# projects

application_id: 8525286
project_number: 5R01AG029623-08
project_title: Role of TWEAK in skeletal muscle metabolism
administering_ic: NIA
award_notice_date: 2013-06-25
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AG
serial_number: 029623
program_official: WILLIAMS, JOHN
project_start_date: 2007-02-01
project_end_date: 2017-06-30
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 1917770
contact_pi: KUMAR, ASHOK
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): During last funding period we identified and established that TWEAK cytokine is a major regulator of skeletal muscle mass during aging and disuse conditions. We have now obtained strong evidence suggesting that the TWEAK causes insulin resistance in skeletal muscle. However the mechanisms by which TWEAK induces muscle atrophy or insulin resistance remain less well understood. PGC-1 cofactor plays a major role in regulation of skeletal muscle mass fiber-type composition and mitochondrial biogenesis. Our preliminary studies have shown that TWEAK suppresses the expression of PGC-1 and mitochondrial content and inhibits insulin signaling in skeletal muscle. We have also found that disuse conditions or type II diabetes involve the inducible expression of TWEAK receptor Fn14 (but not TWEAK itself) in skeletal muscle. Our initial analysis has revealed that both human and mouse Fn14 promoter contains CpG rich regions and that demethylation of Fn14 promoter could be a crucial event for the induction of Fn14 expression in skeletal muscle. In the next phase of this project we will investigate the mechanisms by which TWEAK causes sarcopenia disuse-related muscle atrophy and insulin resistance and how the expression of Fn14 gets up regulated in skeletal muscle in different conditions. We will address the following three specific aims: AIM I. Investigate the role of PGC-1 in TWEAK-mediated skeletal muscle atrophy in vivo. Hypothesis 1: TWEAK causes muscle atrophy and fiber-type switching through down-regulation of PGC-1 expression. AIM II. Investigate the key mechanisms by which TWEAK-Fn14 system induces insulin-resistance in adult and/or aged skeletal muscle. Hypothesis 2: TWEAK induces insulin resistance by inhibiting insulin receptor substrate (IRS1) phosphorylation and diminishing oxidative phosphorylation in skeletal muscle. AIM III: Investigate the molecular events leading to increased expression of TWEAK receptor Fn14 in skeletal muscle. Hypothesis 3: Demethylation of CpG islands in Fn14 promoter followed by binding of SP1 transcription factor triggers the expression of Fn14 in skeletal muscle in catabolicstates. Successful completion of this project will provide critical insights about sarcopenia durin aging and type II diabetes and provide novel avenues for therapeutic interventions.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Address;Adult;Age;Aging;Atrophic;Binding (Molecular Function);Binding Sites;Biogenesis;Chronic Disease;Computer Simulation;Consensus;CpG Islands;Denervation;Development;Diabetes Mellitus;Disease;Down-Regulation;Drug Targeting;Epigenetic Process;Etiology;Event;Fiber;Funding;GLUT4 gene;Genetic;Glucose;HDAC5 gene;Heart failure;Human;IRS1 gene;Immobilization;In Vitro;Injury;Insulin;Insulin Receptor;Insulin Resistance;Lead;MAP3K7 gene;Malignant Neoplasms;Mediating;Mediator of activation protein;Medicine;Methyltransferase;Mitochondria;Modeling;Molecular;Morbidity - disease rate;Mus;Muscle;Muscle Fibers;Muscle Proteins;Muscle function;Muscular Atrophy;NF-kappa B;Natural regeneration;Non-Insulin-Dependent Diabetes Mellitus;Oxidative Phosphorylation;PGC1a Regulation Pathway;PPAR gamma;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Phase;Phosphorylation;Physiological;Play;Population;Promotor (Genetics);Proteins;Regulation;Reporting;Role;Signal Transduction;Skeletal muscle structure;Specificity;Syndrome;System;TRAF6 gene;Testing;Therapeutic Intervention;Transcription Initiation Site;Transgenic Organisms;Ubiquitin;Up-Regulation (Physiology);aged;cofactor;cytokine;demethylation;glucose uptake;human HDAC4 protein;improved;in vivo;insight;insulin sensitivity;insulin signaling;multicatalytic endopeptidase complex;muscle aging;muscle form;muscle metabolism;neuromuscular activity;novel;older patient;overexpression;prevent;public health relevance;receptor;research study;sarcopenia;skeletal muscle wasting;transcription factor;wasting

public_health_relevance:
Skeletal muscle wasting is a debilitating consequence of aging and many chronic diseases such as type II diabetes common at older age. However there is still no approved therapy for treatment of this disorder/syndrome. It is essential to develop new medicines that can preserve skeletal muscle mass during aging. The proposed studies will identify the mechanisms of action of TWEAK cytokine a recently identified mediator of muscle wasting. Successful completion of this project will improve the basic understating of etiology of muscle wasting and type II diabetes and will lead to the identification of a novel drugtarget to preserve muscle mass and function in aging human population.


application_id: 8524443
project_number: 1R43NS083218-01
project_title: SYSTEM FOR AUTOMATED NONINVASIVE MONITORING OF MOUSE SLEEP AND BEHAVIOR
administering_ic: NINDS
award_notice_date: 2013-03-19
opportunity_number: PA-11-134
application_type: 1
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)]
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:
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: 8523656
project_number: 1R43GM106639-01
project_title: REDUCING LAPAROTOMY WOUND FAILURE
administering_ic: NIGMS
award_notice_date: 2013-09-25
opportunity_number: PA-12-088
application_type: 1
activity_code: R43
ic: GM
serial_number: 106639
program_official: SOMERS, SCOTT D
project_start_date: 2013-09-25
project_end_date: 2015-03-24
study_section: Special Emphasis Panel[ZRG1 SBIB-V (12)]
contact_pi_person_id: 1885914
contact_pi: CHIEN, SUFAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 968792007
primary_uei: DHTASEX58M16
duns_number: 968792007
uei: DHTASEX58M16
fips: US
organization_id: 10029830
organization_name: NOVERATECH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021959
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The specific aim of this phase I proposal is to test our newly developed intracellular ATP delivery technique for abdominal wound dehiscence. More than 200000 incisional hernia repairs are performed annually in the United States at a financial cost of nearly 2.5 billion dollars without considering the loss of productivity. Reoperation is risky with a higher recurrence rate. Despite many advances in the field of surgery and surgical technique the formation of hernias following abdominal wall incisions continues to be a perplexing and prevalent problem. Very little emphasis has been placed on prevention despite its obvious importance and the incidence has not been changed over 50 years. The formations of incisional hernias are multifactorial but the exact mechanism is still unknown. Two major contributing factors are wound separation due to intrinsic and extrinsic factors and bacterial infection. These two factors may form a vicious cycle causing a final breakdown. If measures are taken to correct some of the contributing factors hernia formation may be reduced or prevented-a stitch in time saves nine. Noveratech has developed a new technique for the delivery of Mg-ATP directly to the cytosol (ATP-vesicles or VitaSolTM). The technique has been tested in full-thickness excisional skin wounds in mice and rabbits. VitaSolTM healed wounds faster than all control dressings which included Mg-ATP alone lipid vesicles alone a neutral cream and the only FDA-approved prescription growth factor for wound care--Regranex. It generated granulation tissues within 24 hours. In incisional skin wounds VitaSolTM produced wound tissues with much higher tensile strengths breaking strengths and stress/strain ratios. The most striking finding was an extremely early stem cell and macrophage accumulation accompanied by massive collagen production-a phenomenon never seen or reported in the past with any other treatment modalities. Although mechanistic study is not the aim of the current proposal this technique operates via at least three pathways: 1) massive stem/progenitor cell trafficking and leukocyte chemotaxis caused by purinergic receptor activation; 2) improved cell survival and function by intracellularly delivered energy which is especially important for neutrophils lymphocytes and macrophages to exert their bacteriocidal function; and 3) enhanced collagen production by activated macrophages resulting in reduced tissue separation exudation and infection. In this phase I study we plan to expand our preliminary findings to compare VitaSolTM with its individual components in incisional wounds and to test its effects on abdominal fascial healing to prevent herniation. The project will
fill a major gap in current surgical wound management. Noveratech plans to commercialize the product after proven effective in animal and human tests. The success of this product will benefit millions of patients who undergo abdominal surgery each year. The usage of this technique may be expanded to other surgical repair procedures and acute wounds. The potential impact is high.

project_terms:
Abdomen;Acute;Animals;Bacterial Infections;Becaplermin;Caring;Cell Survival;Cell physiology;Collagen;Cream;Cytosol;Employee Strikes;FDA approved;Failure (biologic function);Financial cost;Goals;Granulation Tissue;Growth Factor;Healed;Hernia;Hour;Human;Incidence;Individual;Infection;Laparotomy;Leukocyte Chemotaxis;Lipids;Lymphocyte;Measures;Medical;Modality;Mus;Operative Surgical Procedures;Oryctolagus cuniculus;Pathway interactions;Patients;Phase;Prevention;Procedures;Process;Production;Purinoceptor;Receptor Activation;Recurrence;Repeat Surgery;Reporting;Skin;Stem cells;Sterile coverings;Stress;Surgical incisions;Surgical wound;Techniques;Tensile Strength;Testing;Thick;Tissues;United States;Vesicle;Wound Healing;abdominal wall;commercial application;healing;improved;macrophage;neutrophil;phase 1 study;prevent;productivity loss;public health relevance;repaired;stem;success;trafficking;wound

public_health_relevance:
PUBLIC HEALTH RELEVANCE: More than 200000 incisional hernia repairs are performed annually in the United States and these repairs have very high failure rate. The formation of hernias following abdominal wall incisions continues to be a perplexing and prevalent problem. Very little emphasis has been placed on prevention despite its obvious importance and the incidence remains unchanged over 50 years. We have developed a new technique for intracellular energy delivery and have found its ability to enhance healing process. This is achieved by very early stem cell and macrophage trafficking and proliferation accompanied by massive direct collagen production by macrophages. In this phase I proposal we will expand the usage of the technique to include skin and fascial incisions to further confirm the results. The success of this project will benefit millions of patients with abdominal surgery each year and can be used in other medical conditions. The potential impact is high.


application_id: 8522756
project_number: 1R41AR064596-01
project_title: Intelligent and Automatic Image Segmentation Software for High ThroughputAnalysi
administering_ic: NIAMS
award_notice_date: 2013-07-11
opportunity_number: PAR-09-221
application_type: 1
activity_code: R41
ic: AR
serial_number: 064596
program_official: BOYCE, AMANDA T
project_start_date: 2013-07-15
project_end_date: 2015-06-30
study_section: Special Emphasis Panel[ZRG1 MOSS-Q (14)]
contact_pi_person_id: 8263548
contact_pi: ESSER, KARYN A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078357046
primary_uei: LA54LAMKQ5A6
duns_number: 078357046
uei: LA54LAMKQ5A6
fips: US
organization_id: 10032028
organization_name: CYTOINFORMATICS, LLC
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403568852
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): It is well established that aging and many chronic diseases such as cancer and heart failure are associated with significant losses in skeletal muscle mass and strength in humans. There is agreement across the muscle biology community that important morphological characteristics of muscle fibers such as fiber area the number and position of myonuclei cellular infiltration and fibrosis are critical factors that determine the health and function of the muscle. However at this time quantification of muscle characteristics from standard histological and immunohistological techniques is still a manual or at best a semi-automatic process. This process is labor intensive and can be prone to errors leading to high inter-observer variability. On the other hand when muscle characteristics are calculated by computer-aided image analysis data acquisition times decrease and objectivity improves significantly. The objective of this Phase I STTR project is to build a fully automatic intelligent and high throughput image acquisition and analysis software for quantitative muscle morphological analysis on digitized muscle cross-sections. We propose to utilize the most recent technical advances in machine learning and biomedical image analysis. This includes a newly developed deformable model and mean-shift based seed detection algorithm for better segmentation accuracy; an asymmetric online boosting based machine learning algorithm which allows the software to learn from errors and adjust its segmentation strategies adaptively; and a data parallelization schema using the graphic processing unit (GPU) to handle the computational bottleneck for extremely large scale image such as whole slide scanned specimens. We believe that this software equipped with the most advanced technical innovations will be commercially attractive for the skeletal muscle research community including basic scientists clinician scientists and the pharmaceutical industry. The specific aim are: 1) Develop implement and validate an automatic biological image analysis software package for skeletal muscle tissue; 2) Develop a novel online updated intelligent artificial intelligence unit to enable the software to learn from errors; 3) Build a novel high performance computing unit to enable fast and high throughput automatic image analysis which is capable of processing whole slide scanned muscle specimens. The analysis approach proposed will provide more consistent accurate and objective quantification of skeletal muscle morphological properties and the time for data analysis will be reduced by over a factor of 100 for standalone version and 2000 for parallel version. The long-term goal of Cytoinformatics LLC for the Phase II stage is to apply the software to analyze histology/pathology from human muscle biopsy samples and extension of the software to other biological tissues such as adipose tissue.

project_terms:
Adipose tissue;Aging;Agreement;Algorithms;Appearance;Area;Artificial Intelligence;Basic Science;Biological;Biology;Biometry;Biopsy Specimen;Cell Nucleus;Cellular Infiltration;Characteristics;Chronic Disease;Clinical Research;Communities;Computational Science;Computer Assisted;Computer software;Data;Data Analyses;Defect;Detection;Drug Industry;Eosine Yellowish;Exhibits;Fiber;Fibrosis;Freezing;Future;Goals;Health;Heart failure;Hematoxylin;High Performance Computing;Histology;Human;Human Pathology;Image;Image Analysis;Interobserver Variability;Intervention;Learning;Machine Learning;Malignant Neoplasms;Manuals;Marketing;Methods;Modeling;Morphologic artifacts;Muscle;Muscle Fibers;Muscle function;NIH Program Announcements;Performance;Phase;Pilot Projects;Positioning Attribute;Process;Property;Research;Research Personnel;Resources;Sampling;Scanning;Science;Scientist;Seeds;Shapes;Site;Skeletal muscle structure;Slide;Small Business Technology Transfer Research;Specimen;Speed (motion);Staging;Staining method;Stains;Techniques;Technology;Time;Tissues;United States National Institutes of Health;Update;Yang;base;bioimaging;biomedical informatics;cohort;computer science;data acquisition;design;fluorescence imaging;imaging Segmentation;improved;innovation;muscle form;muscle strength;novel;public health relevance

public_health_relevance:
Important features of muscle fibers such as fiber area the number and position of myonuclei cellular infiltration and fibrosis are critical factors that determine the health of the muscle. However quantification of muscle features from digitized images is still a manual or at best a semi-automatic process. The objective of this Phase I STTR project is to build software using the most recent technical advances in machine learning and biomedical image analyses to significantly move the skeletal muscle basic and clinical research fields ahead.


application_id: 8522048
project_number: 261201000031C-8-0-1
project_title: TAS::75 0849::TAS SURVEILLANCE EPIDEMIOLOGY AND END RESULTS (SEER) PROGRAM
administering_ic: NCI
project_start_date: 2012-09-30
project_end_date: 2013-09-29
contact_pi_person_id: 11520348
contact_pi: TUCKER, THOMAS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The Surveillance Epidemiology and End Results (SEER) Program was established by the National Cancer Institute (NCI) to collect and report periodically on population-based cancer incidence and survival data. It is a core component of the NCI's surveillance activities which provide information used for planning cancer control and research programs and for evaluating the impact of such programs on cancer rates. The SEER Program was initiated in 1972 in response to requirements of the National Cancer Program for assessing the magnitude of the cancer burden in the United States and for identifying factors related to cancer risk and/or patient survival. Objectives of the SEER Program include:  1. Assemble and report on a periodic basis estimates of cancer incidence. 2. Monitor annual cancer incidence trends to identify unusual changes in specific forms of cancer occurring in population subgroups defined by geographic demographic and social characteristics. 3. Provide continuing information on changes over time in extent of disease at diagnosis trends in therapy and changes in cancer patient survival.  4. Identify the occurrence of possible iatrogenic cancers i.e. cancers that are caused by cancer therapy.  5. Serve as a research resource to the National Cancer Institute and conduct studies dealing with current cancer control issues as well as issues related to the operation of the SEER Program which may lead to improved and/or more cost-effective operating procedures.

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


application_id: 8521734
project_number: 1R41HL115849-01A1
project_title: human Microvessel Culture System (hMCS)
administering_ic: NHLBI
award_notice_date: 2013-07-16
opportunity_number: PA-12-089
application_type: 1
activity_code: R41
ic: HL
serial_number: 115849
suffix: A1
program_official: GAO, YUNLING
project_start_date: 2013-07-16
project_end_date: 2014-12-30
study_section: Special Emphasis Panel[ZRG1 IMST-J (15)]
contact_pi_person_id: 1915922
contact_pi: HOYING, JAMES B
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 171510626
duns_number: 171510626
fips: US
organization_id: 10003877
organization_name: ANGIOMICS, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402226139
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2013-07-16
project_abstract:
DESCRIPTION (provided by applicant): Human Microvessel Culture System (hMCS) Angiogenesis-targeting therapies either inhibiting or promoting new vessel growth have the potential for treating numerous diseases including cancer eye diseases cardiac and peripheral vascular disease skin disorders fibro-proliferative diseases and inflammatory conditions such as arthritis. Furthermore growing evidence indicates that for many of these diseases combinations of agents targeting multiple different vascular activities are proving more efficacious. As demand and complexity increases for these therapies there is a growing need for more informative assays of relevant vascular growth and stability. Ideally such an assay should recapitulate as much of the in vivo biological process as possible while maintaining experimental simplicity and cost effectiveness. Angiomics Inc. was founded on proven technology based on the manipulation and culturing of isolated microvessels from a variety of tissues. Utilizing rodent sources this microvessel culture system has been used extensively and effectively as a more comprehensive experimental and discovery platform for a variety of vascular-related activities and therapies. Because the system utilizes intact microvessels angiogenesis is more accurately recapitulated in both the culture and in vivo settings. In this system true neovessels sprout and grow from intact microvessels within a 3-D matrix environment. Consequently all angiogenesis-relevant activities/elements including perivascular cell behavior are present and integrated in the assay. The overall objective of this proposal is to
adapt this proven and versatile microvessel culture system to support human microvessel viability and activity to add utility and value to the platform. It is guided by two Objectives tha 1) identify media components guided by the rodent system and 2) evaluate combinations of candidate growth factors or hypoxia factors that will support human microvessel viability and angiogenesis in culture.

project_terms:
3-Dimensional;Angiopoietin-1;Angiopoietin-2;Arthritis;Biological Assay;Biological Process;Blood Vessels;Cardiac;Coculture Techniques;Complex;Conditioned Culture Media;Data;Disease;Elements;Environment;Experimental Models;Eye diseases;Fractionation;Growth;Growth Factor;Hepatocyte Growth Factor;Human;Hypoxia;Implant;In Vitro;Inflammatory;Investigation;Malignant Neoplasms;Mediating;Mus;Oxygen;Pericytes;Peripheral Vascular Diseases;Pharmacotherapy;Phase;Proteins;Proteomics;Rattus;Reagent;Rodent;Role;Source;Stromal Cells;System;Technology;Testing;Tissues;Vascular Endothelial Growth Factors;angiogenesis;autocrine;base;cell behavior;cost effectiveness;efficacy testing;in vivo;member;paracrine;pre-clinical;public health relevance;research and development;research study;response;skin disorder

public_health_relevance:
Human Microvessel Culture System (hMCS) Comprehensive yet readily performed in vitro angiogenesis assays are needed as the demand for more complex vascular-targeting therapies rises. This project will adapt a proven experimental platform involving 3-D cultures of isolated microvessels to utilize human microvessels thereby expanding its utility to include the research and development of new and complex vascular-targeting drug therapies.


application_id: 8520138
project_number: 5R01AG034605-05
project_title: Hippocampal Electrophysiology and Myelinogenesis in Healthy Cognitive Aging
administering_ic: NIA
award_notice_date: 2013-08-26
opportunity_number: RFA-AG-09-010
application_type: 5
activity_code: R01
ic: AG
serial_number: 034605
program_official: WAGSTER, MOLLY V
project_start_date: 2009-09-01
project_end_date: 2016-08-31
study_section: ZAG1-ZIJ-5(M2)
contact_pi_person_id: 2405844
contact_pi: LANDFIELD, PHILIP W.
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): This application proposes to address a fundamental unresolved question in the field of cognitive aging the nature of the neurobiological factors that distinguish individuals with healthy cognitive aging (HCA) from those with unhealthy cognitive aging (UCA). The focus of the studies will be on biomarkers developing near the age of divergence of unhealthy from healthy cognitive aging as these appear particularly likely to provide important insights into causal mechanisms. A major emphasis of the project will also be testing the hypothesis that midlife activation of myelinogenic programs in the hippocampus is an important factor in converting HCA to UCA. This view derives from our recent work with both microarray and immunohistochemical techniques showing that myelinogenesis is increased around midlife in rats the same age range in which unhealthy cognitive aging begins to appear. The proposed studies will comprise a large multidisciplinary project aimed at obtaining a unique integrated perspective on neurobiological correlates of cognitive aging in an established rat model of aging. It will involve state-of-the-art intracellular electrophysiology in hippocampal slices concomitant Ca2+ imaging in recorded neurons extensive immunohistochemistry with a battery of stains diffusion tensor imaging (MRI/DTI) separate microarray analysis of each individual rat and substantial behavioral testing of each animal. Multiple techniques will be applied in each animal. These studies will pursue the aims of correlating electrophysiological and genomic markers of cognitive aging in the same animals and will relate cognitive function to myelin structure and density in cross-sectional and longitudinal analyses. Further the course of myelinogenesis will be altered in long-term studies that manipulate dietary iron and/or treat with cuprizone. Animals subjected to altered myelinogenesis will be tested on a battery of behavioral electrophysiological microarray and immunohistochemical analyses to test the proposition that conversion to UCA has been slowed and if it has to determine through which hippocampal pathways this occurred. Overall these studies should substantially elucidate neurobiological markers distinguishing UCA from HCA and should importantly determine the role of myelinogenic programs in cognitive aging. Further the proposed longitudinal studies should have direct translational relevance.  PUBLIC HEALTH RELEVANCE: This proposed research will be conducted in an established rat model of aging which shows demonstrated relevance to human aging. These studies will elucidate neurobiological markers of and processes influencing the divergence of healthy and unhealthy cognitive aging. Therefore the proposed studies should have both predictive and therapeutic value in determining the course of human cognitive aging.

