date: 2011-04-15
project_end_date: 2015-12-31
study_section: Special Emphasis Panel[ZRG1-VH-B(02)M]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Although heart failure is inevitable disease its management depends on the understanding of the mechanism of ailing to failing myocardium. During heart failure the heart undergoes compensatory remodeling (i.e. left ventricle hypertrophy (LVH) and vascular angiogenesis. Unfortunately during end-stage heart failure there is dis-coordination between the LVH and angiogenesis (i.e. LVH persists but angiogenesis declines). This leads to continue increase in LV wall stress leading to failure. Remodeling by its very nature implies synthesis degradation and re-arrangement of intra and inter cellular matrix. Matrix metalloproteinases (MMPs) are designer architecture and tailor. The long-term goal of this project is to understand the differential role of MMPs in structural and functional heterogeneity in myocardial remodeling. The selective MMP-2 gene ablation reduces survival and exacerbates cardiac failure-induced by myocardial inflammation. MMP-9 gene ablation is cardioprotective. In human heart end-stage failure MMP-9 activation supersedes the MMP-2 activation. The hypothesis of this proposal is that MMP-2 is constitutive and during compensatory phase activates proteinase activated receptor-1 (PAR-1 a GPCR) and releases growth factors via the activation of anti-stress (PKB/AKT). Chronic stress leads to mitochondrial mitophagy and activation of MMP-9 and MMP-13 (an interstitial collagenase in rodent and MMP-1 in human). TIMP-3 (an apoptotic/autophagic factor) and anti-angiogenic statins are released The hypothesis will be tested by following three specific aims: Specific Aim #1: To determine whether the induction of MMP-2 PAR-1 G1s and AKT causes compensatory hypertrophy and mitochondrial mitophagy causes MMP-9 activation and decreases G1s and AKT in de-compensatory heart failure. Specific Aim #2: To determine whether the MMP-2 releases angiogenic growth factors during compensatory remodeling and MMP-9 releases anti-angiogenic statins in de-compensatory heart failure. Specific Aim #3: To determine whether the mitochondrial mitophagy attenuates angiogenesis in part by activating MMP-9 releasing TIMP-3 and generating statins during de-compensatory heart failure. These studies will delineate the causative role of PAR-1 MMP TIMP G1s and mitophagy in switch from compensatory LVH and angiogenesis to de-compensatory LVH and anti-angiogenesis and will have therapeutic ramifications for chronic heart failure.

project_terms:
Ablation;Address;Angiography;Angiostatins;Antibodies;Apoptotic;Architecture;Attenuated;Autophagocytosis;Barium;Biological Assay;Blood Vessels;Blood flow;Cardiac;Chronic;Chronic stress;Cytoskeleton;DNA;Disease;Endostatins;Enzyme-Linked Immunosorbent Assay;Failure (biologic function);Fibroblast Growth Factor;G-Protein-Coupled Receptors;Gelatinase A;Gelatinase B;Genes;Goals;Growth Factor;Heart;Heart failure;Heterogeneity;Human;Hypertrophy;In Situ Nick-End Labeling;Inflammation;Interstitial Collagenase;Lasers;Left Ventricular Hypertrophy;Left ventricular structure;Matrix Metalloproteinases;Measures;Mitochondria;Mus;Myocardial;Myocardium;Nature;Outcome;Oxygen Consumption;PAR-1 Receptor;Pathogenesis;Pathway interactions;Phase;Protein Array;Proto-Oncogene Proteins c-akt;Rodent;Role;Small Interfering RNA;Staging;Stress;Testing;Therapeutic;Tissue Inhibitor of Metalloproteinase-1;Tissue Inhibitor of Metalloproteinase-3;Tissue Inhibitor of Metalloproteinases;Transforming Growth Factor beta;Vascular Endothelial Growth Factors;Ventricular Remodeling;angiogenesis;antiangiogenesis therapy;collagenase 3;constriction;density;in vivo;inhibitor/antagonist;matrigel;public health relevance;tissue inhibitor of metalloproteinase 4

public_health_relevance:
These studies will delineate the differential role of mitochondrial mitophagy and anti- angiogenesis mechanisms in end-stage heart failure. The differential role of different MMPs in angiogenesis and anti-angiogenesis in transition from compensatory hypertrophy to de-compensatory heart failure will be determined. The positive outcome of this project will have therapeutic ramifications for chronic heart failure.


application_id: 8600894
project_number: 5R01CA143428-04
project_title: Rel B mediated-redox regulation of radiation therapy
administering_ic: NCI
award_notice_date: 2013-12-09
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: CA
serial_number: 143428
program_official: BERNHARD, ERIC J
project_start_date: 2011-01-01
project_end_date: 2015-11-30
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: ST CLAIR, WILLIAM H
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Accumulating data suggest that prostate cancers exist in an elevated state of oxidative stress and that reactive oxygen species (ROS) contribute importantly to the cytotoxic effect of ionizing radiation (IR). However ROS also participate in cellular signaling processes leading to adaptive responses that reduce the effectiveness of radiation therapy. Thus despite rapid advances in treatment techniques the outcome of radiation therapy especially for patients with tumors with unfavorable prognoses remains to be improved. The goal of this project is to identify novel mechanisms that could lead to the development of specific measures for effective treatment of aggressive prostate cancers. We have identified the alternative pathway of the redox sensitive nuclear factor kappa beta (NF-?B) as a major contributor to prostate cancer growth and progression. Preliminary data indicate that: 1) aggressive prostate cancers have high nuclear RelB a member of the alternative pathway of NF-:B and manganese superoxide dismutase (MnSOD) a critical antioxidant enzyme levels; 2) suppression of RelB in androgen independent-aggressive prostate cancer cells results in reduction of interleukin 8 (IL8) levels in tumor cells and reduced tumor growth in vivo; 3) overexpression of RelB in androgen responsive prostate cancer cells results in enhanced tumor growth and production of IL8 but reduced prostate specific androgen (PSA) production; and 4) suppression of RelB nuclear translocation enhances radiation sensitivity of prostate cancer. Based on these novel and important preliminary findings we hypothesize that RelB regulates prostate cancer response to radiation via a MnSOD dependent NF-?B switch to activate expression of IL8 and suppress expression of PSA in prostate cancer cells. We propose that clinical testing for recurrent tumor growth should involve measuring levels of IL8 in addition to employing the standard PSA test. Combining these tests will enhance accurate cancer detection and prognosis. To test this hypothesis and validate the proof-of-concept for the combined use of IL8 and PSA as prognostic factors three interrelated specific aims will be addressed. Aim 1 will elucidate the mechanism by which MnSOD modulates the effect of RelB on the transcription of IL8 and PSA in prostate cancer cells using biochemical and molecular biology approaches. Aim 2 will examine the role of IL8 in the protection against the effects of radiation therapy of prostate cancer. Aim 3 will determine whether serum IL8 level is a predictive marker of prostate cancer response to radiation therapy using samples from cancer patients.  These mechanistic based bench to bedside approaches should provide novel insights into the mechanisms of prostate cancer resistant to radiation therapy and may provide practical predictive measures for prostate cancer diagnostic treatment planning and surveillance.

project_terms:
Address;Affinity Chromatography;Androgens;Animal Model;Antioxidants;Basic Science;Binding (Molecular Function);Biochemical;Biological Assay;Cancer Center;Cancer Detection;Cancer Diagnostics;Cancer Etiology;Cancer Patient;Cancer Prognosis;Cessation of life;Clinical;Clinical Research;Cultured Cells;Data;Development;Diagnosis;Diagnostic Neoplasm Staging;Effectiveness;Enzymes;Family;Gene Expression;Genes;Genetic Transcription;Goals;Growth;Human;Immunoprecipitation;Interleukin-8;Ionizing radiation;Kentucky;Lead;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Manganese Superoxide Dismutase;Measures;Mediating;Modeling;Molecular Biology;NF-kappa B;Nuclear;Nuclear Translocation;Outcome;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Patients;Physicians;Play;Predictive Factor;Production;Prognostic Factor;Prostate;Prostate-Specific Antigen;Proteomics;Radiation;Radiation Tolerance;Radiation therapy;Reactive Oxygen Species;Recurrent tumor;Regulation;Resistance;Risk;Role;Sampling;Serum;Site-Directed Mutagenesis;Small Interfering RNA;Techniques;Testing;Time;Transcriptional Regulation;Translating;Tumorigenicity;Universities;Visit;base;bench to bedside;cancer diagnosis;cancer type;cytotoxic;cytotoxicity;effective therapy;follow-up;improved;in vivo;inflammatory marker;insight;member;men;neoplastic cell;novel;outcome forecast;overexpression;prostate cancer cell;public health relevance;research clinical testing;research study;response;signal processing;treatment planning;treatment strategy;tumor;tumor growth

public_health_relevance:
Prostate cancer is the most frequently diagnosed cancer in men and the number of men who die from prostate cancer is unacceptably high. The results obtained from this study will provide insights into the novel mechanisms by which interleukin 8 (IL8) and prostate specific antigen (PSA) are differentially regulated and will test a proof-of-concept for using their relationship to predict the efficacy of radiation therapy for treating prostate cancer. Thus this study will enable physicians to tailor risk-adjusted strategies for treatment of prostate cancer.


application_id: 8600276
project_number: 5R01EY021497-03
project_title: Modulation of EGFR Signaling to Promote Corneal Epithelial Wound Healing
administering_ic: NEI
award_notice_date: 2013-12-18
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: EY
serial_number: 021497
program_official: MCKIE, GEORGE ANN
project_start_date: 2012-01-01
project_end_date: 2015-12-31
study_section: Anterior Eye Disease Study Section[AED]
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 develop strategies to restore and maintain the integrity of the corneal epithelium. Activation of the epidermal growth factor receptor (EGFR) is necessary and sufficient for the homeostasis and repair of the corneal epithelium. Despite evidence that the EGFR is a viable target for corneal epithelial wound healing its use therapeutically has been limited. Understanding the molecular details of how signaling by the receptor is regulated will provide clues for utilizing EGFR-targeted therapies. One such regulatory mechanism is ligand-stimulated EGFR endocytosis. The internalization and subsequent endocytic trafficking of the receptor negatively controls EGFR signaling by targeting the active receptor to lysosomes for degradation. Our studies will determine how endocytosis affects EGFR signaling in the corneal epithelium. Based on our recent findings and reports in the literature we propose the following hypothesis: slowing the endocytic trafficking of the liganded EGFR will prolong EGFR signaling and enhance corneal wound healing. This overall hypothesis will be tested with the following Aims. In Aim 1 we will test the hypothesis that different endogenous EGFR ligands possess different routes and/or kinetics of endocytic trafficking. Secondarily we will determine if those ligands that promote EGFR recycling will enhance corneal epithelial cell migration and wound healing. Using immortalized and primary human corneal epithelial cells we will examine the kinetics and routes of EGFR endocytic trafficking in response to endogenous EGFR ligands. These ligands have been reported to have varying kinetics and/or routes of EGFR endocytic trafficking in other cell lines. The effect of these ligands on EGFR endocytic trafficking in corneal epithelial cells is unknown due to differences in the level of EGFR expression and intrinsic properties of the corneal epithelial cells. Once we determine how these ligands impact EGFR endocytic trafficking in the corneal epithelium we will determine how they affect the cell biology of corneal epithelial cells (cell migration) and corneal wound healing using an in vivo model (Sprague- Dawley rats). In Aim 2 we will test the hypothesis that the inhibition of EGFR endocytic trafficking will prolong receptor activity and enhance the rate of corneal epithelial cell migration and wound healing. Using the tissue culture cells described above we will disrupt endocytic trafficking at selected stages in the endocytic pathway (at the plasma membrane pre-early endosome and in the late endosome/multivesicular body) and assess whether the phosphorylation of the EGFR and downstream effectors is prolonged. Next we will determine if such changes are reflected in EGFR-mediated corneal epithelial cell migration and wound healing. In Aim 3 we will determine if other EGFR family members (ErbB2 3 and 4) play a role in promoting corneal wound healing if they do so more efficaciously that EGFR. If we are able to develop strategies for enhancing EGFR signaling we have the potential for therapeutically accelerating the rate of corneal wound healing and minimize patient discomfort the risk of infection and blindness.

project_terms:
Affect;Attenuated;Back;Binding (Molecular Function);Biochemical Genetics;Biological Assay;Blindness;Blocking Antibodies;Cell Line;Cell membrane;Cells;Cellular biology;Clinical;Complex;Cornea;Corneal Injury;Corneal Ulcer;Development;Drug Targeting;Early Endosome;Effectiveness;Endocytosis;Epidermal Growth Factor;Epidermal Growth Factor Receptor;Epithelial Cells;Epithelium;Eye;Family member;Film;Future;Goals;Homeostasis;Human;In Vitro;Infection;Kinetics;Laboratories;Ligands;Light;Literature;Lysosomes;Mediating;Molecular;Multivesicular Body;Pathway interactions;Patients;Phosphorylation;Play;Property;Proteins;Publications;Publishing;Reagent;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Recycling;Reporting;Research;Retina;Risk;Role;Route;Severities;Signal Transduction;Sprague-Dawley Rats;Staging;System;Testing;Therapeutic;Tissues;Transforming Growth Factors;Translating;Work;Wound Healing;base;cell growth;cell motility;corneal epithelium;desensitization;in vivo;in vivo Model;inhibitor/antagonist;injured;late endosome;migration;prevent;receptor;receptor expression;receptor internalization;receptor recycling;repaired;research study;response;restoration;small molecule;therapeutic target;tissue/cell culture;tool;trafficking

public_health_relevance:
The epidermal growth factor receptor (EGFR) promotes cellular changes in the cornea epithelium such as cell growth proliferation and migration but has clinical limitations in promoting corneal wound healing. The goal of this research is to develop strategies to better use the EGFR as a therapeutic target by 1) identifying the molecular mechanisms that regulate EGFR signaling in the cornea and 2) by-pass those regulatory mechanisms to prolong EGFR signaling accelerate corneal wound healing and restore tissue homeostasis.