project_terms:
Address;Age;Age-Months;Aging;Anemia;Animal Feed;Animal Model;Animals;Astrocytes;Behavioral;Binding (Molecular Function);Bioenergetics;Bioinformatics;Biological Markers;Brain;Cholesterol;Cognition;Cognitive;Cognitive aging;Corpus Callosum;Cuprizone;Data;Diet;Dietary Iron;Diffusion Magnetic Resonance Imaging;Elderly;Electrophysiology (science);Event;Exhibits;Fostering;Gene Expression;Genes;Genomics;Guanosine Triphosphate Phosphohydrolases;Health;Hemochromatosis;Hippocampus (Brain);Human;Image;Immune;Immunohistochemistry;Impaired cognition;Individual;Inflammation;Inflammatory;Intake;Intervention;Investigation;Iron;Left;Link;Lipids;Liver;Longitudinal Studies;Magnetic Resonance Imaging;Measures;Mediating;Memory;Methods;Microarray Analysis;Modeling;Monkeys;Myelin;Nature;Neurites;Neurobiology;Neurons;Oligodendroglia;Oxidative Stress;Pathway interactions;Performance;Phase;Play;Process;Protocols documentation;Rattus;Regulation;Research;Resources;Role;Sampling;Serum;Signal Transduction;Slice;Staining method;Stains;Stimulus;Structure;Techniques;Testing;Therapeutic;Translating;Up-Regulation (Physiology);Validation;Work;age related;aged;aging brain;base;behavior test;biological adaptation to stress;cognitive function;density;indexing;insight;interest;iron deficiency;middle age;morris water maze;multidisciplinary;myelination;programs;protein degradation;response;trafficking;young adult

public_health_relevance:
This proposed research will be conducted in an established rat model of aging which shows demonstrated relevance to human aging. These studies will elucidate neurobiological markers of and processes influencing the divergence of healthy and unhealthy cognitive aging. Therefore the proposed studies should have both predictive and therapeutic value in determining the course of human cognitive aging.


application_id: 8520059
project_number: 5R21OH010195-02
project_title: Aging Neuromuscular Behavior and Risk of Occupational Low Back Pain
administering_ic: NIOSH
award_notice_date: 2013-07-24
opportunity_number: PAR-09-139
application_type: 5
activity_code: R21
ic: OH
serial_number: 010195
program_official: FREDERICK, LINDA J
project_start_date: 2012-07-01
project_end_date: 2015-06-30
study_section: Safety and Occupational Health Study Section[SOH]
contact_pi_person_id: 10388308
contact_pi: BAZRGARI, BABAK
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 (provided by applicant): Low back disorders and low back pain (LBP) in particular remain as the most common and debilitating work-related musculoskeletal disorder. An increasing LBP prevalence with aging along with an increasing participation of older individuals at work motivates a better understanding of underlying mechanisms linking aging with LBP. Abnormal mechanics of the spinal column (i.e. higher spinal loads and lower stability) under various work activities/events can eventually result in LBP. Spine biomechanics depend on the physical demands of a task/event (e.g. external loading) passive trunk mechanical characteristics (e.g. stiffness and damping) and active mechanical neuromuscular response to equilibrium and stability requirements. Despite current knowledge on the age-related degradation of trunk tissues the overall resultant changes in trunk mechanical behaviors (TMB - both active and passive) are unknown. It is also unknown how changes in TMB with age can influence spine biomechanics under various work activities/events. On the basis of contemporary causal biomechanical theory and our pilot data two hypotheses were shaped and will be investigated in the present application. Particularly linking aging with LBP via causal biomechanical theory suggests that: 1) there are age-related changes in TMB and 2) that these changes adversely affect spine biomechanics. Adverse effects on spine biomechanics are increases in spinal loads and decreases in spine stability for a given task/event (e.g. lifting/slp). Changes in TMB that could adversely affect spine biomechanics may include stiffer trunk reduced damping increased reflex latency and decreased reflex response. The aim of present application is to explore such relationships between aging and spine biomechanics by addressing two specific aims: Aim 1: How does TMB change with age? Aim 2: Do such age-related changes in TMB adversely affect spine biomechanics? TMB and spine biomechanics will be evaluated using a novel set of in vivo experimental methods including passive torso tests (i.e. stress-relaxation) and sudden loading experiments coupled with finite element modeling and a series of system identification techniques. The emphasis here is on aspects of the biomechanical theory that link a risk factor (i.e. aging) to abnormal spine mechanics specifically via the influences of the risk factor on TMB and spine mechanics and which have not yet been explored. Availability of a new set of powerful tools to comprehensively assess TMB and spine biomechanics will enable us to explore these facets of the causal biomechanical theory for the first time. A better understanding of potential causal mechanisms not only contributes to prevention but also is critical for efficient rehabilitation and safe return-to-wor of workers with occupational LBP. By quantifying age-related alterations in TMB and the resultant effects on spine biomechanics we expect to establish a foundation from which to develop and implement age-appropriate controls for LBP.

public_health_relevance:
The potential role of age-related changes in mechanical behaviors of the human trunk and in the development of low back pain via their adverse effects on spine biomechanics will be explored in this application. Consistent with the research objectives of NIOSH the project seeks to investigate and identify the relationships between a risk factor here aging and associated occupational diseases and injuries. It also addresses the strategic goal to reduce the incidence and severity of low back pain which is present within most sectors in the recent National Occupational Research Agenda and with particular emphasis on older workers.


application_id: 8519768
project_number: 7R01GM092874-03
project_title: Regulation of EGFR Signaling by the Endocytic Pathway
administering_ic: NIGMS
award_notice_date: 2012-08-17
opportunity_number: PA-07-070
application_type: 7
activity_code: R01
ic: GM
serial_number: 092874
program_official: AINSZTEIN, ALEXANDRA M
project_start_date: 2010-09-30
project_end_date: 2014-08-31
study_section: Molecular and Integrative Signal Transduction Study Section[MIST]
contact_pi_person_id: 1925445
contact_pi: CERESA, BRIAN P.
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary The long-term goal of our laboratory is understand how signaling transduction by cell surface receptors isregulated. Ultimately we would like to develop strategies for selectively activating or inhibiting these cellularactivities and bypass limitations of the receptor such as low receptor number or receptor desensitization.Every extracellular ligand (growth factor hormone neurotransmitter etc) binds to a unique cell surfacereceptor that induces intracellular biochemical changes that are integrated to invoke a specific change in cellphysiology. While the exquisite specificity of this system has been long appreciated the molecular mechanismby which it occurs is poorly understood. Understanding how an overlapping set of biochemical responsesproduces a specific physiology is the key to this problem. To better understand this important process we areusing the prototypical receptor tyrosine kinase the epidermal growth factor receptor (EGFR) as a model. TheEGFR is critical for many developmental and homeostatic processes; stimulation of the EGFR leads to avariety of cellular changes including cell proliferation differentiation migration and viability. Furtheroverexpression of the EGFR is associated with many cancers. We and others believe that the magnitude and duration of signaling to these biochemical intermediatesdictates how cell physiology is altered. One way the magnitude and duration of receptor signaling is modulatedis through the internalization and degradation of the receptor following ligand binding. In addition to activatingintracellular signaling pathways ligand binding also causes most cells surface receptors to internalize viaclathrin-coated pits. Once inside the cell the ligand:receptor complex moves through a series of well-definedendocytic stages until it ultimately reaches the lysosome where it undergoes degradation. It has been shownpreviously by a number of groups that disrupting this process can alter the effect that activated EGFRs have onthe cell. However these studies have been limited to distinguishing between cell surface and intracellularreceptors. The overarching hypothesis of our research is that the endocytic pathway is a key positive andnegative regulator of cell surface receptor signaling. In Aim I we will use cultured cells and selectively disrupt EGFR trafficking through the endocytic pathway.We will assess EGFR signaling at each of these endocytic stages. Further we will determine whetherdifferences in signaling occur due to changes in the receptor itself receptor:effector interactions or theduration/magnitude of signaling. Aim II we will build on our recent findings that spatially restricting the EGFRin cancer cells (MDA-MB-468 mammary adenocarcinoma cells) dramatically changes cell growth and viabilityproperties. We will build on this model to determine which signals emanate from the cell surface and which areproduced within the cell. Finally in Aim III we will explore how the endocytic pathway negatively regulatesEGFR signaling. In these studies we will determine the mechanism of signal inactivation and determine if it isunique for the receptor or effectors are inactivated in this same manner. Completion of these studies will reveal how EGFR signaling is regulated downstream of the receptor. Thiswill guide the production of more targeted therapies to inhibit EGFR signaling (i.e. cancer) or activation ofEGFR signaling (i.e. corneal wound healing).

public_health_relevance:
Project Narrative The epidermal growth factor receptor (EGFR) is a fundamental cell surface protein that functions bydetecting the presence of growth factors outside the cell and converting the information into biochemicalchanges within the cell. Proper function of the EGFR is necessary for development and homeostasis of thewhole organism; overexpression/hyperactivation of the EGFR is associated with many cancers. Theimmediate goal of this research is to better understand the molecular mechanisms that regulate the biologicalpathological functions of the EGFR and use that information for treatment of diseases associated with theEGFR.


application_id: 8519709
project_number: 4R42DA032191-02
project_title: Transdermal Naltrexone for Opiate Addiction and Alcoholism
administering_ic: NIDA
award_notice_date: 2013-11-29
opportunity_number: PA-11-097
application_type: 4
activity_code: R42
ic: DA
serial_number: 032191
program_official: PARK, MOO KWANG
project_start_date: 2012-08-01
project_end_date: 2014-07-01
study_section: Special Emphasis Panel[ZRG1-MOSS-D(12)B]
contact_pi_person_id: 1866585
contact_pi: STINCHCOMB, AUDRA L.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178031683
primary_uei: EKBZRSBPS8A3
duns_number: 178031683
uei: EKBZRSBPS8A3
fips: US
organization_id: 10006751
organization_name: ALLTRANZ, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): According to the National Survey of Drug Use and Health (NSDUH) of 2008 7.2 million Americans are in need of treatment for Substance-Related Disorders (SRDs) and a large proportion of those need treatment for opiate pain reliever heroin and alcohol addiction. Naltrexone (NTX) an opioid antagonist is currently used in oral tablet form to help maintain opioid addicts in a drug-free state. NTX is also FDA-approved for the treatment of alcohol dependence. Substantial clinical evidence exists for the benefits of NTX treatment in smoking cessation especially in women. Very intriguing clinical trial data has also been observed in amphetamine-dependent individuals which is especially important as methamphetamine dependence has no FDA-approved treatment options. Treatment with NTX in the 90's produced variable success rates in addicts; however current clinical NTX therapy is being optimized based on human pharmacogenetic data. A 30-day depot injection of the drug has been approved for the treatment of opiate addiction and alcoholism; however postmarketing reports of serious injection site reactions (cellulitis abscess and necrosis) have recently required patient warning updates.  Transdermal delivery systems offer a number of improvements over other delivery systems. Patches do not require swallowing eliminating oral side effects; nor do they require skin puncture by syringe needles eliminating pain and patient visits to a physician. Permeation through the skin allows the drug to directly enter the systemic circulation and avoid the first pass effect decreasing gastric side effects and liver damage effects in hepatocompromised drug abusers and alcoholics.  Transdermal delivery of NTX is desirable for addicts and alcoholics in order to help reduce side effects associated with oral/depot injection therapies and improve compliance. NTX itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. Microneedle-enhanced transdermal delivery is an efficient and painless method for increasing the skin permeation of many drugs including NTX. Microneedle products are currently in late-stage clinical trials for vaccine development but this proposed product would be the first microneedle delivery system for multiple day sustained release systemic treatment. We hypothesize that NTX in combination with microneedle treatment will provide a therapeutic transdermal delivery rate of NTX. The initial screening of the prototype patch will be completed in a Yucatan miniature pig pharmacokinetic study to verify that the patch system developed in vitro performs well in vivo (dose ranging study). The final studies for this proposal will be a group of critical GLP dermatotoxicology studies in animals to assess skin irritation and sensitization potential of the final patches. This final data will be used to apply for an IND so that a Phase I clinical trial may begin at the end of this project. We will create a marketable and safe drug that will significantly aid in the treatment of addiction.

project_terms:
Abscess;Adverse effects;Alcohol abuse;Alcohol dependence;Alcoholism;American;Amphetamines;Analgesics;Animals;Blood Circulation;Cellulitis;Clinical;Clinical Trials;Data;Deglutition;Development;Diagnostic;Dose;Drug Formulations;Drug Kinetics;Drug abuse;Drug abuser;Drug usage;FDA approved;Family suidae;Funding;Health;Heroin;Heroin Abuse;Heroin Dependence;Human;In Vitro;Individual;Injection Site Reaction;Injection of therapeutic agent;Investigational Drugs;Investigational New Drug Application;Lead;Methamphetamine dependence;Methods;Naltrexone;Narcotic Antagonists;Necrosis;Needles;Opiate Addiction;Opiates;Opioid;Oral;Pain;Painless;Patients;Pharmaceutical Preparations;Pharmacogenetics;Phase;Phase I Clinical Trials;Physicians;Plasma;Population;Preparation;Property;Puncture procedure;Reporting;Research;Rest;Skin;Staging;Stomach;Substance-Related Disorders;Surveys;Syringes;System;Tablets;Testing;Therapeutic;Toxic effect;Toxicology;Translational Research;United States;Update;Visit;Woman;Work;addiction;alcohol craving;alcohol use disorder;alcoholism therapy;base;cost;drug addiction pharmacotherapy;improved;in vivo;irritation;liver injury;meetings;pre-clinical;problem drinker;prototype;public health medicine (field);research and development;screening;skin irritation;smoking cessation;success;vaccine development

public_health_relevance:
According to the National Survey of Drug Use and Health (NSDUH) of 2008 7.2 million Americans are in need of treatment for Substance-Related Disorders (SRDs) and a large proportion of those need treatment for opiate pain reliever and heroin addiction. Additionally over 8.5% of the U.S. population and 75 million people worldwide meet the diagnostic criteria for alcohol use disorders (AUDs) with alcohol abuse being among the top three preventable public health problems in the U.S. and the world. The proposed preclinical translational research will accelerate testing of naltrexone delivered via a transdermal microneedle system to assess its benefits as a lead candidate in the search for improved alcoholism opiate and other drug addiction pharmacotherapies.


application_id: 8518433
project_number: 5R01HD064993-05
project_title: Aging of Frontal Structure and Function in Down Syndrome and Dementia
administering_ic: NICHD
award_notice_date: 2013-07-22
opportunity_number: RFA-HD-09-028
application_type: 5
activity_code: R01
ic: HD
serial_number: 064993
program_official: URV, TIINA K
project_start_date: 2009-09-30
project_end_date: 2015-04-05
study_section: ZHD1-MRG-C(28)
contact_pi_person_id: 8662513
contact_pi: HEAD, ELIZABETH
other_pis: SCHMITT, FREDERICK
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:
Project Summary/AbstractDown syndrome (DS) is the major cause of intellectual disability in humans and it is estimatedthere are over 300000 individuals with this genetic disorder in the United States. Virtually all DSindividuals have sufficient neuropathology for a diagnosis of AD in their 40th year. Howeverdementia may not develop until up to a decade later and some people remain cognitively intact.Thus we seek to follow a group of adults ranging in age from 20-40 years over a 5 year periodof time to identify age and dementia-associated changes in cognition and in particular focus onfrontal lobe function. Our aims are four-fold. Aim 1 will cognitively characterize a cohort ofadults with DS and follow individuals for a period of 5 years. Aim 2 will use magnetic resonanceimaging to measure white matter integrity on an annual basis in longitudinally followed people.Aim 3 will assay plasma drawn annually from the cohort and measure signaling protein changesto identify biomarkers of AD development and that are also correlated with cognition. Aim 4 willstudy archived and new autopsy brain samples from DS adults to identify molecular pathwaysthat change prior and during AD development. The outcomes of the proposed studies willcontribute to the development of noninvasive biomarkers that will assist in early AD diagnosis inDS and monitor disease progression. Further novel biomarkers that are mechanistically relatedto aging AD neuropathology and dementia will also provide outcomes for the design of futuretherapeutic clinical trials to treat or prevent dementia in DS.

project_terms:
Accounting;Activities of Daily Living;Adult;Affect;Age;Age of Onset;Age-Years;Aging;Alzheimer's Disease;Anisotropy;Archives;Autopsy;Biological Assay;Biological Markers;Blood;Brain;Caring;Categories;Cell Adhesion Molecules;Chromosomes Human Pair 21;Clinical;Cognition;Cognitive;Color;Data;Dementia;Development;Diagnosis;Diffusion Magnetic Resonance Imaging;Digit structure;Disease;Disease Progression;Dissociation;Down Syndrome;Elements;Event;Evolution;Fiber;Functional disorder;Future;Genes;Growth Factor;Hereditary Disease;Human;Image;Impaired cognition;Impairment;Individual;Intellectual functioning disability;International;Intervention;Intervention Studies;Lead;Link;London;Magnetic Resonance Imaging;Measures;Medial;Memory impairment;Methods;Modeling;Molecular;Monitor;Myelin;Neurobiology;Neurofibrillary Tangles;Oligodendroglia;Outcome;Parietal Lobe;Pathogenesis;Pathology;Pathway interactions;Pattern;Performance;Persons;Phase;Plasma;Plasma Proteins;Prevalence;Process;Proteins;Quality of life;Raven;Reaction Time;Receptor Signaling;Risk;Sampling;Scanning;Senile Plaques;Short-Term Memory;Signaling Protein;Sorting - Cell Movement;Structure;Testing;Therapeutic;Therapeutic Clinical Trial;Time;United States;Vaccination;abstracting;age related;aging brain;base;chemokine;cognitive function;cohort;cytokine;design;disease diagnosis;early onset;executive function;frontal lobe;frontal lobe function;functional decline;high risk;improved;in vivo;indexing;inhibitor/antagonist;insight;interdisciplinary approach;middle age;nervous system disorder;neuropathology;novel;novel therapeutics;overexpression;prevent;secretase;skills;therapeutic development;tool;visual search;white matter;white matter change

public_health_relevance:
Project NarrativeThe proposed study will identify new ways in which to detect Alzheimer disease (AD) in adultswith Down syndrome (DS) by monitoring changes in cognitive function measuring brainchanges by magnetic resonance imaging and profiling patterns of proteins in the plasma. Inparallel autopsy studies of brain samples will help us to understand how noninvasive cognitiveimaging and blood measures reflect the development of AD in DS. Treatments for AD in DS willbe more effective if the disease is detected early and identifying biomarkers will greatly facilitatethe development of therapeutics.


application_id: 8518284
project_number: 5R21DA034095-02
project_title: A Human Laboratory Study to Investigate Buspirone for Cocaine Use Disorders
administering_ic: NIDA
award_notice_date: 2013-07-22
opportunity_number: PA-10-269
application_type: 5
activity_code: R21
ic: DA
serial_number: 034095
program_official: HAMPSON, AIDAN
project_start_date: 2012-08-01
project_end_date: 2016-01-31
study_section: Special Emphasis Panel[ZRG1-RPIA-N(09)F]
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cocaine use disorders are an unrelenting public health concern. Intensive research efforts have yielded behavioral interventions that reduce cocaine use however these interventions are not universally effective and treatment effects diminish over time. Development of a pharmacotherapy that enhances the efficacy of these interventions is a priority for the National Institute on Drug Abuse. In the central nervous system cocaine blocks the reuptake and induces release of dopamine and serotonin thus a successful cocaine pharmacotherapy will likely need to target both of those neurotransmitters. Buspirone an anxiolytic medication with limited abuse potential is an antagonist at dopamine autoreceptors and a partial agonist at serotonin 5- HT1A receptors; both of these receptors play crucial roles in the abuse-related effects of cocaine. Dopamine autoreceptors stabilize dopaminergic tone and antagonists at these receptors can increase dopamine release. Moreover medications with partial agonist activity have been recognized as valuable tools for managing opioid and nicotine use disorders due to their ability to stimulate receptors when neurotransmitter tone is low (i.e. during abstinence) and block receptors when neurotransmitter tone is high (i.e. following a lapse). Although buspirone produces pharmacological effects that are likely beneficial for treating cocaine dependence we are unaware of any human laboratory research that has tested the influence of buspirone on the behavioral effects of cocaine a notable gap in the literature considering that such research can efficiently screen potential medications prior to the conduct of large-scale clinical trials. This study will assess the reinforcing subject- rated cognitive performance and physiological effects of cocaine during maintenance on buspirone. By determining how buspirone impacts the behavioral effects of cocaine we will provide important evidence regarding the potential efficacy of this compound for managing cocaine use disorders. These results will help to broaden the current clinical neuroscience paradigm of cocaine medications development efforts beyond a focus on dopamine systems. In addition demonstrating the initial efficacy of a commercially available drug will impact clinical research more quickly than waiting for novel molecules to be available for testing in humans.

project_terms:
12 year old;Abstinence;Agonist;American;Animals;Anti-Anxiety Agents;Autoreceptors;Basic Science;Behavior Therapy;Behavioral;Buspirone;Clinical;Clinical Research;Clinical Trials;Cocaine;Cocaine Dependences;Cocaine Users;Cognitive;Data;Development;Disease;Dopamine;Dopamine Agonists;Dopamine Antagonists;Dose;Double-Blind Method;Drug usage;Health;Human;In Vitro;Intervention;Laboratories;Laboratory Research;Laboratory Study;Literature;Maintenance;Measures;Modeling;National Institute of Drug Abuse;Neuraxis;Neurosciences;Neurotransmitters;Nicotine Use Disorder;Opioid;Performance;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Physiological;Placebo Control;Placebos;Play;Receptor Serotonin 5-HT1A;Relative (related person);Reporting;Research;Role;Sample Size;Sampling;Schedule;Self Administration;Serotonin;Stimulus;Surveys;Synapses;System;Testing;Time;Translating;Treatment Efficacy;United States;Urine;cocaine use;dopamine system;effective therapy;in vivo;meetings;novel;pre-clinical;preclinical study;public health medicine (field);receptor;reinforcer;research study;reuptake;success;tool;treatment effect

public_health_relevance:
A successful pharmacological adjunct for managing cocaine use disorders will likely need to target more than the dopamine system. Buspirone an anxiolytic with limited abuse potential is a serotonin 5HT1A receptor partial agonist and dopamine autoreceptor antagonist that may be effective in treating cocaine dependence. This project will test the influence of buspirone maintenance on the reinforcing effects of cocaine in the human laboratory to further demonstrate its potential efficacy in cocaine use disorders.


application_id: 8518260
project_number: 5R00CA139050-05
project_title: KiSS1 treatment of pancreatic adenocarcinoma
administering_ic: NCI
award_notice_date: 2013-08-07
opportunity_number: PA-07-297
application_type: 5
activity_code: R00
ic: CA
serial_number: 139050
program_official: YOVANDICH, JASON L
project_start_date: 2011-09-21
project_end_date: 2014-08-31
study_section: NSS
contact_pi_person_id: 8230129
contact_pi: MCNALLY, LACEY R
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:
Currently pancreatic adenocarcinonna is the 4th leading cause of cancer death in the United States with a median survival of <6 month and a dismal 5-yr survival rate of 1-3%. The majority of patients diagnosed with pancreatic adenocarcinoma have disseminated disease at the time of diagnosis. Because clinical trials performed over the last 30 years also clearly demonstrated that only minimal progress has been made in patient survival new strategies are desperately needed. The goal of this research is to develop a novel therapeutic approach using a metastasis suppressor to treat metastatic pancreatic adenocarcinoma and thereby improve patient survival. The metastasis suppressor KiSS1 is a secreted protein that inhibits metastasis of human melanoma breast and ovarian cancer xenograft models. KiSSI expression levels are significantly lower in pancreatic cancer tissues from patients than normal pancreatic tissues. The hypothesis of this proposal is that metastasis of pancreatic adenocarcinoma can be significantly reduced (or prevented) by therapeutic strategies including KiSSI a metastasis suppressor. Preliminary studies indicate that restoration of KiSSI greatly reduces both hepatic (97.5%) and pulmonary metastasis (99.4%) of pancreatic cancer in an orthotopic xenograft mouse model. Building upon these data the proposed in vitro and in vivo experiments will evaluate the efficacy of KiSSI treatment alone or combined with chemotherapy. Importantly since KiSSI is a secreted cytostatic protein this strategy does not depend on restoration of KiSSI in all cancer cells. Rather the effects of KiSSI are local including via a by-stander effect and systemic due to secretion of KiSSI. Specific aim #1 will evaluate treatment of metastatic pancreatic cells transfected with KiSSI plasmid with chemotherapy in a xenograft mouse model. Aim #2 will address KiSSI delivery and enable testing of KiSSI in a model system by producing a KiSSI-expressing adenovirus. Aim #3 will evaluate the treatment of metastatic tumors with the Ad-KiSS1 virusi Specific aim #4 will evaluate combination treatment with Ad-KiSS1 virus and chemotherapy in established metastatic and primary tumors in a xenograft model.