application_id: 8599456
project_number: 5K01ES017105-05
project_title: Ubiquitous pollutant acrolein inhibits IFN?? antiviral signaling: relevance to HC
administering_ic: NIEHS
award_notice_date: 2013-12-23
opportunity_number: PA-09-040
application_type: 5
activity_code: K01
ic: ES
serial_number: 017105
program_official: SHREFFLER, CAROL A
project_start_date: 2010-01-01
project_end_date: 2015-12-31
study_section: ZES1-LKB-J(K6)
contact_pi_person_id: 9367807
contact_pi: JOSHI-BARVE, SWATI
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):  Chronic Hepatitis C virus (HCV) infection remains a global health concern with nearly 200 million carriers worldwide. It can be a precursor to cirrhosis hepatocellular carcinoma and end-stage liver disease. In the absence of a vaccine the current FDA approved standard of care for chronic hepatitis C is a combination of pegylated interferon-alpha (IFN1) and ribavirin. Unfortunately this regimen is only effective in about 50% of patients emphasizing the need for studies defining the molecular mechanisms underlying resistance to IFN1. Clinical studies have identified several potential cofactors that may contribute to the failure of anti-HCV therapy including obesity diabetes alcohol abuse oxidative stress cigarette smoking and environmental pollutants. Acrolein is a ubiquitous highly reactive environmental and industrial pollutant and is designated by the U.S. Environmental Protection Agency (EPA) as a high priority air and water pollutant. Notably acrolein is also formed endogenously as a byproduct of lipid peroxidation (LPO) and is itself known to cause oxidative stress. Moreover acrolein is a major component of cigarette smoke and recent studies suggest that smokers with chronic hepatitis C have a lower response rate to IFN1 compared to non-smokers. We have convincing preliminary data showing that non-toxic concentrations of acrolein significantly down-regulate IFN1 signaling and antiviral gene expression in vitro (cultured human hepatic cells) and in vivo (mice).  Published literature and our own compelling data strongly support our hypothesis that acrolein adversely influences IFN1 therapy outcomes by inhibiting or disrupting IFN1 mediated signaling and antiviral gene expression in hepatocytes and that high acrolein exposure (environmental and/or endogenous) will correlate with poor IFN1 response in HCV infected individuals. Our hypotheses will be tested by examining the effects of acrolein on early IFN1-mediated signaling (including components of the Jak/STAT pathway) and antiviral gene expression using well established in vitro and in vivo experimental systems as well as an HCV replicon that directly reports on HCV viral replication. Additionally the investigators will establish a clinical/translational aspect of our hypothesis by conducting a retrospective analysis using banked serum urine and/or liver biopsy samples from healthy uninfected individuals and HCV-infected patients (responders and non-responders). This analysis will explore a possible correlation between acrolein exposure and poor IFN1 response (lack of sustained virologic response SVR).  The investigators expect their studies will elucidate critical mechanisms underlying resistance to IFN1 treatment and will identify potential targets for novel therapeutic intervention.    Public Health Relevance:  Acrolein is one of the major reactive aldehydes ubiquitously present in foods water and in the environment. It is a major constituent of cigarette smoke. Recent data suggest that HCV- infected smokers have worse IFN1 therapeutic outcomes compared with non-smokers. Acrolein is also generated endogenously due to cellular metabolism and this may constitute a significant source of intracellular acrolein in situations of oxidative stress and inflammation. Elevated acrolein adducts have been detected in several disease conditions that are also known to be associated with failure of IFN therapy. Hence based on available literature and the investigators' own compelling preliminary results they have opted to use acrolein as the model compound for this study. The aim of the study is to determine the contribution of acrolein to the mechanisms of IFN1 resistance. The investigators have preliminary evidence to demonstrate that acrolein at nontoxic concentrations significantly down-regulates IFN1 signaling and antiviral/anti-HCV gene expression.

project_terms:
Acrolein;Acrylates;Air Pollutants;Alcohol abuse;Aldehydes;Alzheimer's Disease;Amino Acids;Antiviral Agents;Atherosclerosis;Automobile Exhaust;Binding (Molecular Function);Biocide;Biological Markers;Biological Models;Biology;Biopsy Specimen;Cell Line;Cessation of life;Chemical Weapons;Chronic Disease;Chronic Hepatitis C;Cirrhosis;Clinical;Clinical Research;Cysteine;Data;Development;Diabetes Mellitus;Disease;Dose;Double-Stranded RNA;Environment;Environmental Exposure;Environmental Pollutants;Exposure to;FDA approved;Failure (biologic function);Family;Fatty acid glycerol esters;Food;Free Radicals;Functional disorder;Future;Gene Expression;Genes;Genotype;Hepatitis C;Hepatitis C virus;Hepatocyte;Histidine;Human;Hydroxyl Radical;Imidazole;In Vitro;Individual;Industrial Waste;Inflammation;Interferons;Kidney Failure;Ligand Binding;Ligase;Lipid Peroxidation;Literature;Liver;Liver diseases;Lysine;Mediating;Medicine;Messenger RNA;Metabolism;Methionine;Modeling;Modification;Molecular;Mus;Non-Insulin-Dependent Diabetes Mellitus;Non-smoker;Nucleic Acids;Obesity;Organic Chemicals;Outcome;Oxidative Stress;PTPN11 gene;Pathway interactions;Patients;Pegylated Interferon Alfa;Phospholipids;Phosphorylation;Plastics;Play;Polyamines;Polymers;Primary carcinoma of the liver cells;Protein Phosphatase 2A Regulatory Subunit PR53;Protein Tyrosine Kinase;Protein phosphatase;Proteins;Publications;Publishing;Rattus;Regimen;Replicon;Reporting;Research;Research Personnel;Resistance;Response Elements;Ribavirin;Role;STAT protein;STAT1 gene;STAT2 gene;Serum;Side;Signal Transduction;Smoke;Smoker;Smoking;Source;Specimen;Staging;System;TYK2;Testing;Therapeutic;Tissues;Transcriptional Activation;Treatment outcome;United States;United States Environmental Protection Agency;Urine;Vaccines;Viral;Water;Water Pollutants;Wood material;adduct;amino group;anti-hepatitis C;base;chronic liver disease;cigarette smoke;cigarette smoking;cofactor;cooking;eIF-2 Kinase;efficacy testing;global health;improved;in vivo;insight;liver biopsy;mouse model;novel therapeutic intervention;oligoadenylate;pollutant;protein activation;public health relevance;receptor;receptor internalization;response;standard of care;therapy outcome

public_health_relevance:
Acrolein is one of the major reactive aldehydes ubiquitously present in foods water and in theenvironment. It is a major constituent of cigarette smoke. Recent data suggest that HCV-infected smokers have worse IFN therapeutic outcomes compared with non-smokers. Acroleinis also generated endogenously due to cellular metabolism and this may constitute a significantsource of intracellular acrolein in situations of oxidative stress and inflammation. Elevatedacrolein adducts have been detected in several disease conditions that are also known to beassociated with failure of IFN therapy. Hence based on available literature and our owncompelling preliminary results we have opted to use acrolein as the model compound for thisstudy. The aim of this study is to determine the contribution of acrolein to the mechanisms ofIFN resistance. We have preliminary evidence to demonstrate that acrolein at nontoxicconcentrations significantly down-regulates IFN signaling and antiviral/anti-HCV geneexpression.


application_id: 8599053
project_number: 1R01NS084823-01
project_title: Mechanisms of Homocysteine-Induced Fibrinogen-Amyloid Plaque Formation
administering_ic: NINDS
award_notice_date: 2013-06-25
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: NS
serial_number: 084823
program_official: CORRIVEAU, RODERICK A
project_start_date: 2013-07-01
project_end_date: 2018-04-30
study_section: Special Emphasis Panel[ZRG1 VH-B (03)]
contact_pi_person_id: 6869069
contact_pi: LOMINADZE, DAVID
other_pis: TYAGI, SURESH C.
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The plaques in the brain during Alzheimer's diseases (AD) are primarily composed of amyloid-b (Ab) peptide. Although a strong association between Ab fibrinogen (Fg) and elevated level of homocysteine (Hcy) i.e. hyperhomocysteinemia (HHcy) during AD is well- documented the mechanism of amyloid plaque formation is unclear. The long-term goal of this project is to understand the mechanisms of cerebrovascular permeability leading to amyloid plaque formation. We have shown that elevated levels of Hcy and Fg i.e. hyperfibrinogenemia (HFg) increase cerebrovascular permeability and Fg can cross vascular endothelial cell (EC) layer secondary to activation of matrix metalloproteinase-9 (MMP-9). In addition increased levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) which enhances collagen content in subendothelial matrix (SEM) are associated with AD. In pilot studies we found that while HHcy enhances vascular permeability through mainly the paracellular pathway HFg activates mainly the transcellular transport. We also found that blood level of Fg is increased during HHcy. Therefore Fg can have an additive effect in HHcy-induced cerebrovascular permeability. We found that HHcy increases collagen level in SEM and Fg and Ab depositions in brain vasculature. While HHcy increases MMP-9 activity and enhances the paracellular transport as well as homocyteinylates Fg (making fibrin clots more rigid) Fg enhances the transcellular transport through caveolin-1 (Cav-1) signaling (via phosphorylation of Cav-1). However the role of Hcy and Fg in Hcy-Fg-Ab-collagen complex formation is unclear. The hypothesis of this proposal is that HHcy increases vascular permeability by primarily affecting the endothelial cell (EC) junction proteins and activating MMP-9 and indirectly by increasing blood content of Fg which enhances transcellular transport leading to an enhanced Hcy- Fg-Ab-collagen complex formation. We will test this hypothesis with three specific aims: 1) To determine whether the HHcy instigates cerebrovascular permeability via paracellular transport leading to enhanced cerebrovascular crossing of fibrinogen 2) To determine whether the fibrinogen deposition enhances cerebrovascular permeability mainly through caveolar transcytosis via Cav-1 signaling secondary to MMP-9 activation 3) To determine whether the HHcy increases fibrinogen-Ab-collagen complex accumulation in mouse brains secondary to increasing tissue inhibitor of metalloproteinase-1. To define specific causative effects of Hcy Fg MMP-9 Cav-1 and TIMP-1 in Fg-Ab-collagen complex formation the studies will be done on pial vessels of wild type (WT) Cystathionine b-Synthase heterozygote (CBS+/-) mice (a model of HHcy) MMP-9 gene knockout (MMP9-/-) CBS and MMP-9 double knockout (CBS+/-/MMP9-/-) Cav-1 gene knockout (Cav1-/-) Fg g-chain-deficient (Fg-/-) CBS+/-/Fg-/- HFg transgenic (HFg) HFg/MMP9-/- CBS+/-/Cav1-/-/MMP9-/- CBS+/- /HFg CBS+/-/HFg/MMP9-/- TIMP-1 gene knockout (TIMP1-/-) CBS+/-/TIMP1-/- double knockout Fg-/-/MMP1-/- and CBS+/-/Fg-/-/TIMP1-/- mice using a newly developed dual-tracer probing method that allows separation of paracellular from transcellular transport. Formation of Fg-Ab-collagen complex in brain cortex will be assessed with immunohistochemical analysis. The results of the proposed research should uncover the molecular mechanisms regulating Hcy-Fg-Ab-collagen complex formation and lead to effective strategies for the treatment of cerebrovascular complications during diseases such as AD.

project_terms:
Affect;Aging;Alzheimer's Disease;Amyloid;Binding (Molecular Function);Blood;Brain;CAV1 gene;Caveolae;Coagulation Process;Collagen;Complex;Cryoultramicrotomy;Cystathionine;Dementia;Deposition;Development;Disease;Endothelial Cells;Extravasation;Fibrin;Fibrinogen;Gelatinase B;Goals;Heterozygote;Homocysteine;Homocystine;Hyperhomocysteinemia;Immunohistochemistry;Intercellular Junctions;Interstitial Collagenase;Knock-out;Knowledge;Lead;MMP9 gene;Matrix Metalloproteinases;Measures;Methods;Mission;Modeling;Molecular;Mus;Neurodegenerative Disorders;Pathway interactions;Peptides;Permeability;Phosphorylation;Pilot Projects;Presenile Alzheimer Dementia;Proteins;Research;Role;Sampling;Secondary to;Senile Plaques;Signal Transduction;TIMP1 gene;Testing;Therapeutic;Tissue Inhibitor of Metalloproteinase-1;Tracer;Transgenic Organisms;United States National Institutes of Health;Vascular Endothelial Cell;Vascular Permeabilities;caveolin 1;cerebrovascular;design;knockout gene;novel;occludin;public health medicine (field);public health relevance;transcytosis;treatment strategy;vascular endothelial cadherin-2;venule

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


application_id: 8598474
project_number: 5R01EY012354-14
project_title: Isolation of Congenital Stationary Night Blindness Genes
administering_ic: NEI
award_notice_date: 2013-12-18
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: EY
serial_number: 012354
program_official: GREENWELL, THOMAS
project_start_date: 1999-02-01
project_end_date: 2016-12-31
study_section: Neurotransporters, Receptors, and Calcium Signaling Study Section[NTRC]
contact_pi_person_id: 1885008
contact_pi: GREGG, RONALD G
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Alleles;Binding (Molecular Function);Brain;Candidate Disease Gene;Cations;Cells;Coin;Complex;Data;Defect;Disease;Dissection;Elements;Feedback;Functional disorder;Future;G-Protein-Coupled Receptors;GRM6 gene;Genes;Glutamate Receptor;Glutamates;Goals;Grant;Health;Human;Knock-out;Knockout Mice;Knowledge;L-Type Calcium Channels;Lateral;Lead;Left;Light;Literature;Mediating;Metabotropic Glutamate Receptors;Mus;Mutant Strains Mice;Mutate;Mutation;Nature;Neurons;Neurotransmitters;Night Blindness;Pathway interactions;Photoreceptors;Point Mutation;Positioning Attribute;Property;Protein Isoforms;Proteins;Publishing;Retinal;Retinal Cone;Retinal Ganglion Cells;Rods (Retina);Role;Signal Transduction;Skeletal muscle structure;Staging;Synapses;Synaptic Transmission;Therapeutic;Transmembrane Domain;Vision;Visual system structure;ganglion cell;horizontal cell;human disease;luminance;member;mutant;neurotransmitter release;novel;public health relevance;research study;response;trafficking;transmission process

public_health_relevance:
Vision requires a light signal to be converted to an electrical signal which is then transmitted to the brain via a neuronal network. The group of diseases being studied is referred to as complete congenital stationary night blindness. They have defects in signal transmission between photoreceptors and the second order neurons in the pathway. The studies in this proposal will characterize the nature of the defects and determine new proteins critical to function. Such knowledge is essential to future efforts to restore normal vision.


application_id: 8598380
project_number: 1R21AI106260-01A1
project_title: Borrelia burdorferi Ebfc regulon
administering_ic: NIAID
award_notice_date: 2013-06-07
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: AI
serial_number: 106260
suffix: A1
program_official: BREEN, JOSEPH J
project_start_date: 2013-06-15
project_end_date: 2015-05-31
study_section: Special Emphasis Panel[ZRG1 IDM-A (80)]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Successful infection of a host requires that the invading pathogen control production of its virulence determinants. The infectious agent must sense its environment then respond by increasing production of appropriate factors and repressing production of unnecessary ones. These features are especially critical for vector-borne pathogens which must not only efficiently infect two extremely different host types but also be transmitted back and forth between hosts. Deciphering the regulatory pathways used by pathogens to control production of infection-associated proteins will provide significant insight into the infectious nature of those organisms. Moreover regulatory pathways are attractive candidates for development of novel preventative and curative therapies. We discovered that the Lyme disease spirochete Borrelia burgdorferi utilizes a site-specific DNA-binding protein named EbfC to regulate expression of over 50 different genes (>5% of its genome). The EbfC regulon includes genes known to be differentially expressed during the bacteria's infectious cycle and to be associated with mammalian infection. We hypothesize that EbfC is critical for global regulation of bacterial gene expression and that dysregulation of the EbfC regulon will prevent efficient mammalian infection. To address that hypothesis we will critically examine the effects of EbfC on all aspects of the borrelial mammal-tick infectious cycle    
       The vast majority of other bacteria species including many pathogens encode homologs of EbfC. Almost nothing is known about those other bacteria's homologs so our studies will have impacts upon almost the entire domain Eubacteria. Thus our continued studies will focus efforts toward production of improved preventative and curative therapies for not only Lyme disease but also many other significant human infectious diseases.