project_terms:
Address;Adenoviruses;Animal Model;Animals;Apoptosis;Biological Models;Bioluminescence;Blood;Breast Melanoma;Cancer Etiology;Cancer Patient;Cells;Cessation of life;Cherry - dietary;Chronic Disease;Clinical;Clinical Trials;Combination Drug Therapy;Cytostatics;Cytotoxic Chemotherapy;Data;Diagnosis;Diaphragm (Anatomy);Disease;Early treatment;Enzyme-Linked Immunosorbent Assay;Evaluation;Failure (biologic function);Future;Goals;Grant;Growth;Hematoxylin and Eosin Staining Method;Hepatic;Histology;Hour;Human;Image;Immunohistochemistry;Implant;In Situ Nick-End Labeling;In Vitro;Infection;Injection of therapeutic agent;Instruction;Investigation;Label;Liver;Luciferases;Lung;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Measures;Messenger RNA;Metastatic Lesion;Metastatic Neoplasm to the Liver;Metastatic Neoplasm to the Lung;Metastatic Pancreatic Adenocarcinoma;Methods;Modeling;Monitor;Morphology;Mus;Neoplasm Metastasis;Organ;Pancreas;Pancreatic Adenocarcinoma;Patients;Pharmaceutical Preparations;Plasmids;Preparation;Primary Neoplasm;Principal Investigator;Progress Reports;Protein Analysis;Proteins;Proto-Oncogene Proteins c-akt;Publishing;Research;Route;SCID Mice;Sampling;Signal Transduction;Staging;Subgroup;Survival Rate;System;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Transfection;Treatment Efficacy;United States;Update;Viral;Virus;Western Blotting;Xenograft Model;Xenograft procedure;base;bioluminescence imaging;cancer cell;chemotherapeutic agent;chemotherapy;conditionally replicative adenovirus;cytotoxic;design;fluorescence imaging;gene therapy;implantation;improved;in vivo;in vivo Model;mouse model;neoplastic cell;novel therapeutic intervention;p65;pancreas xenograft;pancreatic cancer cells;pancreatic neoplasm;prevent;programs;research study;response;restoration;tumor;tumor growth;tumor xenograft

public_health_relevance:
RELEVANCE (See instructions): These studies will be the first to examine KiSSI treatment on established metastasis and provide vital information on the potential benefits of this treatment for patients with pancreatic adenocarcinoma.


application_id: 8518023
project_number: 2R44ES020135-02
project_title: Advanced training platform and methodologies for emergency responders and skilled
administering_ic: NIEHS
award_notice_date: 2013-06-12
opportunity_number: RFA-ES-12-005
application_type: 2
activity_code: R44
ic: ES
serial_number: 020135
program_official: REMINGTON, JAMES W
project_start_date: 2011-09-01
project_end_date: 2015-05-31
study_section: Special Emphasis Panel[ZES1 JAB-D (EL)]
contact_pi_person_id: 10166727
contact_pi: NICOLALDE, ROBERTO JAVIER
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 963949107
primary_uei: VKSAV1S1KC77
duns_number: 963949107
uei: VKSAV1S1KC77
fips: US
organization_id: 10027501
organization_name: NICOLALDE R AND D, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40509
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): There is a need to be able to deliver just-in-time training and reference materials for first responders and skilled support personnel. Mobile computing platforms are becoming ubiquitous and provide an ideal means to reach users at any time in any location. The process of translating existing reference materials into mobile-friendly formats is currently manual and very labor intensive. Nicolalde R&D LLC is well under way to commercialize its mTraining mobile technology and service prototyped during a phase I SBIR from NIEHS. The mTraining technology is an objective and checklist-based method for delivering just-in-time training and reference materials making it an effective Electronic Performance Support System (EPSS) for providing workers easy access to information after training and on site prior to or during an assignment. It provides short incident specific awareness and safety training that can be delivered prior to responding to an emergency situation. The proposed development under this phase II SBIR includes: a) a back-end document processing engine that is able to automatically parse analyze mark-up and organize documents so that their content is easily cross-referenced linked and re-organized for effective delivery on a mobile training platform or other electronic medium. This will be connected to a server and database architecture to facilitate its operation and support storing and accessing content; b) the front-end interface for the mobile training platform (mTraining) was prototyped in Phase I of this project for delivering training content to emergency responders skilled support personnel and volunteers before or during an incident. The improved back-end architecture will support intelligent search capabilities for a large repository of training documents with different
structures. This capability relies on the document processing engine's ability to semi-automatically extract relevant data and automatically translate this data into a structured format.
This data can then be used for display in the mobile application stored into databases and automatically populated into ontologies. Throughout this project the participatory-based design paradigm has been used for facilitating the integration of user requirements and the fast prototyping and testing of design alternatives. This approach will continue to be utilized in Phase
2 of the project.

project_terms:
Access to Information;Architecture;Awareness;Back;Case Study;Data;Databases;Development;Educational Curriculum;Educational Materials;Electronics;Emergency Situation;Environmental Health;Focus Groups;Human Resources;Information Technology;Link;Location;Manuals;Medical;Medical Students;Methodology;Methods;National Institute of Environmental Health Sciences;Natural Language Processing;Ontology;Performance;Phase;Process;Provider;Research Infrastructure;Retrieval;Safety;Semantics;Services;Simulate;Site;Small Business Innovation Research Grant;Source;Specific qualifier value;Structure;Support System;Technology;Testing;Time;Time Management;Training;Training and Education;Translating;Update;base;computer based Semantic Analysis;design;emergency service/first responder;improved;innovation;interest;operation;public health relevance;repository;research and development;response;tool;usability;volunteer

public_health_relevance:
The proposed research and development will advance the field of environmental health and safety training by bringing to it new and innovative advanced training technologies that are based on the mobile and just-in-time paradigm. Furthermore the research and development proposed herein will advance the mobile information technology field by developing robust and scalable tools for processing and linking information residing in different source documents that are semantically related.


application_id: 8517949
project_number: 1R43AI102326-01A1
project_title: Enhanced baculovirus vectors with higher titers and increased genome stability
administering_ic: NIAID
award_notice_date: 2012-12-27
opportunity_number: PA-12-088
application_type: 1
activity_code: R43
ic: AI
serial_number: 102326
suffix: A1
program_official: CASSETTI, CRISTINA
project_start_date: 2013-01-01
project_end_date: 2014-12-31
study_section: Special Emphasis Panel[ZRG1 IDM-U (10)]
contact_pi_person_id: 9710810
contact_pi: FATH-GOODIN, ANGELIKA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The baculovirus expression vector system (BEVS) has been successfully utilized to produce thousands of proteins for use as vaccines therapeutics and for structure-function studies. One limitation of BEVS is the propensity of baculoviruses to accumulate transposon insertions into the fp25k gene leading to the "few polyhedra (FP)" phenotype. This mutation shifts the balance of virus production from occlusion-derived viruses which are not infectious in tissue culture to budded viruses which are the form of virus that is used in baculovirus expression. These higher levels of budded virus would be advantageous for BEVS users but FP mutants are also deficient in transcription from the polyhedrin promoter which drives expression of target genes. Baculoviruses also rapidly accumulate defective interfering particles (DIP) which are linked to a sharp decrease in target gene expression due to deletion of the target gene and/or viral genes needed for its expression. One factor that promotes DIP formation is transposition into fp25k. The goal of this project is to develop baculovirus expression vectors that allow for manipulation of the fp25k gene. By reducing or eliminating expression of FP25K during virus amplification we expect to obtain 5- to10- fold higher levels of budded virus titers because most of the replicative potential of the cel would go to producing budded virus instead of occlusion-derived virus. Then FP25K expression would be restored when target protein expression is desired. This would significantly lower costs for large-scale production of baculovirus-expressed proteins because high titer BV stocks would be easier to produce and the occurrence of deleterious mutations would be reduced. ParaTechs will pursue two complementary approaches to achieve this goal. One involves the production of a virus with an inducible fp25k gene that can be turned off during amplification and activated during target protein expression. The other approach utilizes a virus with a deletion in fp25k coupled with a cell line that expresses FP25K. Each of these approaches has advantages and disadvantages both in the design phase and for the end user. Experiments described in this proposal will determine which provides higher levels of BV production polyhedrin-linked expression and stable genome maintenance. Ultimately the system developed here would be combined with ParaTechs vankyrin expression technology which increases polyhedrin-driven expression in BEVS from 2- to 20-fold.

project_terms:
Adoption;Baculoviruses;Biological;Cell Line;Cells;Coupled;Cytolysis;Defective Viruses;Development;Disadvantaged;Engineering;Equilibrium;Gene Expression;Gene Targeting;Genes;Genetic Transcription;Genome;Genome Stability;Goals;Health;Human Resources;Infection;Insect Viruses;Insecta;Link;Literature;Maintenance;Marketing;Methods;Modification;Mutate;Mutation;Phase;Phenotype;Production;Promotor (Genetics);Proteins;Recombinant Proteins;Recombinants;Research Personnel;Silent Mutation;Site;Staging;Structure;System;Technology;Vertebral column;Viral;Viral Genes;Virus;cell transformation;commercialization;cost;design;experience;expression vector;innovative technologies;large scale production;mutant;novel;phase 2 study;prevent;protein expression;public health relevance;recombinant virus;research study;screening;therapeutic vaccine;tissue culture;user-friendly;vector

public_health_relevance:
The baculovirus expression vector system (BEVS) is commonly utilized to produce thousands of proteins for use as vaccines therapeutics and for structure-function studies. Unfortunately many researchers are not aware that certain mutations rapidly accumulate leading to lower levels of target gene expression. ParaTechs has developed a strategy to prevent these mutations while simultaneously providing higher levels of virus production stable genome maintenance and target gene expression.


application_id: 8517537
project_number: 5R21AG040542-02
project_title: Muscle Fat and NK Lymphocytes in Aging
administering_ic: NIA
award_notice_date: 2013-07-25
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: AG
serial_number: 040542
program_official: WILLIAMS, JOHN
project_start_date: 2012-08-01
project_end_date: 2017-07-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 1882143
contact_pi: LUTZ, CHARLES T.
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): We propose that both sarcopenia (loss of muscle mass) and obesity contribute to age-related immunosenescence by negatively regulating natural killer (NK) lymphocyte number and function. Preliminary studies showed an inverse correlation between body mass index and NK cell number in elderly women but not in young adult women. Therefore the interplay between skeletal muscle and adipose tissue may contribute to control of human NK cell development survival and function in the elderly. Skeletal muscle and fat are known to regulate each other via cytokines including adipose-derived tumor necrosis factor (TNF) and IL-6 which negatively impact NK cells. Muscle produces lower levels of these cytokines but produces abundant IL-15 which controls fat and is both absolutely required and rate-limiting for NK cell development and survival. Based on our observations we propose two hypotheses:  Muscle promotes NK development and survival and fat negatively regulates NK cells.  Muscle supports NK cells via IL-15 and fat inhibits NK cells via TNF and IL-6.  Our novel hypotheses lead to two predictions that will be tested in the elderly. 1) NK cell number and function will correlate directly with skeletal muscle strength and mass and correlate inversely with visceral fat mass. 2) Plasma IL-15 will correlate directly with muscle strength and mass and NK cell number and function but correlate inversely with visceral fat.  Our interdisciplinary teamhas expertise in muscle biology NK immunity body composition measurement and biostatistics. Our highly innovative work will address for the first time whether skeletal muscle affects NK cells and whether IL-15 has a role in this process. Our work will have a highly significant impact because it will open completely new areas of investigation and may suggest novel ways to treat both sarcopenia and declining immunity in aging.

project_terms:
Abbreviations;Address;Adipocytes;Adipose tissue;Affect;Age;Aging;Area;Biological Assay;Biology;Biometry;Body Composition;Body mass index;Cell Count;Cell physiology;Cessation of life;Clinical Research;Coin;Communicable Diseases;Communication;Complex;DNA Nucleotidylexotransferase;Development;Dose-Limiting;Dual-Energy X-Ray Absorptiometry;Elderly;Elderly woman;Enzyme-Linked Immunosorbent Assay;Fatty acid glycerol esters;Goals;Human;Immune system;Immunity;Immunoglobulins;In Situ Nick-End Labeling;Individual;Infection;Inflammatory;Interferons;Interleukin-15;Interleukin-6;Investigation;Kentucky;Killer Cells;Label;Lead;Link;Lymphocyte;Lymphocyte Count;Lymphocyte Function;Malignant Neoplasms;Measurement;Measures;Medical;Membrane;Monoclonal Antibodies;Morbidity - disease rate;Mortality Vital Statistics;Muscle;Muscle Fibers;Natural Killer Cells;Obesity;Peripheral;Peripheral Blood Mononuclear Cell;Plasma;Process;Research Personnel;Role;Skeletal muscle structure;Surface;Techniques;Testing;Thick;Time;Tumor Necrosis Factor-alpha;Universities;Visceral;Woman;Work;X-Ray Computed Tomography;age related;base;cell body (neuron);college;cytokine;fighting;healthy aging;human subject;immune function;immunosenescence;improved;innovation;interleukin-15 receptor;loss of function;monocyte;muscle form;muscle strength;novel;operation;receptor;receptor expression;research and development;sarcopenia;wasting;young adult

public_health_relevance:
We will investigate a new idea that muscle is good for the immune system and fat is bad for the immune system in elderly people. Specifically we will test the effects of muscle and fat on natural killer (NK) lymphocytes that are important in fighting infections and cancer. If this idea is correct it could open up new ways to treat fat accumulation muscle loss and immune system weakness in old age.


application_id: 8517522
project_number: 5R21AA020849-02
project_title: Dietary Fat in Ethanol-Induced Intestinal Barrier Dysfunction in ALD
administering_ic: NIAAA
award_notice_date: 2013-08-12
opportunity_number: PA-10-069
application_type: 5
activity_code: R21
ic: AA
serial_number: 020849
program_official: GAO, PETER
project_start_date: 2012-08-01
project_end_date: 2015-07-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 10484237
contact_pi: KIRPICH, IRINA 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): This application will evaluate Gut-Liver and Diet-Alcohol interactions with respect to the critical role of intestinal barrier integrity/function in he development and progression of alcoholic liver disease (ALD). ALD remains one of the leading causes of liver diseases and a major cause of morbidity and mortality in the United States and worldwide. Why some heavy drinkers develop ALD and other are spared is unclear (we postulate dietary effects-see below). Gut-derived lipopolysaccharide (LPS) plays a crucial role in the development of ALD. Increased intestinal permeability resulting from the disruption of intestinal integrity is a major cause of alcohol-induced endotoxemia. Dietary fat is an important cofactor for the development of ALD. It has been shown that diets enriched in saturated fatty acids protect against alcohol-induced liver disease in rodents whereas dietary polyunsaturated fatty acids (e.g. linoleic acid LA) promote liver damage. Our working hypothesis is that dietary LA potentiates pro-oxidative and pro-inflammatory effects on intestinal epithelial cells with consequent NF-kB activation. These events lead to alterations of intestinal tight junctions through an MLCK-dependent mechanism and contribute to the ethanol-associated disruption of intestinal integrity. We hypothesize that the combined deleterious effects of LA and EtOH on intestinal barrier integrity occur through a common NF-kB-MLCK-mediated mechanism. Increased gut permeability leads to elevated blood endotoxemia and consequent liver injury. Thus inhibition of MLCK will attenuate intestinal tight junction disruption decrease gut leakines and blood endotoxemia and attenuate ethanol/dietary linoleic acid induced liver damage. The Specific Aims of our application are: 1. To determine: a) if linoleic acid induces oxidative stress activates NF-kB and increases pro-inflammatory cytokine production in Caco-2 cells an in vitro model of the intestinal epithelial barrier; b) if linoleic acid enhances ethanol- mediated disruptin of intestinal barrier integrity by deregulation and redistribution of the major tight junctions proteins through an NF-kB-MLCK-mediated mechanism and if this effect is additive or synergistic. 2. To determine: a) whether dietary linoleic acid potentiates intestinal oxidative stress and promotes intestinal inflammation through NF-kB activation in an animal model of ALD; b) whether dietary linoleic acid-mediated intestinal inflammation contributes to ethanol-associated intestinal tight junction dysfunction through the MLCK-mediated mechanism in vivo; and c) if pharmacological inhibition/genetic deletion of MLCK can attenuate tight junction alterations decrease gut permeability and blood endotoxemia and consequently attenuate liver injury in a mouse model of ALD. Dietary modulation may represent a novel preventive/therapeutic approach in ALD and MLCK could be a specific novel therapeutic target.

project_terms:
Acetaldehyde;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Attenuated;Blood;Caco-2 Cells;Chronic;Development;Diet;Dietary Fats;Endotoxemia;Endotoxins;Epithelial;Epithelial Cells;Ethanol;Event;Fatty Acids;Fatty acid glycerol esters;Functional disorder;Genetic;Goals;Immune system;In Vitro;Individual;Inflammation;Inflammatory;Inflammatory disease of the intestine;Injury;Interleukin-1;Intestines;Joints;Lead;Linoleic Acids;Lipopolysaccharides;Liver;Liver diseases;Mediating;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Myosin Light Chain Kinase;NF-kappa B;Organ;Oxidative Stress;Pathogenesis;Permeability;Play;Polyunsaturated Fatty Acids;Preventive;Production;Proteins;Rodent;Role;Saturated Fatty Acids;TNF gene;Therapeutic;Tight Junctions;Tissues;Transcriptional Activation;United States;Unsaturated Fats;Unsaturated Fatty Acids;Work;alcohol effect;base;cell type;chronic alcohol ingestion;claudin-1 protein;cofactor;cytokine;in vitro Model;in vivo;liver injury;mouse model;new therapeutic target;novel;novel therapeutic intervention;occludin;prevent

public_health_relevance:
ALD remains one of the leading causes of liver diseases and a major cause of morbidity and mortality in the United States and worldwide. Why some heavy drinkers develop ALD and other are spared is unclear (we postulate dietary effects-see below). Interactions between the gut immune system and the liver are critical components of ALD. Diet may represent a novel therapeutic approach in ALD and this is the goal of this proposal.


application_id: 8517162
project_number: 5R37HD029957-21
project_title: Early Development with Williams or Down Syndrome
administering_ic: NICHD
award_notice_date: 2013-07-01
application_type: 5
activity_code: R37
ic: HD
serial_number: 029957
program_official: KAU, ALICE S
project_start_date: 1993-03-01
project_end_date: 2016-07-31
study_section: NSS
contact_pi_person_id: 1901361
contact_pi: MERVIS, CAROLYN B.
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2013-08-01
project_abstract:
PROJECT SUMMARY (Seeinstructions): The overall objective of the proposed research is to delineate and make sense of the process of lexical development and its relations to socio-communicative development grammatical development and both general and specific aspects of nonlinguistic cognitive development. The research will focus on the language and cognitive development of children with Williams syndrome and children with Down syndrome. Williams syndrome is associated with relative strengths in language (especially concrete vocabulary and grammar) and verbal short-term memory and severe weakness in visuospatial cognition. In contrast Down syndrome is associated with severe weaknesses in expressive language (especially grammar) and in verbal short-term memory and relative strength in nonlinguistic aspects of cognition. Because of these differences in the general nature of the relations between language and nonlinguistic cognition inclusion of these two groups of children in the same studies provides a unique opportunity to distinguish factors that are likely to be universal and necessary to language development from those that are specific to particular rates or paths to language development. The proposed research consists of a longitudinal study of early language and cognitive development beginning in late infancy a longitudinal study of cognitive and language development of school-age children as measured by standardized assessments and cross-sectional studies of language development especially socio-communicative development. Both observational and experimental methods will be used. There are three specific aims. The first is to delineate the different types of early lexical growth curves and examinetheir relations to later patterns of language and cognitive development. The second is to examine socio-communicative development and its role in language and cognitive development. The third is to determine the longitudinal trajectories of language and cognitive abilities of children with Williams syndrome and factors that influence these trajectories. The researchwill have implications both for theoretical models of the relations between language and cognitive development and for the design of cognitive language and reading intervention for children with developmental or intellectual disabilities.

project_terms:
Birth;Child;Child Development;Cognition;Cognitive;Cross-Sectional Studies;Development;Developmental Delay Disorders;Developmental Disabilities;Down Syndrome;Foundations;Growth;Instruction;Intellectual functioning disability;Intervention;Language;Language Development;Longitudinal Studies;Methods;Nature;Nursery Schools;Pattern;Reading;Recommendation;Relative (related person);Research;Role;School-Age Population;Short-Term Memory;Speech;Theoretical model;Visuospatial;Vocabulary;Williams Syndrome;base;design;infancy;lexical;lexical processing;programs;social skills;standardize measure

public_health_relevance:
RELEVANCE (See instructions): The results of the proposed research will provide a basis for recommendations regarding speech/language and developmental intervention for children with developmental delay in birth - 3 and preschool programs. The results also will increase the research foundation for the design of language social skills and reading intervention for school age children with developmental or intellectual disabilities.


application_id: 8517123
project_number: 5R01EY019891-04
project_title: Role of 14-3-3o in development and repair of corneal epithelium
administering_ic: NEI
award_notice_date: 2013-08-01
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 019891
program_official: MCKIE, GEORGE ANN
project_start_date: 2010-09-01
project_end_date: 2015-08-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 8891723
contact_pi: LI, QIUTANG
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Exposure of the corneal epithelium to the environment leaves this important barrier susceptibleto injury. Accordingly the corneal epithelium has a remarkable self-renewal capacity. This selfrenewal is mediated by a reservoir of limbal stem cells which migrate to sites of injury wherethey proliferate and differentiate to replace the damaged epithelium. This proposal is directedtoward understanding the role of 14-3-3 in corneal epithelial differentiation. 14-3-3 is a family ofproteins that bind phosphoproteins and regulate their subcellular localization. 14-3-3 is theepithelial-specific family member and using a mouse genetic model we demonstrate its crucialrole in corneal epithelial differentiation Mutation of both copies of the gene leads to defectivecorneal epithelial development in the embryo. Heterozygous mutation allows for normalembryonic development; however the corneal epithelial differentiation in response to injuryremains impaired. Thus 14-3-3 gene dosage distinguishes corneal epithelial developmentembryologically from corneal epithelial differentiation following injury. This defect indifferentiation leads to outgrowth of undifferentiated cells which eventually form an opaquecorneal plaque with associated inflammation and neovascularization. This plaque formsspontaneously as the heterozygous mice age and we provide evidence that this is linked to adry eye-like effect resulting from a defective meibomian gland which fails to secrete lipid.Notch1 is essential for corneal epithelial differentiation via its activation of genes important forboth differentiation (including genes in the vitamin A pathway) as well as cell cycle arrest andwe have found that 14-3-3 mutant cells fail to activate Notch1. Expression of activated Notch1restores differentiation in mutant cells and accordingly the defective differentiation phenotypeand the resulting corneal plaque formation closely resemble that seem with tissue-specificknockout of the Notch1 gene. We link 14-3-3 to cell surface expression of the EGF receptor(EGFR) and thus to the Erk signaling pathway which is activated by binding of EGF to thisreceptor. This is important because EGF signaling represses Notch1 and this signaling must beextinguished for Notch1 expression and subsequent corneal epithelial differentiation. Wepropose studies to further characterize the linkage between 14-3-3 EGFR and Notch1 (andits target genes) in corneal epithelia differentiation. These studies involve both cell culture andgenetic cross using 14-3-3 mutant mice.

project_terms:
Affect;Age;Aging;Alleles;Anterior;Binding (Molecular Function);Calcium;Cell Culture Techniques;Cell Cycle Arrest;Cell Differentiation process;Cell Proliferation;Cell surface;Cells;Complex;Cornea;Corneal Diseases;Corneal Injury;Corneal Opacity;Defect;Development;Differentiation Antigens;EGF gene;Embryo;Embryonic Development;Environment;Epidermal Growth Factor Receptor;Epithelial;Epithelial Cells;Epithelium;Eye;Eye Part;Failure (biologic function);Family;Family member;Gene Activation;Gene Dosage;Gene Targeting;Genes;Genetic Crosses;Genetic Models;Heterozygote;Homeostasis;Individual;Inflammation;Injury;Invaded;Knock-out;Link;Lipids;MEKs;Mediating;Molecular;Molecular Genetics;Mus;Mutant Strains Mice;Mutation;Pathway interactions;Pattern;Phenotype;Phosphoproteins;Phosphoserine Motif;Phosphotransferases;Play;Prevention strategy;Process;Proliferating;Property;Protein Binding;Protein Family;Proteins;Receptor Signaling;Role;Series;Signal Pathway;Signal Transduction;Site;Stem cells;Testing;Tissues;Transgenic Mice;Tumor Suppressor Proteins;Undifferentiated;Vision;Vitamin A;Wound Healing;base;blind;corneal epithelium;design;eye dryness;in vivo;limbal;meibomian gland;mutant;neovascularization;notch protein;null mutation;prevent;progenitor;programs;receptor;receptor expression;repaired;research study;response to injury;self-renewal

public_health_relevance:
The integrity of the cornea the most anterior part of the eye is indispensable for vision.Forty-five million individuals worldwide are bilaterally blind and another 135 million haveseverely impaired vision in both eyes because of the loss of corneal transparency. Ourproposed experiments aim to elucidate the essential role of 14-3-3 in corneal epithelialhomeostasis and wound healing and to understand the molecular network that controlsthe process. We shall study the cornea epithelium development and wound healingprocess barrier integrity and the molecular/genetic properties of 14-3-3 mutant mice.We hope to better understand corneal disease development and provide new strategiesfor prevention and treatment.


application_id: 8516420
project_number: 5R01AG033036-05
project_title: The effects of bilingualism on age-related cognitive and neurobiological declines
administering_ic: NIA
award_notice_date: 2013-07-25
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 033036
program_official: WAGSTER, MOLLY V
project_start_date: 2009-09-15
project_end_date: 2016-07-31
study_section: Cognitive Neuroscience Study Section[COG]
contact_pi_person_id: 7993908
contact_pi: GOLD, BRIAN TIMOTHY
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:
Program Director/Principal Investigator (Last First Middle):Executive control refers to a set of supervisory processes that enable humans to flexibly shape thoughtsand behavior in order to accomplish internal goals. Normal human aging is associated with markeddecline in executive control functions. However recent evidence suggests that lifelong bilingualism mayattenuate age-related declines of some executive control functions. These findings suggest thatbilingualism may promote neuroplasticity and/or compensatory brain reserve. However despitepotentially large social and scientific implications considerable knowledge gaps exist in this field. Thepresent work will fill several of these gaps through a series of studies aimed to understand the influencesof bilingualism on cognition and neurobiology in aging. Specific Aim 1 is to obtain more detailedinformation about the influence of lifelong bilingualism on high-level working memory processes. SpecificAims 2-4 use cutting-edge neuroimaging methods to understand the neurobiological bases of bilingualexecutive control advantages. These aims are to understand potential functional neuroanatomic (Aim 2)structural grey matter (Aim 3) and white matter microstructure (Aim 4) bases of bilingual performanceadvantages by linking imaging patterns directly to behavioral performance. Specific Aim 5 is to determinewhich bilingual cognitive/neurobiological advantages correlate with degree of experience/practice with thesecond language. Given the projected increase in the aged population it is important to understand howspecific lifestyle factors may affect age-related cognitive and neurobiological declines. Results from thepresent proposal will provide a detailed description of how an accessible lifestyle variable can offset age-related cognitive declines through neurobiological plasticity and/or compensatory brain reserve. Finallyresearch relevant to understanding the consequences of bilingualism is an issue of fundamentalimportance in our increasingly multilingual society.PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

project_terms:
Address;Affect;Age-associated memory impairment;Aging;Anisotropy;Attenuated;Behavior;Behavioral;Brain;Brain region;Cognition;Cognitive;Conflict (Psychology);Educational Intervention;Functional Magnetic Resonance Imaging;Functional disorder;Goals;Human;Image;Knowledge;Language;Life Style;Link;Maintenance;Methods;Neurobiology;Neuronal Plasticity;Pattern;Performance;Population;Principal Investigator;Process;Research;Series;Shapes;Short-Term Memory;Societies;Staging;Structure;Thinking function;Update;Variant;Work;age related;aged;base;bilingualism;executive function;experience;gray matter;imaging modality;improved;interest;lifestyle factors;memory process;neurobiological mechanism;neuroimaging;neuromechanism;neuroprotection;peer;programs;relating to nervous system;research study;response;social;white matter

public_health_relevance:
Program Director/Principal Investigator (Last First Middle):Project Narrative/RelevanceNormal human aging is associated with decline of executive control functions. Recent evidence suggeststhat bilingualism may attenuate some of these age-related declines by promoting neuroplasticity and/orcompensatory brain reserve. By providing a more precise understanding of the mechanisms that arebolstered by bilingualism the present proposal will help identify cognitive/neurobiological markers thatremain malleable in aging in response to an accessible lifestyle variable.PHS 398/2590 (Rev. 11/07) Page Continuation Format Page


application_id: 8515892
project_number: 5R01AA018274-05
project_title: Alcohol Tolerance and Behavioral Disinhibition in Humans
administering_ic: NIAAA
award_notice_date: 2013-08-12
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AA
serial_number: 018274
program_official: GRANDISON, LINDSEY
project_start_date: 2009-09-20
project_end_date: 2015-08-31
study_section: Special Emphasis Panel[ZRG1-BBBP-E(02)M]
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Abstract Alcohol tolerance refers to a diminished intensity of response as doses are repeated. Tolerance haslong been implicated as a factor contributing to alcohol abuse and dependence by encouraging the use ofescalating doses to reinstate initial effects of the drug. Alcohol is also well-known for its acute impairing effectson neurocognitive processes involved in the regulation of behavior and attention. Yet little research hasexamined how such disturbances might reduce self-control over actual alcohol use leading to patterns ofabusive drinking (e.g. binge drinking). Moreover despite interest in tolerance as a phenotypic marker foralcohol use disorders little research has sought to determine how differences in alcohol sensitivity andtolerance might characterize populations at-risk for alcohol abuse such as those with externalizing disorders(e.g. ADHD). The proposal is based on the working hypothesis that abuse potential of alcohol is determinedby sensitivity to its reward-enhancing effects and to its disinhibiting effects. The proposed studies examine thecontribution of tolerance to abuse potential as measured by changes in alcohol effects on basic mechanismsinvolved in the control and regulation of behavior. Studies will investigate: 1) the sensitivity of controlmechanisms to the impairing effects of alcohol and their contribution to abuse potential; 2) tolerancedevelopment to the impairing effects on mechanisms that control behavior and attention; 3) the contribution ofsuch tolerance to the abuse potential of alcohol; 4) the degree to which the inhibitory and attentional deficitsassociated with ADHD influence alcohol sensitivity and the development of tolerance; and 5) the degree towhich the developmental course of tolerance is affected by concomitant use of stimulant drugs commonly usedin the management of ADHD.

project_terms:
Accounting;Acute;Acute Alcoholic Hepatitis;Adderall;Address;Adult;Affect;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcohols;Attention;Attention deficit hyperactivity disorder;Attentional deficit;Behavior;Behavior Control;Behavioral;Behavioral Model;Biochemical;Characteristics;Comb animal structure;Cues;Development;Disease;Disinhibition;Dose;Drug usage;Euphoria;Health;Human;Impairment;Informal Social Control;Knowledge;Laboratories;Laboratory Animals;Learning;Liver Cirrhosis;Measures;Methods;Methylphenidate;Modeling;Naltrexone;Neurocognitive;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Play;Populations at Risk;Predisposition;Procedures;Process;Regulation;Reporting;Research;Rewards;Risk;Risk Factors;Role;Self Administration;Self-control as a personality trait;Series;Signal Transduction;Study Section;Techniques;Testing;Training;Treatment Efficacy;Work;abstracting;acamprosate;alcohol and other drug;alcohol effect;alcohol exposure;alcohol poisoning;alcohol sensitivity;alcohol use disorder;base;binge drinking;disinhibitory psychopathology;drinking;drinking behavior;early onset;interest;programs;response

public_health_relevance:
Project Narrative Excessive alcohol use contributes to many adverse health consequences (e.g. alcohol poisoningacute alcoholic hepatitis and liver cirrhosis). Tolerance has long been implicated as a factor contributing toalcohol abuse and dependence by encouraging the use of escalating doses to reinstate initial effects of thedrug. Yet little research has examined how tolerance might increase the risk for alcohol abuse. The proposedstudies examine the contribution of tolerance to abuse potential as measured by changes in the ability of thedrug to alter basic mechanisms involved in the control and regulation of behavior. The findings of this researchwill provide an understanding of how drinkers' susceptibility to alcohol's acute behavioral-impairing effects canpose an early-onset risk factor for later alcohol dependence by promoting a continued pattern of abusive bingedrinking. The research strategies also will provide methods for testing the role of neurocognitive mechanismsin the treatment efficacy of existing pharmacotherapies such as naltrexone and acamprosate as well as someinvestigational medications that might operate via neurocognitive control mechanisms.


application_id: 8515876
project_number: 5R01AA013388-08
project_title: Hippocamppal neurotoxicity induced by ethanol withdrawal
administering_ic: NIAAA
award_notice_date: 2013-07-30
opportunity_number: PA-07-329
application_type: 5
activity_code: R01
ic: AA
serial_number: 013388
program_official: REGUNATHAN, SOUNDAR
project_start_date: 2003-06-01
project_end_date: 2015-08-31
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 8535960
contact_pi: PRENDERGAST, MARK A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Brain injury is among the most prominent effects of prolonged alcohol use or abuse and evidence suggests that females may be more sensitive than males to the neurotoxic effect of prolonged alcohol intake. Thus examination of biochemical pathways involved in this form of brain injury may be of value in identifying therapeutic targets to be exploited in treating alcohol-related brain injury. Excess activity of N-methyl-D-asparate (NMDA)- type glutamate receptors has been implicated in both the behavioral and neurotoxic effects of alcoholism particularly during alcohol withdrawal when excess release of glutamate and polyamines occurs. Preliminary findings suggest that the rat female brain may be more sensitive to the toxic effects of polyamine exposure during ethanol withdrawal. Polyamines are endogenous substances that act as allosteric activators of NMDA receptors at NR2 subunits. Substances that further promote activity of NMDA receptor systems such as glucocorticoids are hypothesized to exacerbate alcohol withdrawal effects. Indeed prolonged alcohol intake is associated with hypercortisolemia resulting from alcohol effects the hypothalamic pituitary adrenal (HPA) axis. However the consequences of elevated stress hormone release with regard to alcohol-related neuronal injury have been little studied particularly with regard to potential sex differences that may exist. The proposed in vitro and in vivo rodent studies will test the hypothesis that alcohol-induced activation of the HPA axis promotes NMDA receptor- mediated seizure and/or neurotoxicity during alcohol withdrawal in a sex-dependent manner by: (1) stimulating the synthesis of polyamines via upregulation of the synthetic enzyme ornithine decarboxylase an effect dependent upon glucocorticoid receptor (GR) activation; and (2) upregulating the expression of polyamine-sensitive NR2B subunits thus promoting NMDA channel opening and neuronal excitation and/or neurotoxicity in a GR-dependent manner. These studies will employ biochemical immunohistochemical confocal imaging and behavioral studies using an in vivo "moderate" binge-alcohol exposure paradigm that produces peak BALs of ~160 mg/dl and organotypic hippocampal slice cultures in parallel studies. The aim of these studies is to elucidate the means by which glucocorticoids may exacerbate alcohol withdrawal effects in males and females as these relevant biochemical pathways may represent therapeutic targets to be exploited in the treatment of alcohol withdrawal effects.  PUBLIC HEALTH RELEVANCE Brain injury is among the most common consequences of alcohol abuse or dependence and limited evidence suggests that the female brain may be more sensitive than the male brain to injurious effects of alcohol use. These studies will examine effects of alcohol on the stress hormone response and will test the hypothesis that stress hormones stimulate biochemical cascades that produce alcohol withdrawal excitability and brain injury particularly in the female brain. It is the goal of these studies to identify a potential novel therapeutic target for the treatment of alcohol-related brain injury.

project_terms:
Abstinence;Acute;Adrenal Cortex Hormones;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcohol withdrawal syndrome;Alcoholism;Alcohols;Anxiety;Attenuated;Behavioral;Biochemical;Biochemical Pathway;Blood;Brain;Brain Injuries;Corticotropin-Releasing Hormone;Corticotropin-Releasing Hormone Receptors;Dependence;Ethanol;Exposure to;Female;Funding;Glucocorticoid Receptor;Glucocorticoids;Glutamate Receptor;Glutamates;Goals;Health;Hippocampus (Brain);Hormones;Image;In Vitro;Injury;Intake;Mediating;Modeling;Molecular Target;Neuronal Injury;Neurons;Ornithine Decarboxylase;Pathway interactions;Polyamines;Rattus;Receptor Activation;Research Personnel;Rodent;Seizures;Sex Characteristics;Slice;Stress;System;Testing;Toxic effect;Tremor;Up-Regulation (Physiology);Western Blotting;Withdrawal;alcohol abstinence;alcohol abuse therapy;alcohol content;alcohol effect;alcohol exposure;clinically relevant;craving;design;drinking;hypercortisolemia;hypothalamic-pituitary-adrenal axis;imaging modality;in vivo;in vivo Model;male;neurotoxic;neurotoxicity;new therapeutic target;novel;paraventricular nucleus;receptor;receptor binding;response;sex;synthetic enzyme;therapeutic target

public_health_relevance:
Brain injury is among the most common consequences of alcohol abuse or dependence and limitedevidence suggests that the female brain may be more sensitive than the male brain to injurious effects ofalcohol use. These studies will examine effects of alcohol on the stress hormone response and will testthe hypothesis that stress hormones stimulate biochemical cascades that produce alcohol withdrawalexcitability and brain injury particularly in the female brain. It is the goal of these studies to identify apotential novel therapeutic target for the treatment of alcohol-related brain injury.


application_id: 8515743
project_number: 5R01AR060701-04
project_title: The role of satellite cells in adult skeletal muscle growth and maintenance
administering_ic: NIAMS
award_notice_date: 2013-07-31
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AR
serial_number: 060701
program_official: BOYCE, AMANDA T
project_start_date: 2010-09-17
project_end_date: 2015-08-31
study_section: Special Emphasis Panel[ZRG1-MOSS-R(02)M]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: MCCARTHY, JOHN JOSEPH
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The loss of skeletal muscle mass is of clinical importance because it is associated with increased morbidity and mortality as well as a marked deterioration in the quality of life. A broad patient population is affected by significant losses in muscle mass including those afflicted by various systemic diseases (cancer sepsis HIV- AIDS) chronic physical inactivity as a result of long term bed rest rheumatoid arthritis and limb immobilization and sarcopenia the age associated loss in muscle mass and strength. Satellite cells are currently an attractive therapeutic target given their stem cell characteristics and essential role in post-natal muscle growth and regeneration. What remains controversial is the necessity of satellite cells in other aspects of muscle plasticity such as hypertrophy re-growth following atrophy and muscle maintenance with aging. In an effort to resolve this fundamental issue a novel mouse line was created which enables the specific ablation of satellite cells in mature skeletal muscle. The Pax7-DTA mouse will be used to investigate the physiological function of satellite cells in skeletal muscle hypertrophy (Aim 1) and re-growth following muscle atrophy (Aim 2). The results from the proposed experiments are expected to provide fundamental knowledge on the function of satellite cells in adult skeletal muscle plasticity which will help define the therapeutic value of satellite cells in treating the loss of muscle mass in various clinical conditions.    PUBLIC HEALTH RELEVANCE: Loss of muscle a common symptom associated with many chronic diseases physical inactivity or aging negatively impacts a person's quality of life increases the susceptibility to other complications of disease and can even lead to death. Treatments designed to restore or prevent muscle loss have in part focused on using muscle stem cells referred to as satellite cells. The goal of the proposed research is to determine if satellite cells are necessary for adult muscle growth and thus are an appropriate target for therapy for skeletal muscle loss.

project_terms:
A Mouse;Ablation;Accounting;Acquired Immunodeficiency Syndrome;Adult;Affect;Age;Aging;Apoptotic;Area;Atrophic;Bed rest;Biology;Cell Separation;Cessation of life;Characteristics;Chronic;Chronic Disease;Clinical;Collagen;Consensus;Deterioration;Diphtheria Toxin;Disease;Elderly;Extracellular Matrix;Fiber;Fluorescence;Gene Expression;Goals;Grant;Growth;HIV;Hindlimb Suspension;Homeostasis;Hypertrophy;Immobilization;Immunohistochemistry;Knowledge;Label;Lead;Limb structure;Maintenance;Malignant Neoplasms;Measures;Mechanics;Mediating;Modeling;Molecular Profiling;Morbidity - disease rate;Morphology;Mortality Vital Statistics;Mus;Muscle;Muscle function;Muscle satellite cell;Muscular Atrophy;Natural regeneration;Outcome Measure;Persons;Physiological;Population;Predisposition;Property;Quality of life;Recovery;Research;Resources;Rest;Rheumatoid Arthritis;Risk;Role;Sepsis;Signal Transduction;Skeletal muscle structure;Soleus muscle structure;Staging;Stem cells;Symptoms;Systemic disease;Technical Expertise;Testing;Therapeutic;Weight;base;in vivo;insight;member;muscle form;muscle hypertrophy;muscle strength;novel;patient population;prevent;public health relevance;research study;response;restoration;sarcopenia;satellite cell;skeletal muscle growth;skeletal muscle plasticity;therapeutic target;therapy design;tool;wasting

public_health_relevance:
RelevanceLoss of muscle a common symptom associated with many chronic diseases physical inactivity or agingnegatively impacts a person's quality of life increases the susceptibility to other complications of disease andcan even lead to death. Treatments designed to restore or prevent muscle loss have in part focused on usingmuscle stem cells referred to as satellite cells. The goal of the proposed research is to determine if satellitecells are necessary for adult muscle growth and thus are an approprioate target for therapy for skeletal muscleloss.


application_id: 8514830
project_number: 1P30GM106396-01
project_title: Molecular Targets Phase III CoBRE
administering_ic: NIGMS
award_notice_date: 2013-06-21
opportunity_number: PAR-10-196
application_type: 1
activity_code: P30
ic: GM
serial_number: 106396
program_official: CANTO, MARIA TERESA
project_start_date: 2013-07-01
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZGM1 TWD-C (C3)]
contact_pi_person_id: 1898718
contact_pi: MILLER, DONALD M.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Accounting;Animal Model;Antineoplastic Agents;Area;Biostatistics Core;Cancer Center;Cell Separation;Centers of Research Excellence;Clinical Trials;Core Facility;Development;Ensure;Faculty;Flow Cytometry;Funding;Goals;Growth;Human;Institution;Leadership;Malignant Neoplasms;Molecular Models;Molecular Target;Phase;Research;Research Infrastructure;Research Personnel;Role;Testing;Training;Translating;Translational Research;United States National Institutes of Health;Universities;cancer therapy;career;drug development;drug discovery;inhibitor/antagonist;member;metabolomics;molecular modeling;novel;novel therapeutics;pre-clinical;programs;public health relevance;success;tumor metabolism

public_health_relevance:
Cancer metabolism and cancer drug development are currently very important areas of research. The MT COBRE program has trained leaders in this area; the funding of Phase III will ensure the continued success and growth of the core facilities and this program.


application_id: 8514459
project_number: 5R01AG026307-07
project_title: Self-Regulation Immunological Aging and Health in Older Adults
administering_ic: NIA
award_notice_date: 2013-07-23
opportunity_number: PA-09-216
application_type: 5
activity_code: R01
ic: AG
serial_number: 026307
program_official: NIELSEN, LISBETH
project_start_date: 2006-07-15
project_end_date: 2017-07-31
study_section: Special Emphasis Panel[ZRG1-BBBP-T(02)M]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C.
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_terms:
Accounting;Age;Aging;Back;Behavioral;Biological Assay;Biological Markers;Biology;Blood;Cardiovascular Diseases;Cell Aging;Cognitive;Collaborations;Communicable Diseases;Data;Data Set;Elderly;Emotional;Funding;Health;Immune;Immune response;Immune system;Immunology;Individual;Individual Differences;Inflammatory;Influenza vaccination;Informal Social Control;Interleukin-6;Link;Longitudinal Studies;Lymphocyte;Malignant Neoplasms;Measures;Mental Depression;Mental Health;Natural Killer Cells;Neuropsychology;Outcome;Pain;Personal Satisfaction;Physical activity;Psychological Factors;Research;Research Personnel;Resistance;Rest;Risk;Risk Factors;Role;Sampling;Serum;Short-Term Memory;Stress;T-Lymphocyte;Testing;Time;Vaccination;Visit;Work;age related;clinically relevant;cognitive function;cohort;cytokine;experience;feeding;healthy aging;heart rate variability;high risk;indexing;inflammatory marker;innovation;longitudinal analysis;longitudinal design;member;physical conditioning;prospective;psychologic;psychosocial;public health relevance;receptor;satisfaction;senescence;shift work;social;waist circumference

public_health_relevance:
With age come changes in the immune system that can increase the risk of poor health. However not all older adults experience these changes to the same degree. This project will continue to track a cohort of older adults examining psychological factors that may be protective for psychological and physical health and delay immunological aging as well as those factors that may confer risk and the interactions between protective and risk factors.