project_terms:
Address;Animal Model;Animals;Back;Bacteria;Bacterial Gene Expression Regulation;Biochemical;Biology;Borrelia;Borrelia burgdorferi;Communicable Diseases;DNA-Binding Proteins;Data;Development;Disease;Environment;Eubacterium;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genome;Homologous Gene;Human;Infection;Infectious Agent;Invaded;Investigation;Lyme Disease;Mammals;Molecular Biology;Molecular Profiling;Names;Nature;Order Spirochaetales;Organism;Pathogenesis;Plasmids;Play;Preparation;Process;Production;Proteins;Publications;RNA Sequences;Recombinants;Regulation;Regulatory Pathway;Regulon;Role;Site;Staging;Techniques;Testing;Ticks;Virulence;Work;genetic regulatory protein;graduate student;human disease;improved;insight;mutant;novel;pathogen;pathogenic bacteria;prevent;protein expression;public health relevance;research study;transcriptome sequencing;vector

public_health_relevance:
Pathogens must regulate expression of their genes to produce factors necessary for human infection while repressing synthesis of unnecessary factors so we hypothesize that disruption of essential regulatory networks will impair the ability
of pathogenic bacteria to infect and cause disease. We discovered a new type of regulatory protein EbfC which exerts significant effects on gene expression in the Lyme disease agent Borrelia burgdorferi. In addition almost every other bacterial pathogen encodes a homolog of EbfC so our studies are important for understanding a great number of human diseases.


application_id: 8597993
project_number: 5R21AA020848-02
project_title: Probiotics and HIF signaling in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2013-11-11
opportunity_number: PA-10-069
application_type: 5
activity_code: R21
ic: AA
serial_number: 020848
program_official: RADAEVA, SVETLANA
project_start_date: 2012-12-10
project_end_date: 2015-11-30
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The pathogenesis of alcoholic liver disease (ALD) is multi-factorial. Animal and human studies suggest that gut-derived endotoxin is a critical factor contributing to ALD. Endotoxins are derived from the cell wall of Gram-negative bacteria and normally penetrate the gut epithelium in only trace amounts due to tightly regulated intestinal barrier function. However endotoxin leakiness is increased under pathological conditions such as alcohol abuse. The barrier function of the intestinal epithelium is provided by paracellular apical junction complexes including tight junctions and adherens junctions located at the apical end of epithelial cells and by mucus layers. Protection of the mucus layer involves mucins and a number of regulatory peptides such as intestinal trefoil factors (ITFs) which play critical rols in formation and stabilization of the barrier enhancement of rapid intestinal repair ('restitution) modulation of mucosal differentiation processes and modulation of the mucosal immune response. Formation and restitution of the barrier is also dependent on uninterrupted mucosal blood flow and ongoing glycolysis. Intestinal epithelial cells are positioned between an anaerobic lumen and a highly metabolic lamina propria forming a steep physiologic oxygen gradient. Physiological and pathological hypoxia induces hypoxia-inducible factor (HIF) -1 and -2 which represent a major adaptation response by upregulating a variety of gene products such as intestinal ITF mucins and glycolytic enzymes. Our preliminary studies showed that chronic alcohol feeding decreased intestinal HIF-2 ITF and tight junction expression leading to increased endotoxemia and ultimately liver injury. Supplementation of a probiotic strain lactobacillus rhamnosus GG (LGG) attenuates those deleterious effects and ALD. However the mechanisms are unknown. Our central hypothesis is that alcohol feeding causes a change favoring oxidative stress inflammation and mitochondrial damage which reduces HIF responsive signaling and the targeted proteins leading to disruption of gut barrier function increased endotoxemia and subsequent ALD and that probiotic supplementation will attenuate alcohol-induced liver injury by potentiating HIF regulated responses. To test this hypothesis we will carry our following specific aims: Specific Aim 1. Determine the effects of ethanol and probiotics on intestinal HIF signaling and mechanisms in ALD. Specific Aim 2. Determine whether HIF signaling is required for the protective effect(s) of probiotic supplementation against
alcohol-induced liver injury. We will use intestine-specific HIF-1 and HIF-2 knockout mice to evaluate and compare the role of HIF-1 and HIF-2 in ALD. We will then use prolyl-4 hydroxylase-1 PH.D.1 knockout mice for a gain-of-function strategy to determine whether an increase HIF attenuates alcohol-induced mucus layer dysfunction in ALD. This study will have a major impact on the development of new therapeutic targets for the prevention and treatment of ALD.

project_terms:
Adherens Junction;Affect;Alcohol abuse;Alcohol consumption;Alcoholic Liver Diseases;Alcohols;Animals;Apical;Attenuated;Blood flow;Caco-2 Cells;Cell Wall;Chronic;Cirrhosis;Complex;Development;Endotoxemia;Endotoxins;Enzymes;Epithelial Cells;Fatty Liver;Figs - dietary;Functional disorder;Glycolysis;Goals;Gram-Negative Bacteria;Human;Hypoxia;Hypoxia Inducible Factor;Inflammation;Intestines;Knockout Mice;Lactobacillus casei rhamnosus;Lamina Propria;Liver diseases;Metabolic;Mitochondria;Mucins;Mucosal Immune Responses;Mucous body substance;Mus;Oxidative Stress;Oxygen;Pathogenesis;Pathway interactions;Peptides;Physiological;Play;Positioning Attribute;Prevention;Probiotics;Process;Procollagen-Proline Dioxygenase;Proteins;Proto-Oncogene Proteins c-akt;Role;Signal Transduction;Supplementation;Testing;Tight Junctions;alcohol effect;alcohol exposure;bHLH-PAS factor HLF;chronic liver disease;feeding;gain of function;gastrointestinal epithelium;hypoxia inducible factor 1;intestinal epithelium;liver injury;loss of function;new therapeutic target;prevent;protective effect;public health relevance;repaired;response;trefoil factor

public_health_relevance:
Excessive alcohol drinking is a leading cause of chronic liver disease worldwide which results in a spectrum of liver disorders that range from fatty liver to cirrhosis. The goals of this project are to investigate the effects of probiotic supplementation onalcohol-induced liver injury and the mechanisms related to hypoxia-inducible factor. This study will have a major impact on the development of new therapeutic targets for the prevention and treatment of ALD.


application_id: 8597789
project_number: 1R13AI108234-01
project_title: Autumn Immunology Conference
administering_ic: NIAID
award_notice_date: 2013-06-07
opportunity_number: PA-12-212
application_type: 1
activity_code: R13
ic: AI
serial_number: 108234
program_official: COULTER, NANCY A
project_start_date: 2013-07-01
project_end_date: 2015-06-30
study_section: Special Emphasis Panel[ZAI1 ESB-M (M1)]
contact_pi_person_id: 1863468
contact_pi: WOODWARD, JEROLD G
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal requests funds to support the annual Autumn Immunology Conference (AIC). The AIC was established in 1972 to promote Immunology research in the upper Midwest region of the United States. The conference provides a forum for the exchange of scientific data and ideas fosters collaboration between scientists at different institutions and provides career development and education opportunities to a diverse group of individuals with an interest in Immunology. The scientific focus of the meeting is intentionally broad; it includes basic Immunology and related biomedical fields such as cancer biology pathogenesis vaccine development inflammation and autoimmunity. Special emphasis is given to providing pre- and postdoctoral trainees with an opportunity to share their data participate in scientific and career discussions and to meet and exchange ideas with established investigators. The organizers also seek to attract involve and promote the careers of women and racial/ethnic minorities that are underrepresented in science. These objectives are met by inviting a group of outstanding Immunology researchers (12-13 each year) from around the world to speak at the meeting. All presenters present both an oral and poster presentation in sessions that are designed to provide the greatest opportunity for feedback to the trainees. Finally scholarship programs career development workshops and mentoring luncheons promote the inclusion of minority scientists and seek to recruit undergraduates into the discipline of Immunology.