application_id: 8514414
project_number: 5R01HL074185-10
project_title: Endothelial Myocyte Matrix in Cardiac Remodeling
administering_ic: NHLBI
award_notice_date: 2013-05-31
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 074185
program_official: SCHWARTZ, LISA
project_start_date: 2003-09-05
project_end_date: 2015-03-09
study_section: Special Emphasis Panel[ZRG1-CVS-D(03)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:
Program Director/Principal Investigator (Last First Middle): Tyagi Suresh C.The overall goal of this project is to understand the mechanism of endocardial endothelial-myocyte (E-M)dysfunction in chronic heart failure. Studies from the previous funding period suggested that endocardialendothelial dysfunction is associated with increased oxidized-matrix accumulation (fibrosis) activation of latentresident myocardial matrix metalloproteinases (MMPs) and inactivation of cardiac tissue inhibitor ofmetalloproteinase (TIMP-4) secondary to oxidative and proteolytic stresses. Administration of TIMP-4ameliorated both the formation of reactive oxygen species (ROS oxidative stress) and MMP activation(proteolytic stress). In addition we discovered the induction of proteinase activated receptor-1 (PAR-1).However the role of PAR-1 in fibrosis and E-M uncoupling remains poorly defined. H2S gas is the most potentantioxidant in mitigating oxidative stress and recent studies have implicated a cardioprotective role of H2S. Thecentral hypothesis of this competitive renewal proposal is that during chronic heart failure the oxidative andproteolytic stresses induce PAR-1 leading to generate mitochondrial (mt) ROS and reactive nitrogen species(RNS) and mitochondrial nitric oxide synthase (mtNOS) respectively thus activating the latent resident cardiacMMPs. These events disrupt the MMP/TIMP axis causing fibrosis between endothelium and myocyte.Treatment with H2S alleviates fibrosis and mitigates E-M uncoupling. Therefore the specific aims of thisproposal are: #1: To determine whether chronic left ventricle (LV) volume overload causes mitochondrialoxidative stress (ROS and RNS) by inducing NADPH oxidase (p47 subunit) mtNOS and PAR-1 and H2Salleviates mitochondrial oxidative stress. #2: To determine whether chronic LV volume overload causescardiac fibrosis by increasing collagen/elastin ratio MMP-2 -9 -13 TIMP-1 -3 decreasing TIMP-4 andinducing PAR-1 and H2S mitigates cardiac fibrosis. #3: To determine whether chronic LV volume overloadcauses E-M dysfunction and LVH by inducing PAR-1 and H2S decreases E-M uncoupling. Chronic heart failurewill be created by LV volume overload by aorta-venacava fistula (AVF) in wild type (WT) PAR-1-/+ iNOS-/-MMP-9-/- TIMP-3-/- and TIMP-4++/++ mice treated with or without NaHS a H2S donor.PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

project_terms:
Abbreviations;Acetylcholine;Acids;Antigens;Antioxidants;Aorta;Apoptosis;Arteries;Arteriovenous fistula;Basement membrane;Bradykinin;CD31 Antigens;Cardiac;Cells;Chronic;Clinical;Coin;Collagen;Congestive Heart Failure;Coupling;CpG Island Methylator Phenotype;Cystathionine;Cytoskeleton;Diastole;Diastolic blood pressure;Diastolic heart failure;Dilated Cardiomyopathy;Disulfides;Echocardiography;Elastin;Endothelial Cells;Endothelium;Event;Extracellular Matrix;Fibrosis;Fistula;Functional disorder;Funding;Gases;Gelatinase A;Gelatinase B;Generations;Goals;Heart;Heart failure;Histology;Hydrogen Sulfide;Hydroxyeicosatetraenoic Acids;Hypertrophy;In Situ;Laboratories;Left;Left ventricular structure;Lyase;Matrix Metalloproteinases;Measures;Mediating;Mitochondria;Mus;Muscle;Muscle Cells;Myocardial;NADH;NADPH Oxidase;NG-Nitroarginine Methyl Ester;Nicotinamide adenine dinucleotide;Nitric Oxide;Nitric Oxide Synthase;Nitroprusside;Nuclear;Operative Surgical Procedures;Oxidation-Reduction;Oxidative Stress;PAR-1 Receptor;PECAM1 gene;Poly(ADP-ribose) Polymerases;Preparation;Principal Investigator;Process;Prostaglandins;Protein Kinase C;Proteome;Radiolabeled;Reactive Nitrogen Species;Reactive Oxygen Species;Relaxation;Role;Secondary to;Sodium;Source;Stress;Sulfhydryl Compounds;System;Systole;Techniques;Testing;Time;Tissue Inhibitor of Metalloproteinase-1;Tissue Inhibitor of Metalloproteinase-3;Tissue Inhibitor of Metalloproteinases;Ventricular;Western Blotting;arginine methyl ester;drinking water;human NOS3 protein;in vivo;innovation;novel;prevent;programs;radiotracer;relaxing factor;research study;response;sham surgery;tissue inhibitor of metalloproteinase 4

public_health_relevance:
Program Director/Principal Investigator (Last First Middle): Tyagi Suresh C.The myocyte contraction and relaxation are synchronized only when myocytes are connected by extracellularmatrix (ECM). We coined the term endothelial-myocyte (E-M) coupling because endocardial endothelial (EE)cells derived cardio-active agents modulate myocyte contraction in systole and relaxation in diastole. Theendothelium in the heart is the least studied system because unlike conduit arteries the endocardialendothelium is burried in the muscle and it is difficult to separate its role in myocyte function. We developed anew techniques "cardiac rings" in which endothelium dependent or independent cardiac contraction andrelaxation can be examined separately in LV and RV.There are two novel aspects of this proposal: 1) the proposed experiments will demonstrate the role of PAR-1in the underlying mechanism of fibrosis and endothelial-myocyte uncoupling in heart failure; and 2) will haveclinical translational ramifications of H2S in treating diastolic heart failure.PHS 398/2590 (Rev. 11/07) Page Continuation Format Page


application_id: 8513968
project_number: 5R21DE022867-02
project_title: Pathogenic mechanisms of F. alocis
administering_ic: NIDCR
award_notice_date: 2013-06-19
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: DE
serial_number: 022867
program_official: LUNSFORD, DWAYNE
project_start_date: 2012-07-19
project_end_date: 2015-06-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Periodontal diseases are one of the most common bacterial infections of humans and impose a significant burden on the health care system. Recent developments in molecular based bacterial detection technologies have identified a number of previously unrecognized or under-appreciated organisms as associated with periodontal lesions. One such emerging pathogen is the gram-positive anaerobe Filifactor alocis. This organism is a constituent of subgingival biofilms and is present in elevated numbers at site of periodontal disease as compared to health. F. alocis produces proteases and can invade gingival epithelial cells; however little else is known regarding the potential pathogeniciy of the organism. In order to capitalize on the human microbiome studies it is necessary to functionally characterize the newly identified organisms. Hence in this study we shall contribute to the process of assessing the pathogenic potential of F. alocis in vitro and in vivo. Our preliminary data indicate that F. alocis can induce apoptosis in gingival epithelial cells an eventwith relevance to disruption of periodontal tissue homeostasis. The first goal of the current proposal therefore is to begin to characterize the mechanistic basis of F. alocis-induced apoptosis. We will focus on the MEK-FOXO pathway as preliminary data show that F. alocis can inhibit MEK and potentially activate the pro-apoptotic transcriptional factor FOXO. The role of MEK will be assessed by gene knockin experiments with constitutively mutants and the relevance of FOXO determined by reporter assays and siRNA knockdowns. Secondly we will establish the in vivo characteristics of F. alocis in the mouse chamber model. The ability of F. alocis to survive and replicate in vivo will be established and in addition host cytokine responses neutrophil recruitment and apoptosis will be assayed. These studies will generate both in vitro and in vivo data that will begin to establish the pathogenic credentials of F. alocis and provide a platform for future studies directed toward a more comprehensive understanding of molecular and cellular pathogenic mechanisms. Ultimately the knowledge gained could be translated into novel diagnostic therapeutic or preventive strategies for periodontal diseases.

project_terms:
American;Anaerobic Bacteria;Apoptosis;Apoptotic;Applications Grants;Area;Bacteria;Bacterial Infections;Biological Assay;Cell Death;Cells;Characteristics;Communities;Complex;Consensus;Data;Data Set;Detection;Development;Diagnosis;Diagnostic tests;Disease;Disease Progression;Disorder by Site;Epithelial Cells;Etiology;Evaluation;Event;Future;Genes;Gingiva;Goals;Health;Healthcare Systems;Homeostasis;Human;Human Microbiome;In Vitro;Individual;Induction of Apoptosis;Infection;Invaded;Knowledge;Lead;Lesion;MEK inhibition;MEKs;Measurement;Microbiology;Modeling;Molecular;Mouth Diseases;Mus;Neutrophil Infiltration;Oral health;Organism;Outcome Study;Pathogenicity;Pathway interactions;Peptide Hydrolases;Periodontal Diseases;Phenotype;Plasmids;Porphyromonas gingivalis;Prevention strategy;Prevention therapy;Process;Property;Reporter;Reporting;Rods (Retina);Role;Signal Transduction;Site;Small Interfering RNA;Techniques;Technology;Testing;Therapeutic;Therapeutic Agents;Tissues;Translating;Virulence;Work;base;caspase;cytokine;in vivo;microbial;mouse model;mutant;novel;novel diagnostics;oral microbiome;pathogen;research study;response;subcutaneous;subgingival biofilm

public_health_relevance:
Periodontal diseases afflict millions of Americans and recent molecular techniques have identified a variety of bacteria associated with the disease that have yet to be studied in depth. In this project we will examine the interactions between F. alocis and the human cells that are colonized by the organism and we will determine the ability of the organism to survive in mouse models of infection. The information to be gathered could result in a re-evaluation of the causes of periodontal disease and ultimately be used to identify targets for novel therapeutic agents or diagnostic tests.


application_id: 8513270
project_number: 5F31CA142317-05
project_title: Functional conversion of tumor associated macrophages via cytokine therapy
administering_ic: NCI
award_notice_date: 2013-06-21
opportunity_number: PA-07-106
application_type: 5
activity_code: F31
ic: CA
serial_number: 142317
program_official: MCNEIL FORD, NICOLE
project_start_date: 2009-07-10
project_end_date: 2014-07-09
study_section: Special Emphasis Panel[ZRG1-SBIB-V(29)L]
contact_pi_person_id: 9679618
contact_pi: MITCHELL, COURTNEY JETUN
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Breast cancer is the leading cancer diagnosis in women and second most common cause of women cancer deaths. Although mortality has decreased and incidence has remained steady persons diagnosed with late Stage disease have dismal survival rates. Hence the need for therapies with the ability to prevent cancer altogether. The objective of this project is to determine if IL-12 induced functional conversion of tumor associated macrophages from anti-inflammatory and tumor supportive to pro-immunogenic and anti- tumorigenic can be extended for therapeutic exploitation. The mice 4T1 mammary carcinoma with lung metastases model will be employed to accomplish the objective and achieve the specific aims of this project. Specific aim 1 will examine the immune cells and cytokines that contribute to the maintenance of the IL-12 induced pro-immunogenic functional conversion of the macrophages. Two approaches will be used in this aim. First the IL-12 response of scid mice which are T and B cell deficient will be compared with NK depleted scid mice. Secondly the role of IL-18 and IFN-y in the maintenance of the IL-12 induced conversion will be assessed by neutralizing these cytokines with anti-IFN-y or anti-IL-18. In specific aim 2 the ability of IL-15 and IL-18 to extend the pro-immunogenic status of tumor associated macrophages will be examined by injecting mice bearing 4T1 tumors with the encapsulated IL-12 alone and then injecting the mice subcutaneously with encapsulated IL-15 or IL-18 one to four days later. Specific aim 3 will determine if the extension of the IL-12 induced pro-immunogenic window enhances the efficacy of a tumor-dendritic cell vaccine via immunization of 4T1 bearing mice with a 4T1-dendritic cell fusion vaccine in combination with encapsulated buffer or encapsulated IL-12 alone or in combination with other cytokines as determined by specific aim 2. Analysis for each of our aims will include q-rt-PCR for various anti-inflammatory and tumor supportive as well as pro-immunogenic and anti-tumorigenc factors ELISA for serum IFN-gamma measurement of cytoplasmic levels of IFN-gamma perforin and granzyme B perfusion assisted weight and volume measurements for the primary tumor perfusion assisted quantification of lung metastases and anti- IFN-gamma and CD71 labeling for measurement of number of infiltrating leukocytes. By exploring the effects of IL-12 on tumor associated macrophages we may gain a better understanding of how cytokines and macrophages interact for tumor maintenance and progression.

project_terms:
Anti-Inflammatory Agents;Anti-inflammatory;B-Lymphocytes;Breast Carcinoma;Buffers;Cell fusion;Cells;Cessation of life;Dendritic Cell Vaccine;Dendritic Cells;Diagnosis;Disease;Encapsulated;Enzyme-Linked Immunosorbent Assay;Immune;Immunization;Incidence;Interferon Type II;Interferons;Interleukin-12;Interleukin-15;Interleukin-18;Label;Leukocytes;Lung;Maintenance;Malignant Neoplasms;Measurement;Modeling;Mortality Vital Statistics;Mus;Neoplasm Metastasis;Perfusion;Persons;Primary Neoplasm;Role;Serum;Staging;Survival Rate;T-Lymphocyte;TFRC gene;Therapeutic;Vaccines;Weight;Woman;breast cancer vaccine;cancer diagnosis;cancer immunotherapy;cytokine;cytokine therapy;granzyme B;immunogenic;macrophage;malignant breast neoplasm;perforin;prevent;public health medicine (field);public health relevance;response;tumor;tumorigenic

public_health_relevance:
This project will benefit public health by providing new information regarding potential cancer immunotherapy including including preventative vaccines for breast cancer.


application_id: 8512730
project_number: 5R01EY021231-03
project_title: The functional role of sarcomeric nonmuscle myosin IIB in extraocular muscles
administering_ic: NEI
award_notice_date: 2013-07-16
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: EY
serial_number: 021231
program_official: ARAJ, HOUMAM H
project_start_date: 2011-08-01
project_end_date: 2015-07-31
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 7875119
contact_pi: MONCMAN, CAROLE L.
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): The extraocular muscles (EOMs) are categorized as skeletal muscles; however emerging evidence indicates that they deviate significantly from the prototypical members of this muscle class. For example many myofilament cytoskeletal and extracellular matrix proteins have unique expression patterns in developing and adult EOMs including the sustained expression of embryonic and fetal myosin isoforms (MyHC) the presence of a unique EOM-specific MyHC and co-expression of cardiac and skeletal muscle isoforms of thick and thin filament accessory proteins. We demonstrated that a nonmuscle myosin (nmMyH IIB) is present in the sarcomeric A band of putative tonic EOM fibers. Although small amounts of nmMyH IIB are found in the Z-line of cardiac and skeletal muscles its unique distribution within the A band in EOM tonic fibers is further evidence of the complexity and unconventional developmental program of the eye muscles. We will use genetically engineered mice to delete nmMyH IIB in a tissue and time-specific manner in order to test the following central hypothesis: the sarcomeric distribution of nmMyH IIB in EOM fibers depends on normal visual experience postnatally and is necessary for normal EOM contractile function in the adult. Thus we have defined the following specific aims: 1) determine whether normal visual experience early in life is necessary for the expression and sarcomeric localization of nmMyH IIB in rodent EOMs 2) define the role of nmMyH IIB on sarcomeric structure in rodent EOMs and 3) determine the influence of nmMyH IIB on the contractile function of rodent EOMs. These results will establish the role of nmMyH IIB in EOM fibers during early postnatal development and in the adult and should provide valuable insights into our understanding of the normal EOM phenotype and how it might change with disease.)

project_terms:
Adult;Appearance;Biochemical;Biological Assay;Birth;Development;Disease;Embryo;Extracellular Matrix Proteins;Eye;Eye Movements;Eyelid structure;Fiber;Genetically Engineered Mouse;Imaging Techniques;In Vitro;Life;Longevity;Mesoderm;Microfilaments;Mus;Muscle;Muscle Development;Muscle Fibers;Myocardium;Myofibrillogenesis;Myosin ATPase;Myosin Heavy Chains;Neural Crest;Neuromuscular Junction;Nonmuscle Myosin Type IIB;Pathway interactions;Pattern;Perinatal;Peripheral;Phenotype;Positioning Attribute;Protein Isoforms;Proteins;Rattus;Research Personnel;Rodent;Role;Sarcomeres;Sensory;Skeletal muscle structure;Skin;Slide;Striated Muscles;Structural Protein;Structure;Testing;Thick Filament;Thin Filament;Time;Tissues;Vision;Visual;cell motility;early experience;experience;fetal;in vivo;insight;interest;member;muscular structure;non-muscle myosin;orbit muscle;postnatal;programs;research study;vision development

public_health_relevance:
In addition to the sensory pathways the ability to direct the eyes to items of interest is also key for normal vision. The extraocular muscles are the small muscles responsible for coordinated eye movements. This project will examine the function of a structural protein found in a unique position only in the extraocular muscles and that may be important for normal eye movements.)


application_id: 8512703
project_number: 5T32DK007778-14
project_title: Training Program in Oxidative Stress and Nutrition
project_terms: Oxidative Stress;Training Programs;nutrition
administering_ic: NIDDK
award_notice_date: 2013-08-19
opportunity_number: PA-08-226
application_type: 5
activity_code: T32
ic: DK
serial_number: 007778
program_official: DENSMORE, CHRISTINE L
project_start_date: 2000-08-15
project_end_date: 2015-07-31
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: ST CLAIR, DARET K
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This is a competing renewal of a training program in Nutrition and Oxidative Stress. The primary goal of the training program is to prepare PhD students for successful careers in nutritional sciences. The focus is on nutrition as a modulator of oxidative stress in metabolic diseases cancer and neuroscience/aging. The training program is located in the Graduate Center for Nutritional Sciences (GCNS) a multi-disciplinary center crossing departmental and college boundaries. The goals of the training program are to provide state-of-the-art education in nutritional sciences with an emphasis on oxidative stress and to provide training in ethical conduct of high quality laboratory research focused on nutritional modulation of oxidative stress. Twenty seven training faculty all members of the GCNS will provide training around 3 theme areas (metabolic disease cancer neuroscience/aging) representing strength of current research and research areas significant to the fields of nutrition and chronic disease. Support for 4 trainees is requested based on growth of the programs and training expertise. Students wil [sic] be recruited from an integrated biomedical sciences program or directly into the GCNS increasing the number and quality of the applicant pool of students. Strengths of the training program include a newly revised curriculum integrating basic and clinical aspects of nutritional sciences training faculty with extensive training experience and productive and funded research programs of direct relevance to the training program research cores for training and facilitation of research within the theme areas the use of a multidisciplinary center to increase and diversify opportunities for training. A unique aspect of the training program is an annual symposia [sic] on nutrition and oxidative stress organized by the trainees with excellent opportunites [sic] for trainees to interact with nationally prominent researchers in the fields of nutritional sciences and oxidative stress. A multiple-PI model has been incorporated into the renewal to assure rigorous attention to the major focus areas of nutritional sciences and oxidative stress.    PUBLIC HEALTH RELEVANCE: Most chronic diseases especially those on the rise in prevalence in the US are influenced by nutrition. Imbalances in oxidative mechanisms within cells underly [sic] many of these chronic diseases and nutritional approaches can be used to influence oxidative stress of cells. We propose to train future scientists to identify ways that nutrition can modify oxidative stress in metabolic diseases (diabetes obesity) cancer and neuroscience/aging.


application_id: 8512594
project_number: 5R01HD057446-05
project_title: The MMP system in human ovulation: localization regulation and function
administering_ic: NICHD
award_notice_date: 2013-07-24
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HD
serial_number: 057446
program_official: TAYMANS, SUSAN
project_start_date: 2009-09-15
project_end_date: 2015-07-31
study_section: Cellular, Molecular and Integrative Reproduction Study Section[CMIR]
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The preovulatory LH surge stimulates an increase in ovarian matrix metalloproteinases (MMPs) and their associated inhibitors the TIMPs (collectively referred to as the MMP system) prior to follicular rupture in many species. The paramount role of the MMP system in ovulation is forthcoming from numerous experiments where oocyte release is blocked by MMP inhibitors. Yet other than our preliminary data nothing is known as to progression and temporal patterns of the MMPs and TIMPs involved in the ovulatory process in the human. This question will be addressed in the first Specific Aim by using a unique model where the granulosa theca and stroma from human periovulatory follicles will be collected prior to and at three designated times after hCG (early late and postovulatory). The expression patterns of key members of the MMP and TIMP family associated with follicular rupture in the human will be illuminated. Specific Aim #2 will build upon these observational findings and explore the regulation of these MMPs and TIMPs by known LH stimulated signaling pathways using well characterized models in the rodent and human. However one of the key questions remains as to what are the MMPs and TIMPs actually doing during the process of follicular rupture? We propose that the ovarian MMP system directs the requisite proteolytic or "degradomic" changes necessary for ovulation. Thus Specific Aim #3 will elucidate specific protein targets of MMP action by proteomic profiling allowing us to characterize the function of the MMPs and TIMPs in the ovulatory process. A major strength of this proposal is our extensive expertise with the MMP system that allows an integrated approach to understand the cellular expression regulation and impact of the MMP system on follicular rupture. One novel aspect of this study is the use of well characterized human preovulatory follicles as a foundation to explore the role of the MMP system in the process of human ovulation which has never been accomplished. As such the proposed studies are extremely timely to elucidate the role that this exquisite proteolytic system plays in the coordinated processes of follicular rupture and oocyte release which are key aspects of normal human ovarian physiology. PUBLIC HEALTH RELEVANCE: The proposed studies will investigate the underlying mechanism involved in human ovulation which is a process where the egg is released from the follicle in the ovary. These studies will focus on a family of proteolytic enzymes known as metalloproteinases that we believe breakdown the wall of the ovarian follicle to allow the egg to be released. Only by fully understanding such basic tenets of ovarian function will we be able to promote or inhibit the events associated with metalloproteinase action during the ovulatory process thereby facilitating and increasing fertility or acting in a contraceptive manner to decrease fertility.

project_terms:
Address;Animals;Antibodies;Apoptosis;Cell Surface Proteins;Cleaved cell;Contraceptive Agents;Data;EGF gene;Event;Extracellular Matrix;Family;Fertility;Foundations;Gonadotropins;Growth Factor;Health;Human;Human Chorionic Gonadotropin;Interstitial Collagenase;Knock-out;Matrix Metalloproteinase Inhibitor;Matrix Metalloproteinases;Mediator of activation protein;Metalloproteases;Modeling;Oocytes;Ovarian;Ovarian Follicle;Ovarian Tissue;Ovary;Ovulation;Pattern;Peptide Hydrolases;Physiology;Play;Principal Investigator;Process;Progesterone;Prostaglandins;Proteins;Proteolysis;Proteomics;RNA Interference;Regulation;Rodent;Role;Rupture;Signal Pathway;System;Time;cell growth;cytokine;egg;inhibitor/antagonist;member;novel;programs;research study;theca cell

public_health_relevance:
The proposed studies will investigate the underlying mechanism involved in humanovulation which is a process where the egg is released from the follicle in the ovary.These studies will focus on a family of proteolytic enzymes known asmetalloproteinases that we believe breakdown the wall of the ovarian follicle to allow theegg to be released. Only by fully understanding such basic tenets of ovarian functionwill we be able to promote or inhibit the events associated with metalloproteinase actionduring the ovulatory process thereby facilitating and increasing fertility or acting in acontraceptive manner to decrease fertility.


application_id: 8511887
project_number: 3R01AA018869-04S1
project_title: Cyclic AMP Cytokine Modulation and Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2012-08-20
opportunity_number: RFA-AA-09-006
application_type: 3
activity_code: R01
ic: AA
serial_number: 018869
suffix: S1
program_official: RADAEVA, SVETLANA
project_start_date: 2009-09-20
project_end_date: 2014-08-31
study_section: ZAA1-JJ(06)
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Alcoholic Liver Disease (ALD) remains a leading cause of liver-related deaths in the U.S. and there is still no FDA-approved therapy. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentrations of tumor necrosis factor (TNF) and TNF-inducible proinflammatory cytokines/chemokines such as IL-8 and IL-18 have been reported in patients with alcoholic hepatitis and/or cirrhosis and levels correlated with markers of the acute phase response liver function and clinical outcome. Similarly there are depressed levels of the critical anti-inflammatory cytokine IL-10. Studies in animal models support an etiologic role for cytokines in the liver injury of ALD. The major problem to be investigated in this proposal is the mechanism(s) for this dysregulated cytokine metabolism and our overall goal is the development of novel therapeutic interventions. ALD is associated with an increase in oxidative stress with a concomitant decrease in cellular antioxidants such as glutathione (GSH) and importantly S-adenosyl-L-methionine (SAM) due to subnormal synthesis. Clinical studies have suggested that SAM has beneficial effects in many hepatic disorders including ALD and numerous animal studies have clearly demonstrated the protective effects of SAM against a variety of hepatotoxins. Previous studies from our group evaluated the role of SAM in positively modulating endotoxin (LPS)-stimulated TNF and IL-10 production related to ALD. We showed that SAM decreased LPS stimulated TNF production and increased LPS stimulated IL-10 production and that SAM increased cellular levels of cyclic AMP (cAMP) which is known to positively modulate cytokine production. We therefore began an evaluation of the role of cAMP in dysregulated cytokine production in ALD which is the research focus of this current proposal. We present compelling preliminary data that cAMP is decreased in a macrophage cell line chronically cultured in alcohol and in Kupffer cells from mice chronically fed ethanol intragastrically. Our working hypothesis is that altered phosphodiesterase 4B (PDE4B) and cAMP metabolism cause abnormal TNF and IL-10 metabolism which play a critical role in the development and perpetuation of ALD. Specific Objectives for this proposal are to: 1. Document increased PDE4B expression/activity and decreased cAMP in peripheral blood monocytes from patients with alcoholic hepatitis (AH) and alcoholic cirrhosis and evaluate whether in vitro incubation of monocytes with specific phosphodiesterase inhibitors corrects dysregulated cAMP and cytokine metabolism; 2. Determine whether PDE4 (and specifically PDE4B) inhibition blocks the development of alcohol-induced liver injury in a murine intra-gastric ethanol-feeding model of chronic ALD and in a murine model of AH; 3. Evaluate potential molecular and epigenetic mechanisms whereby cAMP metabolism is altered in alcoholic liver disease; and 4. Evaluate the effects of combined consumption of a commercially- available adenyl cyclase agonist (Misoprostol - increases cAMP production) and a phosphodiesterase inhibitor (Pentoxyfilline - decreases cAMP breakdown) in normal volunteers and in patients with stable alcoholic cirrhosis.    PUBLIC HEALTH RELEVANCE: Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S. and there is still no FDA-approved therapy. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentration levels of tumor necrosis factor (TNF) and TNF-inducible proinflammatory cytokines/chemokines such as IL-8 and IL-18 have been reported in patients with alcoholic hepatitis and/or cirrhosis and levels correlated with markers of the acute phase response liver function and clinical outcome. Similarly there are depressed levels of the critical anti-inflammatory cytokine IL-10. Studies in animal models support an etiologic role for cytokines in the liver injury of ALD. The major problem to be investigated in this proposal is the mechanism(s) for this dysregulated cytokine metabolism and our overall goal is the development of novel therapeutic interventions.

project_terms:
Acute-Phase Reaction;Adenylate Cyclase;Agonist;Alcoholic Hepatitis;Alcoholic Liver Cirrhosis;Alcoholic Liver Diseases;Alcohols;Animal Model;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Attenuated;Biological Models;Cause of Death;Cell Line;Cessation of life;Chronic;Cirrhosis;Clinical;Clinical Research;Consumption;Cyclic AMP;Data;Depressed mood;Development;Disease;Disease model;Endotoxins;Epigenetic Process;Ethanol;Evaluation;FDA approved;Glutathione;Goals;Human;IL8 gene;In Vitro;Inflammatory;Injury;Interleukin-10;Interleukin-18;Isoenzymes;Knockout Mice;Kupffer Cells;Lipopolysaccharides;Liver;Liver diseases;Mediating;Metabolism;Methionine;Misoprostol;Modeling;Modification;Molecular;Mus;Outcome;Oxidative Stress;PDE4B;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Phosphodiesterase Inhibitors;Play;Process;Production;Rattus;Reporting;Research;Role;Serum;Stomach;System;Therapeutic Intervention;Tumor Necrosis Factor-alpha;Whole Blood;Work;alcohol exposure;animal data;base;bench to bedside;chemokine;cytokine;experience;feeding;hepatotoxin;inhibitor/antagonist;liver function;macrophage;monocyte;novel therapeutic intervention;peripheral blood;phosphoric diester hydrolase;protective effect;public health relevance;research study;volunteer

public_health_relevance:
Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in theU.S. and there is still no FDA-approved therapy. Abnormal cytokine metabolism is amajor feature of ALD. Elevated serum concentration levels of tumor necrosis factor(TNF) and TNF-inducible proinflammatory cytokines/chemokines such as IL-8 and IL-18have been reported in patients with alcoholic hepatitis and/or cirrhosis and levelscorrelated with markers of the acute phase response liver function and clinicaloutcome. Similarly there are depressed levels of the critical anti-inflammatory cytokineIL-10. Studies in animal models support an etiologic role for cytokines in the liver injuryof ALD. The major problem to be investigated in this proposal is the mechanism(s) forthis dysregulated cytokine metabolism and our overall goal is the development ofnovel therapeutic interventions.


application_id: 8511813
project_number: 5R01HL114951-02
project_title: Enhancing the effectiveness of human cardiac stem cell therapy
administering_ic: NHLBI
award_notice_date: 2013-06-01
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 114951
program_official: BUXTON, DENIS B
project_start_date: 2012-07-16
project_end_date: 2013-10-07
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 10217681
contact_pi: CAI, CHUANXI
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): Ischemic heart disease remains as the single largest cause of mortality in the United States. Delivery of c-kit positive human cardiac stem cells (hCSCs) is a very promising therapeutic approach in repairing the infarcted heart but is severely limited by the poor survival of donor cells. Carbon monoxide (CO) a byproduct of heme oxygenase 1 (HO-1) has a potent anti- apoptotic cytoprotective effect against ischemia/reperfusion injury to cardiomyocytes. However it is not known whether HO-1/CO is cytoprotective for hCSCs. Our pilot studies found that HO-1/CO plays an important role in mediating hCSC survival ability. Therefore this application focuses on testing our hypothesis that HO-1/CO promotes human cardiac stem cell survival vial the activation of survival signal pathways and the cytokine effects as well as enhances the stem cell therapy efficacy and heart function after transplantation into immunodeficient mouse heart following myocardial infarction. Thus we will examine whether hCSCs pretreated with an HO-1 inducer (CoPP) or a CO releasing molecule (CORM-3) will exhibit greater abilities in cell survival proliferation migration endothelial and cardiomyogenic differentiation (Aim 1) and understand the molecular mechanisms that underlie the effect of HO-1/CO on hCSC survival signal pathways resistance to apoptosis ROS generation and cytokine release (Aim 2). Aim 3 of this proposal will test whether transplantation of the preconditioned eGFP+-hCSCs will result in improvement in invivo hCSC survival and homing endogenous mouse CSC proliferation and differentiation and cardiac structure and function with immunodeficient mouse (SCID) model following myocardial infarction. Knowledge gained from the above experiments will provide the essential implications on the strategies to enhance hCSC survival after transplantation and therefore their efficacy in clinical repairing infarcted myocardium for the cell therapy of patients with ischemic heart disease.

project_terms:
Affect;Antibodies;Apoptosis;Apoptotic;Biological Assay;Carbon Monoxide;Cardiac;Cardiac Myocytes;Cardiomyopathies;Cell Culture Techniques;Cell Proliferation;Cell Survival;Cell Therapy;Cells;Clinical;Clinical Research;Collaborations;Data;Discipline;Echocardiography;Effectiveness;Exhibits;Generations;Genes;Goals;Grant;Growth Factor;HLA-A gene;Heart;Heart Transplantation;Heme Oxygenase (Decyclizing);Homing;Human;Immunodeficient Mouse;Immunohistochemistry;In Vitro;Infarction;Infusion procedures;Injection of therapeutic agent;Knowledge;Laboratories;Left Ventricular Function;Letters;Mediating;Methods;Modeling;Molecular;Molecular and Cellular Biology;Mortality Vital Statistics;Mus;Muscle;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Natural regeneration;Oxidative Stress;Patients;Phosphorylation;Physiology;Pilot Projects;Play;Proteomics;Proto-Oncogene Protein c-kit;Reactive Oxygen Species;Regenerative Medicine;Reperfusion Injury;Reperfusion Therapy;Research;Research Personnel;Research Project Grants;Resistance;Role;SCID Mice;Signal Pathway;Staging;Stem cells;Structure;Testing;Therapeutic;Time;Training;Transplantation;Treatment Efficacy;United States;Up-Regulation (Physiology);Vial device;Western Blotting;angiogenesis;auricular appendage;base;cardiogenesis;cobaltiprotoporphyrin;cytokine;heart function;immunocytochemistry;immunodeficient mouse model;improved;in vivo;knock-down;migration;morphometry;preconditioning;repaired;research study;small hairpin RNA;small molecule;stem cell therapy

public_health_relevance:
Poor survival of donor cells is one of the major challenges in stem cell therapy for ischemic heart disease. This project investigates the effective strategies toenhance the human cardiac stem cell therapy efficacy with small molecules including cobalt protoporphyrin (CoPP) a heme oxygenase 1 inducer which promotes endogenous carbon monoxide generation; or a carbon monoxide donor CORM-3. These studies will show how CoPP/CORM-3 affects the survival ability of human cardiac stem cells in an in vitro cell culture model and how intramyocardial injection of CoPP/CORM-3 pretreated human cardiac stem cells improve heart function in an in vivo immunodeficient mouse model following ischemia-reperfusion injury. The results and broad conclusions will be directly relevant to enhance the efficacy in clinical repairing the infarcted myocardium for the cell therapy of patients with ischemic heart disease.


application_id: 8511660
project_number: 5R01EY021769-02
project_title: The role of Insm1a in photoreceptor differentiation
administering_ic: NEI
award_notice_date: 2013-07-18
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: EY
serial_number: 021769
program_official: NEUHOLD, LISA
project_start_date: 2012-08-01
project_end_date: 2017-07-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 10184513
contact_pi: MORRIS, ANN C
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adoption;Ally;Animal Model;Animals;Biological Assay;Biology;Blindness;Cell Cycle;Cell Cycle Progression;Cell Survival;Cell Transplants;Cells;Data;Degenerative Disorder;Development;Disease;Embryo;Evolution;Eye;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Gene Targeting;Genes;Genetic;Goals;Human;Immunohistochemistry;In Situ Hybridization;In Vitro;Inherited;Injury;Investigation;Laboratories;Luciferases;Mammals;Methods;Modeling;Molecular;Molecular Genetics;Molecular Target;Mus;Mutation;Natural regeneration;Nerve Regeneration;Neurons;Pathway interactions;Photoreceptors;Population;Promotor (Genetics);Protocols documentation;Regulation;Reporter;Retina;Retinal;Retinal Cone;Retinal Degeneration;Retinal Diseases;Retinal Dystrophy;Retinitis Pigmentosa;Rods (Retina);Role;Staging;Stem cells;System;Therapeutic;Transcription Repressor/Corepressor;Transplantation;Vertebrate Photoreceptors;Visual impairment;Zebrafish;Zinc Fingers;base;blastocyst;cell type;chromatin immunoprecipitation;clinical application;digital;effective therapy;gain of function;gene therapy;in vivo;neurogenesis;photoreceptor degeneration;research study;response;retinal neuron;retinal progenitor cell;retinogenesis;stem;therapy development;transcription factor


application_id: 8511586
project_number: 5R43CA162417-02
project_title: Sustained target delivery for treatment of cervical pathologies
administering_ic: NCI
award_notice_date: 2013-07-08
opportunity_number: PA-11-096
application_type: 5
activity_code: R43
ic: CA
serial_number: 162417
program_official: LOU, XING-JIAN
project_start_date: 2012-07-16
project_end_date: 2015-12-31
study_section: Special Emphasis Panel[ZRG1-OTC-T(10)B]
contact_pi_person_id: 2081643
contact_pi: SPENCER, WENDY A
other_pis: GUPTA, RAMESH C
congressional_district: 04
department: Unavailable
primary_duns: 831172668
primary_uei: HSCNW2K7VN97
duns_number: 831172668
uei: HSCNW2K7VN97
fips: US
organization_id: 10023330
organization_name: 3P BIOTECHNOLOGIES, INC.
organization_city: PROSPECT
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400598574
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Cervical cancer which is caused by HPV infection is characterized by the progressive formation of dysplastic lesions known as cervical intraepithelial neoplasia (CIN). Although vaccinations for the prevention of cervical cancer have been developed the current vaccine has a high cost targets only two-thirds of HPV strains and is effective only when administered prior to HPV infection. In the U.S. alone 1.2 million cases oflow-grade CIN and 0.2-0.3 million cases of high-grade CIN are diagnosed annually; yet no FDA- approved drug therapies are available for its treatment. For women diagnosed with low-grade CIN the standard approach is "watchful waiting;" women with high-grade CIN are treated with the loop electrosurgical excision procedure (LEEP). Despite this treatment a significant recurrence rate of high-grade CIN occurs. What is needed is a medical treatment option for resolving these lesions during the early stages of CIN.  Project Goal and Technological Innovation. This project will develop continuous-release implants containing a natural compound - specifically withaferin A - for the prophylactic treatment of high-risk patients with cervical cancer and other cervical pathologies. The implant to be used at the target site promises a significant advance in cancer prevention and treatment. Natural compounds administered orally are often accompanied by limited bioavailability while chemotherapeutics administered intravenously result in undesirable large spikes in the blood. The development of polymeric implants to provide continuous delivery of therapeutic agents directly to the target sitewould substantially lower its effective dose and minimize toxicity concerns generally associated with high oral and i. v. doses.  The main objective of this project is to optimize polymeric implants ("cervical inserts") for continuous ("24/7") release of withaferin A at the target site (ie. the cervix) using a large animal model the goat. The studies described represent the necessary pre-clinical efforts to examine potential toxicity and rate of release of withaferin A from the cervical implants. In addition the concept of continuous local delivery of cancer chemopreventives is a novel and innovative concept that has the potential to revolutionize the clinical management of high-risk individuals. The new patient-friendly device would be an economic treatment. Furthermore prophylactic treatment with natural compounds delivered locally may obviate the need for LEEP. The implant delivery device is currently under a pending patent with one of the PIs (Dr. Gupta) as the inventor.  Hypothesis and Specific Aims. We hypothesize that withaferin A a triterpenoid which has no known toxicity and has significant antiproliferative and anti-viral activities against human cervical cancer cells in vitro and in viv when embedded in polymeric implants will be released continuously at the target site for extended periods and that no tissue or systemic toxicity associated with either the drug or the polymeric materials will be produced. The specific aims are to (1) optimize the formulation of polymeric cervical inserts and determine rate of drug release in vitro; and (2) using a large animal (goat) model determine the rate of drug release from cervical inserts any systemic and tissue toxicity and the levels of the drug in plasma and local surrounding and distal tissues. Future efforts will involve examining still longer-term drug release and potential longer-term or delayed toxicity obtaining FDA approval and conducting a clinical trial with cervical dysplasia patients.

project_terms:
Affect;Animal Model;Animals;Ashwagandha;Biological Availability;Biopsy;Blood;Breast;Cancer cell line;Cancerous;Cervical;Cervical Intraepithelial Neoplasia;Cervical dysplasia;Cervix Neoplasms;Cervix Uteri;Cessation of life;Chemopreventive Agent;Clinical Management;Clinical Research;Clinical Trials;Data;Data Analyses;Development;Devices;Diagnosis;Distal;Dose;Drug Delivery Systems;Drug Formulations;Dysplasia;Economics;Excision;Exhibits;FDA approved;Future;Goals;Goat;Hormones;Human;Human Papillomavirus;Human papilloma virus infection;Implant;In Vitro;Individual;Intravenous;Legal patent;Lesion;Loop electrosurgical excision procedure;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Measures;Medical;Medicinal Plants;Modeling;Mortality Vital Statistics;Operative Surgical Procedures;Oral;Organ;Pancreas;Pathology;Patient observation;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase;Pilot Projects;Plants;Plasma;Preparation;Procedures;Prophylactic treatment;Prostate;Reaction;Recurrence;Reporting;Research;Research Project Grants;Site;Spermatocidal Agents;Staging;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Toxic effect;United States;Vaccination;Vaccines;Vagina;Viral;Viral Physiology;Vulva;Withania;Woman;Work;anticancer activity;cancer cell;cancer prevention;cancer therapy;cervical cancer prevention;commercial application;controlled release;cost;high risk;implant material;implantation;in vivo;innovation;malignant breast neoplasm;meetings;novel;pre-clinical;prevent;screening;targeted delivery;technological innovation;tumor;tumor progression;tumor xenograft

public_health_relevance:
The overall goal of this research project is to develop polymeric cervical implants ("cervical inserts") that can provide continuous release of compounds with therapeutic activity against cervical pre-cancer and cancer directly to the target site. When placed in the cervix these implants can deliver drugs continuously ("24/7") for months potentially obviate the need for electrosurgical excision of pre-cancerous lesions and ultimately prevent the development of cervical cancer. This prophylactic treatment will benefit hundreds of thousands of women in the United States alone who otherwise would require a surgical procedure. Worldwide the benefits of this approach will be far greater because cervical cancer is the second most common cancer among women after breast cancer. In this pilot project we will optimize cervical inserts and assess any potential toxicity associated with both the implant materials and with a naturally-occurring compound (withaferin A) with potent anticancer activity against cervical pre-cancer/cancer using a large animal (goat) model.


application_id: 8510878
project_number: 1R21AG042699-01A1
project_title: Cyclic compressive loading to negate atrophy and impaired regrowth in aged muscle
administering_ic: NIA
award_notice_date: 2013-05-28
opportunity_number: PAS-11-280
application_type: 1
activity_code: R21
ic: AG
serial_number: 042699
suffix: A1
program_official: WILLIAMS, JOHN
project_start_date: 2013-06-01
project_end_date: 2015-05-31
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
other_pis: BUTTERFIELD, TIMOTHY ALAN
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Aging is associated with a decreased ability to recover muscle mass and strength after periods of inactivity to which elderly are often subjected resulting in frailty and functional dependence. Skeletal muscle is not only critically important for the development of force but also serves as a major protein reservoir and is an important predictor of mobility susceptibility to injury and mortality. Therefore it is criticaly important to design interventions to attenuate the decrease in muscle size during periods of disuse and to aid in the regrowth of atrophied muscle. Underlying mechanisms for the diminished capacity of muscle to regrow after disuse in the elderly are still largely unknown but could be related to alterations in the inflammatory processes associated with recovery from atrophy. Massage therapy is used in clinical settings to aid in the repair of inflammatory conditions in muscles and we have found that massage in the form of cyclic compressive loading (CCL) positively modulates the immune response in muscle and aids in the repair of muscle injury and restoration of function in young animals. However the effect of massage therapy on muscle atrophy and regrowth in the aged is completely unexplored. Therefore we hypothesize that CCL is beneficial for the maintenance of muscle size during disuse-induced atrophy and will improve the impaired regrowth response in aged rats. We will investigate this hypothesis with two specific aims. In Aim 1 we hypothesize that CLL attenuates muscle mass lost during disuse-induced atrophy through actions on protein turnover pathways. Male Fischer 344/Brown Norway rats at 10 and 30 months of age will be hind limb suspended for 14 days to induce atrophy. CCL will be applied at two different loads in different groups of rats to gastrocnemius muscles of one leg during hind limb suspension. Changes in muscle size protein synthesis markers of muscle protein synthesis and degradation and force generating capacity will be measured. In Aim 2 we hypothesize that CCL will improve regrowth of muscle in aged rats through its immunomodulatory actions. Rats at 10 and 30 months of age will be hindlimb suspended for 14 days followed by ambulation for 1 2 4 or 14 days. CCL will be applied at two different loads to gastrocnemius muscle of one leg starting immediately after reambulation to assess the effect of CCL on recovery of muscle size after atrophy. Muscles will be assessed for size immune cell infiltration degradation and regeneration and protein synthesis and degradation markers as well as force generating capacity. The experiments proposed in this application will indicate whether massage therapy is beneficial for muscle maintenance in general and muscle size and strength restoration in the aged in particular. The age- associated diminished capacity to recover muscle mass lost during disuse is of great clinical importance and it is critically important to develop strategies that can prevent inactivity-induced atrophy or
aid in the recovery of muscle mass lost during disuse. If our results prove beneficial massage can be directly applied clinically for the maintenance and restoration of muscle size and strength.

project_terms:
Activities of Daily Living;Address;Age;Age-Months;Aging;Animals;Atrophic;Attenuated;Cells;Cellular Infiltration;Clinical;Data;Dependence;Development;Disease;Elderly;Energy Metabolism;Exercise;Exhibits;Frequencies (time pattern);Gastrocnemius muscle structure;Goals;Hindlimb;Immune;Immune response;Infiltration;Inflammatory;Inflammatory Response;Injury;Intervention;Leg;Limb structure;Maintenance;Massage;Measures;Modeling;Mortality Vital Statistics;Muscle;Muscle Proteins;Muscle function;Muscular Atrophy;NIH Program Announcements;Natural regeneration;Necrosis;Operative Surgical Procedures;Pathway interactions;Predisposition;Preventive Intervention;Process;Protein Biosynthesis;Proteins;Rattus;Rattus norvegicus;Recovery;Research;Signal Pathway;Skeletal muscle structure;Suspension substance;Suspensions;Testing;Time;Translating;age related;aged;clinical practice;frailty;improved;juvenile animal;male;muscle aging;muscle form;muscle strength;novel;prevent;protein degradation;public health relevance;repaired;research study;response;restoration;sarcopenia;therapy design

public_health_relevance:
Elderly exhibit a decreased ability to recover muscle mass and strength after periods of inactivity which can result in frailty and functional dependence. Thi research application proposes the use of massage to decrease muscle atrophy during disuse and to increase the ability to regrow muscle size after inactivity in the aged in a rat model. If or results prove beneficial massage can be directly applied clinically for the maintenance and restoration of muscle size and strength.