project_terms:
Address;Allergic Disease;Applied Research;Autoimmunity;Award;Basic Science;Cancer Biology;Collaborations;Communicable Diseases;Data;Discipline;Educational aspects;Educational workshop;Equilibrium;Feedback;Fostering;Funding;Gender;Goals;Grant;Immune System Diseases;Immunology;Individual;Inflammation;Institution;Mentors;Minority;Minority Groups;Mission;National Institute of Allergy and Infectious Disease;Oral;Participant;Pathogenesis;Preparation;Recruitment Activity;Request for Applications;Request for Proposals;Research;Research Personnel;Scholarship;Science;Scientist;Staging;Travel;Underrepresented Minority;United States;United States National Institutes of Health;Vendor;Woman;career;career development;design;interest;meetings;posters;pre-doctoral;prevent;programs;public health medicine (field);public health relevance;symposium;vaccine development

public_health_relevance:
High quality scientific conferences are vital to the public health mission of the NIH. This application requests funding for an annual scientific conference called the Autumn Immunology Conference. The purpose of this meeting is to exchange and disseminate information and to explore contemporary problems in the field of Immunology. Thus it is consistent with the fiscal and programmatic priorities of the National Institutes of Allergy and Infectious Diseases (NIAID) which is to conduct and support basic and applied research to better understand treat and ultimately prevent infectious immunologic and allergic diseases.


application_id: 8597150
project_number: 1R13HD077998-01
project_title: Anatomical and functional modularity of the cerebral cortex
administering_ic: NICHD
award_notice_date: 2013-07-23
opportunity_number: PA-12-212
application_type: 1
activity_code: R13
ic: HD
serial_number: 077998
program_official: PARISI, MELISSA
project_start_date: 2013-07-23
project_end_date: 2014-07-22
study_section: Biobehavioral and Behavioral Sciences Study Section[CHHD-H]
contact_pi_person_id: 1905047
contact_pi: CASANOVA, MANUEL F
other_pis: Not Applicable
congressional_district: 03
department: PSYCHIATRY
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 R13 mechanism would be used to support a scientific conference "Anatomical and functional modularity of the cerebral cortex" focusing on recent studies describing the organization of the cerebral cortex from a modular perspective and how the same provides for translational perspectives into clinical practice. The conference would provide a cohesive forum on the latest anatomical and physiological approaches to understanding the basic components of cortical modularity and their involvement in different pathological states e.g. autism dyslexia and ADHD. It will disseminate for example recent work regarding the use of minicolumns as neural prosthetics agents for cases of stroke/neurodegenerative disorders and how timing in neural firing between different layers of a minicolumn may provide for higher cognitive functions. The symposium seeks to encourage communication and in-depth discussion of a broad range of subjects under the unifying theme of cortical modularity. The topics covered at the conference would span a wide spectrum of resolution that is from minicolumns and their parcellation into different components (e.g. apica dendritic bundles) all the way to macrocolumns and networks of the same. The sessions of the symposium span four major areas: 1) Anatomy and Development (encompassing both embryology and anatomical compartmentalization of neocortical modules) 2) Anthropology (addressing how encephalization has proceeded through the addition of supernumerary minicolumns) 3) Computer modeling and electrophysiology (emphasizing the minicolumn's prowess for parallel processing and how empirical models of neural connectivity help explain the emergent properties of modules) and 4) Pathology (a discussion of several conditions where abnormalities of minicolumns have been implicated).

project_terms:
Address;Anatomy;Anthropology;Area;Attention;Attention deficit hyperactivity disorder;Autistic Disorder;Cerebral cortex;Communication;Computer Simulation;Development;Disease;Dyslexia;Electrodes;Electrophysiology (science);Embryology;Epigenetic Process;Focus Groups;Fostering;Future;Genetic;Goals;Health;Human;Knowledge;Logistics;Maps;Mediating;Molecular Neurobiology;Neuroanatomy;Neurobiology;Neurodegenerative Disorders;Neurons;Neurosciences;Participant;Pathology;Phenotype;Physiological;Physiology;Property;Recruitment Activity;Research Personnel;Resolution;Role;Scientific Advances and Accomplishments;Seminal;Students;System;Time;Training;Training Programs;Videotape;Work;clinical practice;cognitive function;computational neuroscience;interest;lectures;meetings;neocortical;neural model;neural prosthesis;neurophysiology;parallel processing;programs;public health relevance;relating to nervous system;stem;stroke;symposium;synergism

public_health_relevance:
Recent work has advanced our understanding on the modular organization of the cerebral cortex and its role in several human conditions such as autism and dyslexia. The newly gained information has been derived from the standpoint of different scientific perspectives stemming from the disparate fields of anatomy anthropology electrophysiology and pathology. We hope that by bringing together representatives from these fields we will be better able to integrate our knowledge and create synergism for future research endeavors.


application_id: 8596185
project_number: 1R01HL118474-01A1
project_title: Hyperamylinemia in Diabetic Heart Disease: Mechanisms Responses and Prevention
administering_ic: NHLBI
award_notice_date: 2013-08-22
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: HL
serial_number: 118474
suffix: A1
program_official: BUXTON, DENIS B
project_start_date: 2013-08-23
project_end_date: 2017-07-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 9696701
contact_pi: DESPA, FLORIN
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Adjuvant;Affect;Age;Apoptosis;Area;Beta Cell;Binding (Molecular Function);Blood;Calcineurin;Cardiac;Cardiac Myocytes;Cardiotoxicity;Cell membrane;Cells;Data;Deposition;Development;Diabetes Mellitus;Diagnosis;Epidemic;Excretory function;Figs - dietary;Functional disorder;Glucose;Heart;Heart Diseases;Heart Hypertrophy;Heart Injuries;Heart failure;Histone Deacetylase;Hormones;Human;Hyperinsulinism;Hypertrophy;Injury;Insulin;Insulin Resistance;Ion Channel;Ions;Kidney;Left;Lipid Peroxidation;Longitudinal Studies;Mediating;Membrane;Membrane Potentials;Metabolic syndrome;Mitochondria;Modeling;Muscle Cells;Myocardial;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oligonucleotides;Onset of illness;Oxidative Stress;Pancreas;Pathogenesis;Pathway interactions;Patients;Pilot Projects;Plasmin;Poloxamer;Poloxamers;Prediabetes syndrome;Prevention;Process;Production;Property;Protein Isoforms;Rattus;Research;Research Project Grants;Research Proposals;Risk;Role;Sarcolemma;Signal Pathway;Solubility;Structure;Structure of beta Cell of islet;System;Testing;Therapeutic;Tissues;Transgenic Organisms;Vascular System;Ventricular;base;calmodulin-dependent protein kinase II;catalyst;diabetic;high risk;improved;in vivo;inhibitor/antagonist;innovation;islet amyloid polypeptide;overexpression;public health relevance;response;therapeutic target;tool