application_id: 8510829
project_number: 1R21NS079960-01A1
project_title: Neuronal Regeneration of Stroked Brain with Perlecan Domain V
administering_ic: NINDS
award_notice_date: 2013-03-22
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: NS
serial_number: 079960
suffix: A1
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
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;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: 8510539
project_number: 5R01AG033649-05
project_title: Metabolic syndrome and hippocampal Ca2+ dysregulation in aging memory decline
administering_ic: NIA
award_notice_date: 2013-07-11
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 033649
program_official: PETANCESKA, SUZANA
project_start_date: 2009-08-01
project_end_date: 2015-03-31
study_section: Neurobiology of Learning and Memory Study Section[LAM]
contact_pi_person_id: 8361727
contact_pi: THIBAULT, OLIVIER
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Increasing epidemiological and experimental evidence shows that factors associated with metabolic syndrome including glucose dysregulation insulin insensitivity and/or obesity are linked to cognitive decline in aging. Moreover the incidence of obesity and metabolic syndrome are approaching epidemic proportions. The thiazolidinediones (TZD) selective peroxisome proliferator-activated receptor-gamma (PPAR3) agonists improve several aspects of metabolic syndrome including lowering insulin resistance glucose and cholesterol levels in Type 2 diabetics and have also been linked to decreased inflammation and 2-amyloid load in models of Alzheimer's disease (AD). However the mechanisms that link peripheral metabolic syndrome to brain dysfunction are still poorly understood and few studies have analyzed these periphery-brain relationships in aged animals. Over the past years we and others have found considerable electrophysiological and imaging evidence that hippocampal Ca2+ dysregulation with aging correlates with cognitive decline. Recently our gene microarray studies also revealed downregulation of hippocampal insulin and glucose signaling that correlated with aging-related memory impairment. Here we will test the working hypothesis that peripheral components of metabolic syndrome induce alterations in Ca2+ homeostasis in the hippocampus by acting on L-type voltage-gated Ca2+ channels (L-VGCCs) NMDARs Ca2+-induced Ca2+ release (CICR) and the Ca2+-dependent afterhyperpolarization (AHP) thereby negatively affecting synaptic plasticity (LTP) and cognitive function. We will also test the hypothesis that these actions are mediated in part by changes in brain insulin/glucose signaling pathways and can be counteracted by TZDs. Specific Aim # 1 will study F344 male rats fed a normal diet and determine at 7-8 and 18-20 months of age which component of metabolic dysregulation most closely associates with measures of cognitive function and hippocampal electrophysiological/imaging function (L-VGCCs NMDARs CICR AHPs and LTP). Specific Aim #2 will test whether diet-induced obesity (DIO) exacerbates neurobiological cognitive gene expression and neuropathological indices of brain aging and whether interventions with TZDs can slow or reverse this process. Specific Aim #3 will analyze the effects of insulin on hippocampal slices testing for direct effects on electrophysiological markers of aging and will test the sub-hypothesis that neurons from aged animals exhibit insulin resistance. Together these multidisciplinary studies will provide one of the first systematic analyses of links between variables contributing to peripheral metabolic syndrome and cellular mechanisms of brain aging. Therefore even if the central hypothesis is rejected the studies proposed will provide more definitive evidence for the impact o metabolic syndrome as well as the actions of TZDs on the brain.

project_terms:
24-thiazolidinedione;Address;Adipose tissue;Affect;Age;Age-Months;Age-associated memory impairment;Aging;Agonist;Alzheimer's Disease;Alzheimer's disease model;Amyloid;Animals;Attenuated;Behavioral;Biological Markers;Brain;Cells;Cholesterol;Clinical;Cognition;Cognitive;Complement;Development;Diabetes Mellitus;Diet;Down-Regulation;Drug usage;Dyslipidemias;Ensure;Epidemic;Epidemiology;Exhibits;Fatty acid glycerol esters;Functional disorder;Gene Expression;Genes;Glucose;Goals;Grant;Health;Hippocampus (Brain);Homeostasis;Hyperglycemia;Hyperinsulinism;Hypertension;Image;Impaired cognition;Inbred F344 Rats;Incidence;Individual;Inflammation;Insulin;Insulin Resistance;Insulin Signaling Pathway;Intervention;Learning;Link;Longitudinal Studies;Measures;Mediating;Memory;Memory impairment;Metabolic;Metabolic Brain Diseases;Metabolic Marker;Metabolic Pathway;Metabolic syndrome;Monitor;Mouse Strains;N-Methyl-D-Aspartate Receptors;Neurobiology;Neurons;Obesity;Obesity associated disease;Outcome Measure;PPAR gamma;Pathway interactions;Patients;Peripheral;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Pioglitazone;Process;Rattus;Regulation;Reporting;Research;Resistance;Rodent;Rodent Model;Series;Short-Term Memory;Signal Pathway;Signal Transduction;Slice;Societies;Synaptic plasticity;Techniques;Testing;Thiazolidinediones;Time;Tissue Sample;Tissues;Vascular Diseases;Work;age effect;age related;aged;aging brain;aging gene;brain cell;cognitive function;cytokine;diabetic;direct application;feeding;glycemic control;improved;indexing;insulin sensitivity;insulin signaling;male;multidisciplinary;new therapeutic target;normal aging;prevent;public health medicine (field);research study;response;voltage

public_health_relevance:
Metabolic syndrome and diabetes are age- and obesity-related diseases that are rapidly approaching epidemic proportions in our society. Recent studies indicate that there may be a link between metabolic syndrome and cognitive decline. The underlying mechanisms through which individual components of peripheral metabolic dysregulation can negatively impact brain function are not known. Our research will identify new links between brain aging diabetes and obesity. If successful our project could impact public health by providing strong clues to help identify novel therapeutic targets and prevent cognitive decline in aging.


application_id: 8510379
project_number: 5F31AA021028-02
project_title: Redundant Signal Effect and Alcohol Impairment of Behavioral Inhibition in ADHD
administering_ic: NIAAA
award_notice_date: 2013-06-28
opportunity_number: PA-11-111
application_type: 5
activity_code: F31
ic: AA
serial_number: 021028
program_official: WITT, ELLEN
project_start_date: 2012-07-01
project_end_date: 2014-06-30
study_section: Epidemiology, Prevention and Behavior Research Study Section[AA-2]
contact_pi_person_id: 10629876
contact_pi: MILLER, MELISSA A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcohol has been reliably shown to impair performance on a wide range of behaviors relevant for everyday activities. This impairment is especially pronounced in environments that require dividing attention across multiple stimuli. However under certain circumstances the presentation of multiple stimuli can actually facilitate performance. The redundant signal effect refers to the phenomenon by which individuals respond  more quickly and accurately when information is presented as redundant bimodal stimuli (e.g. visually and  aurally) rather than as a single stimulus presented to either modalit alone. Moreover recent research has shown that the presence of redundant stimuli can reduce alcohol's impairing effects on the ability to execute responses. What is not known however is whether the presence of redundant inhibitory signals might reduce alcohol's impairing effects on inhibitory control. Alcohol is well-known for its disinhibiting effects on behavior and studies suggest that impaired inhibition might contribute to alcohol abuse by promoting excessive binge drinking. Therefore it is important to determine the degree to which redundant inhibitory signals reduce the effects of alcohol on inhibitory control. Moreover it is also important to determine th degree to which these signals might improve inhibitory control in individuals at-risk for alcohol abuse such as those characterized by chronic deficits in the ability to inhibit behavior such as those with attention deficit/hyperactivity disorder (ADHD). The proposed research will examine the effects of redundant inhibitory signals on inhibitory control in individuals with ADHD and a comparison group of healthy adults. Moreover the project will determine the degree to which redundant inhibitory signals reduce the disinhibiting effects of alcohol in these two groups.  Given that everyday perception is multisensory the present study provides a unique model of drinkers realworld environments by assessing alcohol's effects on inhibitory mechanisms of behavior in response to multisensory stimuli.

project_terms:
Accounting;Adult;Alcohol abuse;Alcohols;Attention;Attention deficit hyperactivity disorder;Auditory;Behavior;Behavior Control;Behavioral;Behavioral inhibition;Characteristics;Chronic;Clinical;Disease;Drug abuse;Drug usage;Environment;Impairment;Individual;Laboratories;Modality;Modeling;Participant;Perception;Performance;Pharmaceutical Preparations;Population;Reaction Time;Research;Risk;Sensory;Signal Transduction;Stimulus;Testing;Visual;Work;alcohol and other drug;alcohol effect;auditory stimulus;binge drinking;clinical application;comparison group;disinhibitory psychopathology;drinking behavior;improved;multisensory;novel;response;sobriety;visual information;young adult

public_health_relevance:
Alcohol is known for its disinhibiting effects on behavior which is thought to contribute to excessive binge drinking and some clinical populations (i.e. individuals with ADHD) have been identified as being particularly sensitive to the disinhibiting effects of alcohol increasing their risk for alcohol abuse. The present study will examine the degree to which redundant inhibitory signals (signals presented both visually and aurally) can reduce alcohol's impairing effects on the ability to inhibit behavior. The project will provide a novel highly useful model to investigate how alcohol effects on inhibitory control might be altered in contexts that involve redundant inhibitory signals.


application_id: 8509554
project_number: 5R01AA018869-05
project_title: Cyclic AMP Cytokine Modulation and Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2013-08-12
opportunity_number: RFA-AA-09-006
application_type: 5
activity_code: R01
ic: AA
serial_number: 018869
program_official: WANG, JOE
project_start_date: 2009-09-20
project_end_date: 2015-08-31
study_section: ZAA1-JJ(06)
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcoholic Liver Disease (ALD) remains a leading cause of liver-related deaths in the U.S. and there is still no FDA-approved therapy. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentrations of tumor necrosis factor (TNF) and TNF-inducible proinflammatory cytokines/chemokines such as IL-8 and IL-18 have been reported in patients with alcoholic hepatitis and/or cirrhosis and levels correlated with markers of the acute phase response liver function and clinical outcome. Similarly there are depressed levels of the critical anti-inflammatory cytokine IL-10. Studies in animal models support an etiologic role for cytokines in the liver injury of ALD. The major problem to be investigated in this proposal is the mechanism(s) for this dysregulated cytokine metabolism and our overall goal is the development of novel therapeutic interventions. ALD is associated with an increase in oxidative stress with a concomitant decrease in cellular antioxidants such as glutathione (GSH) and importantly S-adenosyl-L-methionine (SAM) due to subnormal synthesis. Clinical studies have suggested that SAM has beneficial effects in many hepatic disorders including ALD and numerous animal studies have clearly demonstrated the protective effects of SAM against a variety of hepatotoxins. Previous studies from our group evaluated the role of SAM in positively modulating endotoxin (LPS)-stimulated TNF and IL-10 production related to ALD. We showed that SAM decreased LPS stimulated TNF production and increased LPS stimulated IL-10 production and that SAM increased cellular levels of cyclic AMP (cAMP) which is known to positively modulate cytokine production. We therefore began an evaluation of the role of cAMP in dysregulated cytokine production in ALD which is the research focus of this current proposal. We present compelling preliminary data that cAMP is decreased in a macrophage cell line chronically cultured in alcohol and in Kupffer cells from mice chronically fed ethanol intragastrically. Our working hypothesis is that altered phosphodiesterase 4B (PDE4B) and cAMP metabolism cause abnormal TNF and IL-10 metabolism which play a critical role in the development and perpetuation of ALD. Specific Objectives for this proposal are to: 1. Document increased PDE4B expression/activity and decreased cAMP in peripheral blood monocytes from patients with alcoholic hepatitis (AH) and alcoholic cirrhosis and evaluate whether in vitro incubation of monocytes with specific phosphodiesterase inhibitors corrects dysregulated cAMP and cytokine metabolism; 2. Determine whether PDE4 (and specifically PDE4B) inhibition blocks the development of alcohol-induced liver injury in a murine intra-gastric ethanol-feeding model of chronic ALD and in a murine model of AH; 3. Evaluate potential molecular and epigenetic mechanisms whereby cAMP metabolism is altered in alcoholic liver disease; and 4. Evaluate the effects of combined consumption of a commercially- available adenyl cyclase agonist (Misoprostol - increases cAMP production) and a phosphodiesterase inhibitor (Pentoxyfilline - decreases cAMP breakdown) in normal volunteers and in patients with stable alcoholic cirrhosis.    PUBLIC HEALTH RELEVANCE: Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S. and there is still no FDA-approved therapy. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentration levels of tumor necrosis factor (TNF) and TNF-inducible proinflammatory cytokines/chemokines such as IL-8 and IL-18 have been reported in patients with alcoholic hepatitis and/or cirrhosis and levels correlated with markers of the acute phase response liver function and clinical outcome. Similarly there are depressed levels of the critical anti-inflammatory cytokine IL-10. Studies in animal models support an etiologic role for cytokines in the liver injury of ALD. The major problem to be investigated in this proposal is the mechanism(s) for this dysregulated cytokine metabolism and our overall goal is the development of novel therapeutic interventions.

project_terms:
Acute-Phase Reaction;Adenylate Cyclase;Agonist;Alcoholic Hepatitis;Alcoholic Liver Cirrhosis;Alcoholic Liver Diseases;Alcohols;Animal Model;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Attenuated;Biological Models;Cause of Death;Cell Line;Cessation of life;Chronic;Cirrhosis;Clinical;Clinical Research;Consumption;Cyclic AMP;Data;Depressed mood;Development;Disease;Disease model;Endotoxins;Epigenetic Process;Ethanol;Evaluation;FDA approved;Glutathione;Goals;Human;IL8 gene;In Vitro;Inflammatory;Interleukin-10;Interleukin-18;Isoenzymes;Knockout Mice;Kupffer Cells;Lipopolysaccharides;Liver;Liver diseases;Mediating;Metabolism;Methionine;Misoprostol;Modeling;Modification;Molecular;Mus;Outcome;Oxidative Stress;PDE4B;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Phosphodiesterase Inhibitors;Play;Process;Production;Rattus;Reporting;Research;Role;Serum;Stomach;System;Therapeutic Intervention;Tumor Necrosis Factor-alpha;Whole Blood;Work;alcohol exposure;animal data;base;bench to bedside;chemokine;cytokine;experience;feeding;hepatotoxin;inhibitor/antagonist;liver function;liver injury;macrophage;monocyte;novel therapeutic intervention;peripheral blood;phosphoric diester hydrolase;protective effect;public health relevance;research study;volunteer

public_health_relevance:
Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in theU.S. and there is still no FDA-approved therapy. Abnormal cytokine metabolism is amajor feature of ALD. Elevated serum concentration levels of tumor necrosis factor(TNF) and TNF-inducible proinflammatory cytokines/chemokines such as IL-8 and IL-18have been reported in patients with alcoholic hepatitis and/or cirrhosis and levelscorrelated with markers of the acute phase response liver function and clinicaloutcome. Similarly there are depressed levels of the critical anti-inflammatory cytokineIL-10. Studies in animal models support an etiologic role for cytokines in the liver injuryof ALD. The major problem to be investigated in this proposal is the mechanism(s) forthis dysregulated cytokine metabolism and our overall goal is the development ofnovel therapeutic interventions.


application_id: 8508902
project_number: 5R21DA031439-02
project_title: Microneedle-enhanced codrug delivery for smoking cessation and appetite suppressi
administering_ic: NIDA
award_notice_date: 2013-04-16
opportunity_number: PA-10-069
application_type: 5
activity_code: R21
ic: DA
serial_number: 031439
program_official: PARK, MOO KWANG
project_start_date: 2012-07-15
project_end_date: 2014-06-30
study_section: Gene and Drug Delivery Systems Study Section[GDD]
contact_pi_person_id: 1866585
contact_pi: STINCHCOMB, AUDRA L.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178031683
primary_uei: EKBZRSBPS8A3
duns_number: 178031683
uei: EKBZRSBPS8A3
fips: US
organization_id: 10006751
organization_name: ALLTRANZ, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Tobacco addiction is a multi-factorial process regulated by a number of pharmacological and physiological effects of tobacco smoke exposure. In addition to the well-known effects of tobacco derived nicotine on brain dopaminergic systems other secondary reinforcers such as body mass regulation are also involved with the compulsive tobacco use. Cigarette smoking is known to reduce appetite and increase the rate of cellular metabolism leading to body mass stabilization or reduction. Current smoking cessation treatments fail in up to 70% of cases for a variety of individualized reasons. One of the main reasons for recidivism especially in females is the potential for weight gain. The problem of weight gain during smoking cessation is well documented and studies consistently recommend incorporation of body weight management strategies to patient management plans. The proposed studies will use a novel microneedle-enhanced transdermal codrug delivery approach to test a new pharmacological approach that we hypothesize will enhance smoking cessation efforts. Bupropion is considered a first-line treatment for smoking cessation but the efficacy of this drug is relatively low. Hydroxybupropion (BUPOH) is an active metabolite of bupropion that may have significant drug delivery and therapeutic effect advantages over bupropion including better chemical stability reduced metabolic drug interaction potential and an equal or higher potency at relevant drug targets. BUPOH itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. Microneedle-enhanced transdermal delivery is an efficient and painless method for increasing the skin permeation of many drugs. The proposed studies will test whether chemical modification optimization of the BUPOH codrug will enhance its microneedle-assisted skin permeation making it suitable for transdermal delivery. Hydroxybupropion will be chemically combined with phentermine (PHEN) a widely used appetite suppressant. PHEN should have a more tolerable side-effect profile if delivered at a constant rate through transdermal delivery. We hypothesize that a transdermal codrug (mutual prodrug or hybrid drug) of PHEN linked to the smoking cessation drug BUPOH will make an effective microneedle-enhanced transdermal pharmacotherapy for smoking cessation and weight loss. The specific aims of this project are to: 1 - synthesize a series of PHEN and BUPOH codrugs designed to elucidate quantitative structure-permeability relationships (QSPR) for microneedle-enhanced transdermal flux and subsequent bioconversion rates. 2 - to measure the drugs' penetration and concurrent bioconversion in skin in vitro with microneedle use and 3 - to characterize the pharmacokinetics of the drugs in guinea pigs in vivo with microneedle use. Correlation of our in vitro data with the in vivo model will aid in the creation of a reliable QSPRdatabase for transdermal codrugs with microneedle use as well as help to identify the most promising codrug/microneedle system for eventual human use.

project_terms:
6 beta-hydroxynaltrexone;Adjuvant;Adverse effects;Appetite Depressants;Area;Body Weight;Body Weight decreased;Brain;Bupropion;Cancer Etiology;Cardiovascular system;Cavia;Centers for Disease Control and Prevention (U.S.);Cessation of life;Chemicals;Clinical;Comorbidity;Data;Databases;Desire for food;Dose;Drug Delivery Systems;Drug Interactions;Drug Kinetics;Drug Targeting;Female;Heating;Human;Human Volunteers;Hybrids;Hydrogen Bonding;Hydrolysis;In Vitro;Kinetics;Link;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Metabolic;Metabolism;Methods;Modification;Molecular;Naltrexone;Nicotine;Painless;Patients;Penetration;Permeability;Persons;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Phentermine;Physiological;Process;Prodrugs;Property;Recommendation;Regulation;Route;Series;Skin;Smoking;Solubility;Solvents;Structure;Synthesis Chemistry;System;Testing;Therapeutic;Therapeutic Effect;Time;Tobacco;Tobacco Dependence;Tobacco smoke;Tobacco use;Toxicity Tests;Translating;United States;Weight Gain;Weight maintenance regimen;Weight-Loss Drugs;Withholding Treatment;Woman;chemical stability;cigarette smoking;cost effective;design;drug efficacy;improved;in vivo;in vivo Model;increased appetite;lipophilicity;malignant breast neoplasm;melting;novel;premature;recidivism;reinforcer;smoking cessation;water solubility

public_health_relevance:
The leading cause of preventable deaths in the United States is cigarette smoking with over 440000 premature deaths occurring each year. Cigarette smoking is known to reduce appetite and increase the rate of cellular metabolism leading to body mass stabilization or reduction. One of the main reasons for recidivism in persons trying to quit smoking is the potential for weight gain especially in women. Regardless of the varied findings of the many studies on smoking cessation and weight gain the primary recommendation has been to incorporate weight loss treatment with smoking cessation. A transdermal codrug (mutual prodrug or hybrid drug) of the popular weight-loss drug phentermine linked to a smoking cessation drug hydroxybupropion could be the ideal pharmacotherapy for the comorbidity.


application_id: 8508267
project_number: 5R01ES019217-03
project_title: Endothelial Progenitor Cells and Particulate Air Pollution
administering_ic: NIEHS
award_notice_date: 2013-08-20
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: ES
serial_number: 019217
program_official: SCHUG, THADDEUS
project_start_date: 2011-09-23
project_end_date: 2016-04-30
study_section: Special Emphasis Panel[ZRG1-CVRS-C(02)M]
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: BHATNAGAR, ARUNI ;POPE, ARDEN
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:
Acetylcholine;Acute;Admission activity;Adult;Affect;Air;Air Pollution;Animals;Antioxidants;Aorta;Arrhythmia;Atherosclerosis;Automobile Exhaust;Biological Markers;Blood Cells;Blood Pressure;Blood Vessels;Bone Marrow;Breathing;Cardiotoxicity;Cardiovascular Diseases;Cardiovascular Pathology;Cardiovascular system;Cell Count;Cell Death;Cell Survival;Cell physiology;Cells;Cessation of life;Chronic;Coagulation Process;Coal;Defect;Deposition;Development;Endothelium;Epidemiologic Studies;Event;Exposure to;Flow Cytometry;Fossil Fuels;Free Radicals;Functional disorder;Generations;Goals;Health;Heart Arrest;Heart failure;Hematopoietic;Hematopoietic stem cells;Homing;Hospitals;Human;Inflammation;Inflammatory Response;Injury;Intervention;Ischemic Stroke;Lead;Location;Maintenance;Measures;Mediator of activation protein;Mesenchymal Stem Cells;MicroRNAs;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Oxidation-Reduction;Oxidative Stress;Paper;Particulate;Particulate Matter;Plants;Plasma;Population;Reaction;Relaxation;Reporting;Risk;Smoke;Steel;Stem cells;Symptoms;Testing;Thrombosis;Time;Toxic effect;Ultrafine;Unstable angina;Wood material;Wound Healing;air filter;angiogenesis;atherogenesis;base;cardiovascular disorder risk;cardiovascular risk factor;cell growth;human tissue;insight;novel;particle;peripheral blood;prevent;repaired;research study;response;stroke;tissue repair;young adult


application_id: 8508217
project_number: 5R03CA164831-02
project_title: Targeting endocrine resistant breast cancer with anacardic acid
administering_ic: NCI
award_notice_date: 2013-06-24
opportunity_number: PAR-11-079
application_type: 5
activity_code: R03
ic: CA
serial_number: 164831
program_official: SEIFRIED, HAROLD E
project_start_date: 2012-07-10
project_end_date: 2015-06-30
study_section: ZCA1-SRLB-2(M1)
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: SCHULTZ, DAVID
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Dietary phytochemicals are potential sources of new drug leads to prevent breast and other cancers. Nuclear Receptor Alternative Site Modulators (NRAMs) are a recently defined class of chemicals with potential application in preventing breast cancer by blocking estrogen receptor  (ER) function through mechanisms other than blocking ligand activation. NRAMs are distinct from currently used chemopreventives such as selective ER modulators (SERMs e.g. tamoxifen (TAM)) and aromatase inhibitors (AI e.g. letrozole) against which tumor cells become resistant. We recently reported that a purified anacardic acid (AnAc 24:1n-5) inhibited the proliferation of ER-positive/TAM-responsive MCF-7 and ER-positive/endocrine-resistant LCC9 and LY2 breast cancer cells but not primary normal human mammary epithelial cells (HMECs). AnAc 24:1n-5 does not compete with [3H]estradiol (E2) for ER or ER but inhibits ER-DNA interaction and transcriptional activity with greater efficacy than ER. These data indicate that AnAc 24:1n-5 functions as a NRAM. AnAc 24:1n-5 is a congener of AnAc constituents found in caju juice (commonly consumed in Brazil) and thus establishes dietary intake as a relevant route for this potential NRAM. Our breast cancer cell-based work provides strong rationale for the proposed pilot study that addresses PAR-11-079 by 1) Investigating the mechanisms of action of AnAc as an NRAM by utilizing ER overexpression and shRNA knockdown approaches to confirm the specificity of AnAc 24:1n-5 as an NRAM. 2) Pilot testing and developing AnAc as a dietary intervention to prevent or retard carcinogen (NMU)-induced mammary tumors in female Sprague- Dawley (SD) rats. 3) Developing sensitive and reliable methods for analysis of AnAc and its metabolites in serum tumors and tissues. 4) Determining the bioavailability and dose-response of AnAc as "foods nutrients and other naturally-occurring food constituents". The hypotheses tested in these Specific Aims is that 1) AnAc acts as an ER-selective NRAM and 2) that AnAc supplied orally in AIN-93M diet will function as a natural chemopreventive to NMU-induced primary mammary tumors in female SD rats. These studies will provide the first in vivo data regarding the efficacy of AnAc in primary mammary tumor prevention and will establish the serum and tissue levels of AnAc after oral consumption.