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


application_id: 8595368
project_number: 1R44AG044157-01A1
project_title: Circulating Blood-Based Diagnostic for Mild Cognitive Impaired Victims
administering_ic: NIA
award_notice_date: 2013-08-27
opportunity_number: PA-12-088
application_type: 1
activity_code: R44
ic: AG
serial_number: 044157
suffix: A1
program_official: REFOLO, LORENZO
project_start_date: 2013-09-01
project_end_date: 2014-02-28
study_section: Special Emphasis Panel[ZRG1 ETTN-M (11)]
contact_pi_person_id: 1860379
contact_pi: WANG, EUGENIA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 805479370
primary_uei: KPMEKJJTDUS5
duns_number: 805479370
uei: KPMEKJJTDUS5
fips: US
organization_id: 10020610
organization_name: ADVANCED GENOMIC TECHNOLOGY, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402416052
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This project aims to generate blood tests for: 1. mild cognitive impairment (MCI) and 2. conversion risk from MCI to full-blown Alzheimer's disease (AD). We have reported that systemic footprints increases in key micro- RNA (miR) levels are identifiable in AD blood samples; here we suggest that this is also true for MCI the pre- AD phase. Our recent results suggest two stages of cognitive decline continuum: Stage 1 for key microRNAs increased from circulating blood of normal elderly controls (NEC) to that of MCI patients but not further to AD; and Stage 2 for specific circulating blood microRNA increases from MCI to AD. This led us to suggest our mo- del: Stage 1 circulating microRNAs as MCI-specific biomarkers and Stage 2 circulating microRNAs as biomark- ers for conversion of MCI to AD. Prototypes of these biomarkers are: Stage 1 miR-181b increases from NEC to MCI levels but not further in AD plasma samples; Stage 2 increased miR-34a & miR-34c levels observed only from MCI to AD but not from NEC to MCI plasma. These results suggest that the MCI cognitive decline may start with increased Stage 1 microRNAs' expression then Stage 2 increases add insult to injury; the for- mer being MCI-specific biomarkers and the latter specific
for AD and/or converter patients. Our goal is then to establish two sets of stage-specific biomarkers based on: a. highly reproducible data for identified blood micro- RNAs; b. training datasets for next-stage development for FDA approval; and c. validated specificity for de- mentia due to AD in contrast to other types of dementia. Toward this end Phase I will study 30 archived sam- ples each of MCI NEC and AD blood to attain: Aim 1 establishing the reproducibility of our protocol for opti- mal blood microRNA assays and identifying lead microRNAs' origins by determining concordance and/or dis- cordance among the above three microRNAs' increases in three circulating blood compartments: peripheral blood mononuclear cells (PBMC) plasma/serum and its derivative exosomes; and Aim 2 identifying other members of four lead array-profiled and PCR-validated microRNA families: miR-34 -181 200 & Let-7 to expand our pool of candidate Stage 1 and Stage 2 biomarkers. In Phase II Aim 1 expands to a larger cohort of 200 MCI patients' samples to establish a Stage 1 biomarker training dataset tracing 21 microRNAs of these 4 families; Aim 2 establishes a repertoire of Stage 2 biomarkers in archived specimens from 22 MCI subjects in our study 12 of whom have converted to AD within the past decade by comparing freshly collected with archived blood samples from converters versus non-converters by qPCR assays of the 21 listed miRNAs and array profiling to identify additional novel ones; and Aim 3 establishes the identified biomarkers as specific for AD in contrast with non-AD dementias i.e. Frontotemporal (FTD) Lewy body (LBD) and Parkinson's disease (PD) with dementia (PDD). Success of this project will provide blood miRNA-based diagnostics for MCI and predict conversion from MCI to AD unprecedented tests to monitor disease onset progression and drug efficacy for novel therapies to retard the decline of MCI to bona fide AD.

project_terms:
Alzheimer's Disease;Archives;Biological Assay;Biological Markers;Bipolar Disorder;Blood;Blood Tests;Blood specimen;Boxing;Brain;Cancer Diagnostics;Cardiovascular Diseases;Cells;Central Nervous System Diseases;Cerebrospinal Fluid;Clinical;Cognitive;Companions;Comparative Study;Data;Data Quality;Data Set;Dementia;Development;Diagnosis;Diagnostic;Disease;Disease Progression;Elderly;Family;Frontotemporal Dementia;Funding;Genomics;Goals;Grant;Healthcare;Healthcare Systems;Huntington Disease;Image;Impaired cognition;Individual;Injury;Lead;Lewy Bodies;Lewy Body Dementia;Magnetic Resonance Imaging;Measurable;Measurement;Messenger RNA;Metric;MicroRNAs;Mind;Mission;Monitor;Nature;Nerve Degeneration;Onset of illness;Parkinson Disease;Parkinson's Dementia;Pathogenesis;Patients;Peripheral Blood Mononuclear Cell;Phase;Plasma;Population;Pregnancy Trimesters;Proteins;Protocols documentation;Reporting;Reproducibility;Risk;Risk Assessment;Sampling;Small Business Innovation Research Grant;Specificity;Specimen;Staging;Technology;Testing;Training;Validation;Work;aging population;base;cohort;commercialization;cost effective;drug efficacy;indexing;member;mental state;mild cognitive impairment;neuropsychological;novel;outcome forecast;prototype;public health relevance;success;tool

public_health_relevance:
Like Alzheimer's disease (AD) health care mild cognitive impairment (MCI) due to AD suffers from the lack of a noninvasive blood test which is a major roadblock to MCI diagnosis; in its absence the disease is largely de- fined by neuropsychological assessment and costly MRI imaging and secondarily by identified cerebrospinal fluid biomarkers a less ideal approach due to its invasive nature. This project aims to generate cost-effective noninvasive blood tests for serial diagnosis and staging of MCI and its conversion to full-blown AD based on unique biomarkers microRNA expressions whose levels in circulating blood are 'footprints' of disease patho- genesis reflecting cognitive declin in brain. Quantitative metrics of circulating key microRNAs may serve as numerical indices for diagnosis of MCI and prognosis of conversion to AD as well as objective drug efficacy measurements for novel therapies to retard the further decline of these victims from developing full-blown Alzheimer's disease and thus halting the tidal wave of a fast-increasing aging population suffering this devastating mind-robbing peril.


application_id: 8592983
project_number: 1R43DE023523-01A1
project_title: Synthesis and Characterization of Polymeric Antioxidant microparticles for the pr
administering_ic: NIDCR
award_notice_date: 2013-09-21
opportunity_number: PA-12-088
application_type: 1
activity_code: R43
ic: DE
serial_number: 023523
suffix: A1
program_official: WANG, CHIAYENG
project_start_date: 2013-09-24
project_end_date: 2014-08-31
study_section: Special Emphasis Panel[ZRG1 MOSS-K (11)]
contact_pi_person_id: 10569650
contact_pi: SHAH, NIHAR MANILAL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078529087
primary_uei: M9JMGN342NR5
duns_number: 078529087
uei: M9JMGN342NR5
fips: US
organization_id: 10032361
organization_name: BLUEGRASS ADVANCED MATERIALS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Every year in the United States approximately 132000 patients undergoing anti-cancer therapy develop oral mucositis (OM) a painful debilitating oral wound condition which is estimated to increase the patient's cost of care by $17000-43000. Most treatments have focused on either palliative care or accelerating the wound healing process through the application of growth factors (GF). Although growth factors such as Palifermin have shown promise in healing OM they carrying the potential for neoplastic growths and do not target the root cause of OM. The most commonly reported molecular mechanism for occurrence of OM is the excessive generation of reactive oxygen species (ROS) due to the anti-cancer chemo- radiation regimes. A potent antioxidant such as curcumin may represent an exciting therapeutic agent in OM prevention as a direct inhibitor of the earliest phase of OM development i.e. oxidative stress. In fact it can be applied before the anti-cancer regimes to prevent the occurrence of OM altogether. Additionally curcumin: 1) has demonstrated ability to inhibit the growth of cancer cells and not trigger neoplastic growths 2) has demonstrated wound healing capacity 3) has proven anti-inflammatory and antimicrobial properties 4) is well tolerated orally and 5) is very inexpensive. However delivery of curcumin physiologically represents a challenge due to its short half-life in physiological environments and
poor aqueous solubility.  The central hypothesis of this project is that curcumin-based polymers composed of natural antioxidants (C-PoNA) can be synthesized into tissue adhesive microparticles and applied prophylactically to oral mucosal surfaces to decrease local cellular oxidative stress and thereby decrease the likelihood of developing chemo/radio-therapy induced OM. As part of fulfilling this hypothesis the research plan has been separated into two specific aims Aim 1: C-PoNA microparticles provide controlled release of curcumin and Aim 2: C-PoNA microparticles adhere to oral mucosal tissues. The first aim focuses on development and characterization of antioxidant polymer formulations while the second aim focuses on demonstrating the ability to deliver select formulations to oral mucosal surfaces via an in vitro model.  After the execution of this proposal C-PoNA microparticle formulation(s) will be identified that can overcome the primary limitations of current curcumin delivery strategies. Microparticles that bond strongly to mucin while permitting long term local release will be obtained. In short completion of this proposal will inform design of preclinical animal trials as e progress into phase II.

project_terms:
Acrylates;Address;Adherence (attribute);Adhesions;Adverse effects;Amines;Animals;Anti-Bacterial Agents;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Biological;Cancer Cell Growth;Caring;Cells;Chemistry;Compliance behavior;Complication;Curcumin;Development;Drug Formulations;Economics;Environment;Esters;Gel;Generations;Growth Factor;Half-Life;Head and Neck Cancer;Healed;Health Care Costs;In Vitro;Injury;Interruption;Kinetics;Lead;Life;Liquid substance;Lubricants;Malignant Neoplasms;Mechanics;Molecular;Mucins;Mucous Membrane;Neoplasms;Oral;Oral Ulcer;Oral cavity;Oral mucous membrane structure;Oxidative Stress;Pain;Palliative Care;Particle Size;Patients;Pharmaceutical Preparations;Phase;Physiological;Plant Roots;Polymers;Powder dose form;Prevention;Process;Property;Protons;Radiation;Radio;Reaction;Reactive Oxygen Species;Reporting;Research;Severities;Solubility;Speed (motion);Surface;Suspension substance;Suspensions;Technology;Therapeutic Agents;Thick;Time;Tissue Adhesives;Tissue Model;Tissues;Treatment Cost;Uncertainty;United States;Vertebral column;Wound Healing;antimicrobial;aqueous;base;biodegradable polymer;cancer therapy;chemical cleavage;controlled release;cost;crosslink;cryogenics;cytotoxicity;design;healing;improved;in vitro Model;inhibitor/antagonist;keratinocyte growth factor;nano;novel therapeutics;oral mucositis;oxidation;pre-clinical;premature;prevent;public health relevance;small molecule;treatment strategy;wound

public_health_relevance:
This research will develop a new therapeutic strategy to prevent the occurrence of oral mucositis (OM). OM is a common side effect to the chemo-radiation treatment against head and neck cancers. These painful and debilitating mouth ulcers result in an increased treatment cost of $17000 to $43000 per patient. The proposed research plan will yield powdered formulations of biodegradable polymers of natural antioxidants that can be applied to the oral cavity via simple mouth rinses. The long term and local release of the potent antioxidant curcumin is expected to prevent the initiation of OM thus drastically improving patient comfort and compliance and preventing interruptions in the critically required anti-cancer therapy.


application_id: 8589832
project_number: 1R01DE023206-01A1
project_title: Structure-based design and synthesis of peptidominetics targeting P. gingivalis
administering_ic: NIDCR
award_notice_date: 2013-07-23
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: DE
serial_number: 023206
suffix: A1
program_official: LUNSFORD, DWAYNE
project_start_date: 2013-07-23
project_end_date: 2018-05-31
study_section: Special Emphasis Panel[ZRG1 MOSS-F (02)]
contact_pi_person_id: 1859425
contact_pi: DEMUTH, DONALD R
other_pis: LUZZIO, FREDERICK ANTHONY
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
project_abstract:
DESCRIPTION (provided by applicant):  Periodontitis is a widespread and costly disease that is primarily manifest in the oral cavity but is also associated with systemic diseases such as atherosclerosis and rheumatoid arthritis. Although several organisms have been identified as periodontal pathogens a recent study suggests that Porphyromonas gingivalis may be a "keystone" pathogen that disrupts host-microbe homeostasis by inducing populational changes in the biofilm that contribute to inflammation. Thus preventing P. gingivalis colonization of the oral cavity may not only limit periodontitis and have a positive impact on severe systemic diseases improving the health status of a significant portion of the adult population. The ideal niche for P. gingivalis is the subgingival pocket but prior to colonizing this niche P. gingivali associates with streptococci in the supragingival biofilm. This interaction is an ideal target for therapeutic intervention since it represents one of the first events that promotes colonization of the oral cavity by P. gingivalis. The basic science discoveries that form the foundation for this proposal arise from our previous work showing that the association of P. gingivalis with streptococci is driven by a protein-protein interaction. Our mechanistic characterization of this interaction led to the development of a peptide (designated BAR) that potently inhibits P. gingivalis colonization of the oral cavity. However peptides are not ideal therapeutic agents due to their high cost of production and susceptibility to degradation. This application addresses these shortcomings using a structure-based approach to design and synthesize non-peptide mimetics of BAR. The first Aim will apply our knowledge of the structure and mechanism of action of BAR to design and chemically synthesize inexpensive peptidomimetic inhibitors of P. gingivalis colonization using an innovative synthetic approach called click chemistry. The second Aim of this study will assess the biologic activity of the compounds to identify lead compounds that potently inhibit P. gingivalis adherence to streptococci and the formation of P. gingivalis biofilms. The most active lead compounds will subsequently be tested in Aim 3 for inhibition of P. gingivalis virulence using an animal model of periodontitis. Thus our prior mechanistic studies uniquely position us to design and develop new potential treatments for periodontitis and its systemic sequelae by specifically targeting P. gingivalis colonization of the
oral cavity. The inherent stability and low toxicity of click chemistry products may also facilitat the rapid formulation of compounds in a mouth rinse varnish or toothpaste that will be suitable for clinical testing.

project_terms:
3-Dimensional;A Mouse;Accounting;Address;Adherence (attribute);Adult;Alveolar Bone Loss;Animal Model;Antigens;Atherosclerosis;Back;Basic Science;Biochemical;Biological Assay;Boxing;C-terminal;Chemistry;Coupled;Development;Disease;Drug Formulations;Enzyme-Linked Immunosorbent Assay;Event;Expenditure;Foundations;Health;Health Status;Heart Diseases;Homeostasis;I-antigen;Infection;Inflammation;Knowledge;Lead;Measures;Mediating;Microbe;Microbial Biofilms;Minor;Modeling;Modification;Molecular Models;Mouth Diseases;Mus;Nuclear Receptors;Oral cavity;Organism;Outcome;Peptide Hydrolases;Peptides;Periodontitis;Population;Porphyromonas gingivalis;Positioning Attribute;Predisposition;Prevention;Production;Protein Binding Domain;Proteins;Publishing;Rheumatoid Arthritis;Streptococcus;Streptococcus gordonii;Structural Models;Structural Protein;Structure;Systemic disease;Testing;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Tissues;Toothpaste;Toxic effect;United States;Variant;Varnish;Virulence;Work;base;cost;cycloaddition;design;feeding;flexibility;improved;inhibitor/antagonist;innovation;microbial;microbial host;mimetics;molecular modeling;mouse model;multidisciplinary;oral biofilm;oral streptococci;pathogen;peptidomimetics;polypeptide;prevent;protein protein interaction;public health relevance;research clinical testing;scaffold;small molecule;subgingival biofilm;synthetic peptide

public_health_relevance:
Periodontitis is a common oral disease that is present in up to 40% of the adult population in the United States. Annual expenditures for treatment and prevention of periodontitis exceed $15 billion. Although periodontitis is primarily manifest in the
oral cavity it is also associated with systemic illnesses such as heart disease and rheumatoid arthritis. An important recent study suggests that Porphyromonas gingivalis may be a "keystone" pathogen that induces populational changes in the oral biofilm that contribute to inflammation. Thus limiting P. gingivalis colonization of the oral cavity may have positive impact
periodontal health and on other systemic illnesses associates with periodontitis. This multidisciplinary study will use molecular modeling and protein structural information to design and synthesize compounds that specifically target the periodontal pathogen P. gingivalis and block its colonization of the oral cavity. These compounds represent new potential therapies that may control or prevent periodontitis and the systemic illnesses associated with this disease.