project_terms:
Acids;Address;Affect;Anacardic Acids;Androgen Receptor;Animal Model;Aromatase Inhibitors;Binding (Molecular Function);Biological Assay;Biological Availability;Brazil;Breast;Breast Cancer Cell;Breast Cancer Prevention;Cancer Patient;Carcinogens;Cathepsins;Cell Proliferation;Cells;Chemicals;Chemoprevention;Chemopreventive Agent;Computer Simulation;Consumption;DNA;DNA Binding;DNA Binding Domain;Data;Development;Diagnosis;Diet;Dietary Intervention;Dietary Phytochemical;Dietary intake;Disease;Disease Resistance;Dose;Elements;Endocrine;Epithelial Cells;Estradiol;Estrogen Receptor Modulators;Estrogen Receptors;Estrogen receptor positive;Estrogens;Female;Food;Gene Targeting;General Transcription Factors;Genetic Transcription;Glucocorticoid Receptor;Goals;Growth;Histology;Human;Hydrocarbons;In Vitro;Ingestion;Juice;Letrozole;Ligands;Liver neoplasms;MCF7 cell;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mammary gland;Mediating;Methods;Methylnitrosourea;Modeling;Nuclear Receptors;Nutrient;Oral;Outcome Measure;Pathologic;Patients;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Pilot Projects;Postmenopause;Progesterone Receptors;Rattus;Recurrence;Reporting;Resistance;Resources;Response Elements;Route;Selective Estrogen Receptor Modulators;Serum;Site;Small Interfering RNA;Source;Specificity;Sprague-Dawley Rats;Staining method;Stains;Tamoxifen;Testing;Tissues;Tocopherols;Translational Research;Tumor Tissue;Woman;Work;Zinc Fingers;base;cancer risk;human GATA1 protein;in vivo;indexing;malignant breast neoplasm;neoplastic cell;overexpression;physical property;prevent;receptor binding;receptor function;response;small hairpin RNA;transcription factor;tumor;tumor growth

public_health_relevance:
It is estimated that 230480 US women will be diagnosed and 39520 will die from breast cancer in 2011. The two goals of this project are 1) to determine if anacardic acid is a Nuclear Receptor Alternate Site Modulator (NRAM) that specifically inhibits estrogen receptor-DNA binding and 2) to test the ability of anacardic acid supplied dietarily to inhibit the development of NMU-induced mammary tumors in rats. This project the first to test AnAc 25:1n-5 as a NRAM to preventative carcinogen-induced breast cancer in an animal model.


application_id: 8507674
project_number: 5P50DA005312-23
project_title: Individual Differences in Facets of impulsivity: An Animal Model
administering_ic: NIDA
award_notice_date: 2013-06-24
opportunity_number: PAR-10-189
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
study_section: ZDA1-EXL-T
subproject_number: 6588
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2013-07-01
budget_end_date: 2014-06-30
project_terms:
Address;Adolescent;Alcohol or Other Drugs use;Amphetamines;Amygdaloid structure;Animal Model;Basic Science;Behavior;Behavioral;Biological;Brain;Cocaine;Disinhibition;Drug abuse;Drug usage;Electrophysiology (science);Esthesia;Exanthema;Failure (biologic function);Goals;Human;Impulsivity;In Vitro;Individual Differences;Instruction;Intervention;Link;Measures;Mediating;Methylphenidate;Moods;Nicotine;Nucleus Accumbens;Patient Self-Report;Personality;Pharmaceutical Preparations;Population;Prefrontal Cortex;Preventive Intervention;Questionnaires;Rattus;Research Personnel;Risk;Self Administration;Staging;System;Testing;Translating;Translational Research;base;design;discounting;field study;follow-up;human subject;in vivo;instrument;monoamine;neurobehavioral;neurobiological mechanism;neurochemistry;neuromechanism;neuronal patterning;non-drug;pre-clinical;preference;programs;research study;young adult


application_id: 8507670
project_number: 5P50DA005312-23
project_title: CDART - Center for Drug Abuse Research Translation
administering_ic: NIDA
award_notice_date: 2013-06-24
opportunity_number: PAR-10-189
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
program_official: LLOYD, JACQUELINE
project_start_date: 1992-09-30
project_end_date: 2017-06-30
study_section: ZDA1-EXL-T(02)P
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adolescence;Advocate;Amygdaloid structure;Basic Science;Cessation of life;Characteristics;Commit;Communities;Development;Disease;Disinhibition;Drug abuse;Drug usage;Educational workshop;Emotional;Environment;Esthesia;Exanthema;Faculty;Funding;Goals;Health;Health Care Costs;Human;Human Resources;Impulsivity;Individual;Individual Differences;Informal Social Control;Institution;Intake;International;Intervention;Investigation;Laboratories;Laboratory Rat;Leadership;Life;Mediating;Mission;Moods;National Institute of Drug Abuse;Personality;Pharmaceutical Preparations;Positioning Attribute;Prefrontal Cortex;Prevention;Prevention Research;Preventive Intervention;Principal Investigator;Professional Organizations;Psychometrics;Publications;Publishing;Rattus;Relative (related person);Research;Research Institute;Research Personnel;Research Project Grants;Resources;Rewards;Risk;Science;Scientist;Series;Stress;Structure;Techniques;Testing;Training;Translating;Translational Research;Translations;Work;base;design;dopamine system;drug abuse prevention;drug of abuse;efficacy trial;evidence base;improved;innovation;interdisciplinary collaboration;intervention program;mindfulness;neurobehavioral;neurochemistry;neuroimaging;neuromechanism;next generation;novel;outreach;programs;psychologic;psychosocial;public health medicine (field);public health relevance;relating to nervous system;response;social;statistics;substance use prevention;symposium;university student;young adult

public_health_relevance:
This research is relevant to public health because drug abuse continues to be a major preventable disorder. Intervening early in life prior to the beginning of dysfunctional drug intake would have life-long positive health consequences thus reducing health costs and the likelihood of early death.    
   
CENTERS CHARACTERISTICS:


application_id: 8507646
project_number: 5R03CA165086-02
project_title: Maternal Exercise Enhances Cancer Protection in Offspring
administering_ic: NCI
award_notice_date: 2013-07-02
opportunity_number: PAR-11-079
application_type: 5
activity_code: R03
ic: CA
serial_number: 165086
program_official: RISCUTA, GABRIELA
project_start_date: 2012-07-09
project_end_date: 2015-06-30
study_section: ZCA1-SRLB-2(M1)
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  To date caloric restriction has shown itself to be the most reproducible and promising intervention to improve cancer outcomes in laboratory animals. An intense and expanding area of research is focused on discovering easily achievable interventions that can have long-lasting positive effects. This proposal will explore maternal exercise during pregnancy as a potential short-term intervention that can provide a lifetime of benefits for the next generation. In a small pilot study in mice offspring born to exercised dams had improved glucose regulation and enhanced stress protection compared to offspring born to sedentary dams. These preliminary findings contribute to the hypothesis that maternal exercise during pregnancy and nursing protects mature offspring against chemical carcinogens because of increased activities of antioxidant enzymes. The first aim is designed to test whether maternal exercise during pregnancy is a realistic intervention that can protect mature offspring from chemical carcinogens. The second aim will look to elucidate the role of the stress-induced transcription factor nuclear factor erythroid-2 related factor 2 as a potential mechanism for long-lasting protection by perinatal exercise. These studies will provide important information on the potential positive impact maternal exercise may have on offspring cancer protection.

project_terms:
910-Dimethyl-12-benzanthracene;Acetates;Adopted;Adult Children;Anthracenes;Antioxidants;Area;Behavior;Binding (Molecular Function);Birth;Breeding;Caloric Restriction;Carcinogens;Cardiovascular Diseases;Cells;Chemicals;Commit;Development;Diabetes Mellitus;Diet;Discipline of Nursing;Drug Metabolic Detoxication;Enzymes;Epidemic;Exercise;Female;Future;Gene Targeting;Generations;Genetic Transcription;Goals;Health;Home environment;Housing;Inbred ICR Mice;Intervention;Laboratory Animals;Litter Size;Liver;Malignant Neoplasms;Measures;Modeling;Mus;Neonatal;Obesity;Outcome;Oxidative Stress;Papilloma;Parents;Partner in relationship;Pathway interactions;Perinatal;Phorbol;Phorbols;Pilot Projects;Pregnancy;Probability;Proteins;Research;Resistance;Response Elements;Role;Running;Signal Transduction;Skin;Skin Tissue;Staging;Stress;Testing;Topical application;Tumor Promoters;Ultraviolet Rays;Very Light Exercise;biological adaptation to stress;blood glucose regulation;carcinogenesis;chemical carcinogen;design;improved;keratinocyte;male;melanocyte;neglect;next generation;novel;nuclear factor-erythroid 2;offspring;response;sedentary;transcription factor;trend;tumor;unborn child

public_health_relevance:
The benefits of exercise have been studied extensively but the effects of maternal exercise during pregnancy on long-term outcomes in offspring have been neglected. The goal is to use maternal exercise in mice as an intervention to increase cancer protection in the offspring through increased activity of antioxidant enzymes.


application_id: 8507589
project_number: 5R01AG039732-03
project_title: The Role of Adipose Tissue in Age-dependent Sensitivity to Critical Illness
administering_ic: NIA
award_notice_date: 2013-07-25
opportunity_number: PA-10-042
application_type: 5
activity_code: R01
ic: AG
serial_number: 039732
program_official: FRANKOWSKI, DAVID WITT
project_start_date: 2011-08-01
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1-BDCN-M(02)M]
contact_pi_person_id: 8163817
contact_pi: SAITO, HIROSHI
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Aging is characterized by an altered stress response that underlies a compromised resistance to disease or injury. Activation of inflammatory and coagulant pathways is a frequent consequence of severe critical illnesses and results in the progression of systemic inflammatory response syndrome (SIRS). Recent evidence suggests that adipose tissue-derived signaling proteins including cytokines coagulation factors and hormones may play an important role in the inflammatory response. Our long-term goals are to identify the mechanisms by which adipose tissue contributes to age-dependent severity of SIRS and to develop therapeutic strategies for decreasing vulnerability to critical illnesses in the aged. For these studies we will use two widely accepted mouse models of SIRS - acute endotoxemia induced by injection with bacterial endotoxin lipopolysaccharide and an intra-abdominal sepsis model induced by cecal ligation and puncture. The objective of this project is to identify and evaluate the expression of adipose-derived inflammatory and coagulant factors that differ by aging upon inflammatory stress. Our central hypothesis is that expression patterns of inflammatory / coagulant factors in the adipose tissue during SIRS are significantly altered by aging and that this alteration contributes to age-dependent severity of critical illnesses. To achieve the above goals we will pursue the following three specific aims: (1) To define the role of adipose tissue in age-related alterations of coagulation during critical illness. (2) To understand the mechanisms of age-related inflammatory cytokine production in the adipose tissue during critical illness. (3) To evaluate methods of body fat loss as potential therapies and preventative measures for reducing severity of critical illness in the aged. These studies will provide significant insight into the association of the previously neglected adipose organ in aging and critical illness.

project_terms:
Abbreviations;Acute;Adipose tissue;Age;Age Reporting;Aging;Animal Model;Blood Coagulation Factor;Body fat;Burn Trauma;Cessation of life;Coagulants;Coagulation Process;Complication;Critical Illness;Death Rate;Development;Disease Resistance;Disseminated Intravascular Coagulation;Elderly;Endotoxemia;Endotoxins;Excision;Foundations;Functional disorder;Gene Chips;Genes;Genetic;Goals;Growth Factor;Health Care Costs;Hormones;In Vitro;Incidence;Inflammation;Inflammatory;Inflammatory Response;Injection of therapeutic agent;Injury;Interleukin-1 Receptors;Interleukin-6;Intra-abdominal;Knockout Mice;Ligation;Link;Lipopolysaccharides;Lung;Measures;Mediating;Mediator of activation protein;Methods;Modeling;Mortality Vital Statistics;Mus;Operative Surgical Procedures;Organ;Organ Culture Techniques;Pathway interactions;Patients;Pattern;Plasminogen Activator Inhibitor 1;Plasminogen Activator Inhibitor 2;Plasminogen Inactivators;Play;Predisposition;Preventive;Process;Production;Puncture procedure;Role;Sepsis;Sepsis Syndrome;Severities;Signaling Protein;Source;Stress;System;TNF gene;Testing;Therapeutic;Thromboplastin;Thrombosis;Transgenic Organisms;Transplantation;Visceral;Visit;Wild Type Mouse;acute pancreatitis;age related;aged;biological adaptation to stress;cytokine;dietary restriction;effective therapy;improved;insight;middle age;mouse model;mutant;neglect;older patient;public health medicine (field);research study;therapy development

public_health_relevance:
This project is relevant to public health because it will enhance our understanding of the roles of adipose tissue in increased severity of critical illness in the elderly. This project will also provide information for the development of treatments and preventative therapies to decrease incidence rates and deaths related to critical illness in the aged. Preventative therapies will likely result in reduced patient visits and decreased health care costs. The development of effective treatments for systemic inflammation of which there are currently none available will be beneficial to elderly patients who suffer from critical illnesses.


application_id: 8505521
project_number: 5R44HD065388-03
project_title: FastFES Neural Prothesis for Stroke Ambulation and Rehabilitation
administering_ic: NICHD
award_notice_date: 2013-06-25
opportunity_number: PA-10-050
application_type: 5
activity_code: R44
ic: HD
serial_number: 065388
program_official: CRUZ, THERESA
project_start_date: 2011-04-01
project_end_date: 2015-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-F(15)B]
contact_pi_person_id: 7771781
contact_pi: HARTMAN, ERIC C
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 129360637
duns_number: 129360637
fips: US
organization_id: 4168101
organization_name: CUSTOMKYNETICS, INC.
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403401290
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2013-07-01
budget_end_date: 2015-06-30
project_abstract:
DESCRIPTION (provided by applicant):  This FastTrack SBIR proposal aims to disseminate a Functional Electrical Stimulation (FES) technology for stroke ambulation and neuromotor rehabilitation. The FastFES paradigm integrates two rehabilitation approaches fast-paced treadmill walking and FES in a manner that has been shown to both improve gait kinematics when the stimulation is active and to improve performance in clinical tasks with long-term intervention. Precisely timed FES patterns provide: 1) a plantarflexion (PF) assist effect during the terminal double-stance phase of gait; and 2) a dorsiflexion (DF) assist effect during the swing phase. Compared to commercially available DF-only systems the FastFES device will provide improved paretic leg ground reaction forces during push-off as a result of the PF stimulation pattern. This will act to propel the paretic leg through the swing phase of the gait cycle and thus provide more normal gait kinematics. The technology has been developed at the University of Delaware in the laboratory of Dr. Stuart Binder-Macleod PT PhD. The FastFES system will include a leg-worn stimulator that is wirelessly coupled to an instrumented footswitch system. Instrumentation will provide robust and reliable gait cycle measurements to facilitate coordination of the complex FES patterns to the client's volitional gait. A clinician configuration pendant will allow clinicians to program advanced features of the device and to manage multiple users in a clinical environment. The device will also record gait cycle data to summarize its use and to aid the clinician in assessing the device's effectiveness for a particular client. The Phase I project will prove concept feasibility by demonstrating that customKYnetics' stimulator can implement the FastFES's variable frequency train (VFT) stimulation pattern such that contractions of human skeletal muscle are of comparable quality to those produced by the laboratory stimulator. The Phase II project will involve significant engineering efforts to develop the commercialization-ready system and will include a validation study at UD in which individuals with paresis secondary to a stroke iteratively evaluate device prototypes. Efficacy will be demonstrated through a long-term single-blinded randomized controlled clinical intervention study. Outcomes will include kinematic assessment of the client's gait pattern (with and without stim) and assessments of changes in clinical function. The target market for the device will be rehabilitation clinics that serve the stroke market. The device will also be suitable for home/community-use. The product will provide clear differentiation over existing products in the space. The target price for a clinical system will be $5000. The addressable market is estimated at 10000 units for a clinical system and at least 500000 units for a home system.

project_terms:
Award;Biomechanics;Blinded;Client;Clinic;Clinical;Communities;Complex;Coupled;Data;Delaware;Development;Devices;Doctor of Philosophy;Effectiveness;Electric Stimulation;Engineering;Environment;Frequencies (time pattern);Gait;Health;Health Benefit;Hemipareses;Home environment;Human;Individual;Intervention;Intervention Studies;Knee;Laboratories;Leg;Marketing;Measurement;Measures;Muscle;National Institute of Nursing Research;Outcome;Paresis;Pattern;Performance;Phase;Poaceae;Positioning Attribute;Price;Quadriceps Muscle of the Thigh;Randomized;Reaction;Rehabilitation therapy;Research Infrastructure;Secondary to;Shoes;Skeletal muscle structure;Small Business Innovation Research Grant;System;Technology;Time;TimeLine;Training;Universities;Walking;Work;base;commercialization;cost;design;improved;instrument;instrumentation;kinematics;neural prosthesis;novel;programs;prototype;relating to nervous system;stroke;stroke rehabilitation;validation studies;volunteer

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  The proposed work may benefit health through development of a functional electrical stimulation system indicated for ambulation and neuromotor rehabilitation following stroke (795000 cases per year). Due to the novel combination of plantarflexion and dorsiflexion stimulation during ambulation the proposed FastFES system may provide improved leg ground reaction forces and provide more normal gait kinematics.


application_id: 8505438
project_number: 5R01DA018822-08
project_title: Gated Carbon Nanotube Membrane Transdermal Drug Delivery
administering_ic: NIDA
award_notice_date: 2013-06-19
application_type: 5
activity_code: R01
ic: DA
serial_number: 018822
program_official: POLLOCK, JONATHAN D
project_start_date: 2006-09-30
project_end_date: 2014-06-30
study_section: Gene and Drug Delivery Systems Study Section[GDD]
contact_pi_person_id: 7929219
contact_pi: HINDS, BRUCE JACKSON
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2013-07-01
project_abstract:
DESCRIPTION (provided by applicant): Nicotine fentanyl and clonidine are established transdermal drug therapies that could be substantially improved using programmable variable drug delivery rates. With the development of a membrane that can be turned on or off with applied electrical bias simple electronics can be employed to provide a well controlled dosing regimen and create a security/safety feature for patch activation only when the electronic device is present. Transdermal nicotine therapy could be enhanced by creating nicotine plasma levels more similar to smokers' plasma levels with a decreased incidence of cigarette craving. Clonidine therapy could be programmed for a slow dosage rate increase and then a slow dosage rate decrease compatible with opiate withdrawal treatment. Transdermal fentanyl therapy could be improved by allowing a flexible dosage regimen for noninvasive patient controlled analgesia with added safety and security features. Recently we have developed a method to form a permeable membrane based on the hollow cores of carbon-nanotubes (CNT) passing perpendicularly through a polymer film. These inner-cores are 7.5-nm in diameter with carboxylate groups only at the ends of the CNTs. Since the CNT is electrically conductive while polystyrene film is insulating it would be possible to draw a charged molecule into the CNT core with an applied bias. By chemically functionalizing the tip of the CNT cores with sulfonated terminated ligands that will block/open the core with an applied bias dynamic delivery rates can be utilized for transdermal delivery. An electrically gated membrane could have broad applications in numerous drug delivery systems with production costs for membranes anticipated to be about $0.20/sq.ft. This membrane would also be expected to have minimal skin irritation potential as compared to iontophoresis the current non-invasive programmable drug delivery method that could eventually compete with this system on the market. We hypothesize that three non-invasive programmable transdermal drug delivery systems can be successfully developed using CNT membranes combined with an applied electrical bias. The following specific aims should result in the development of three prototype drug delivery systems with improved therapeutic characteristics for smoking cessation opiate withdrawal and chronic pain treatment. Specific Aim 1: to quantify the nicotine fentanyl and clonidine flux rates through the CNT membranes as a function of size polarity and binding affinity of the molecular gate keeper at the entrance to each CNT pore. Specific Aim 2: to prove the ability to open and close the pore entrance with applied bias to charged long-chained molecules- bonded to CNT tips. Specific Aim 3: to study the transdermal delivery rates in human skin in vitro for constant rates and voltage gated delivery rate changes including the quantification of the dynamic response time to gated release. Specific Aim 4: to characterize the pharmacokinetics of the drugs in hairless guinea pigs and Yucatan miniature pigs in order to evaluate the in vivo success of constant rate and gated delivery.

project_terms:
Affinity;Alkanes;Alkanesulfonates;Binding (Molecular Function);Caliber;Carbon Nanotubes;Cavia;Characteristics;Charge;Cigarette;Clonidine;Development;Devices;Dose;Drug Delivery Systems;Drug Kinetics;Electronics;Family suidae;Fentanyl;Film;Human;In Vitro;Incidence;Ionic Strengths;Iontophoresis;Ligands;Longitudinal Studies;Marketing;Membrane;Methods;Molecular;Nanotubes;Nicotine;Opiates;Patient-Controlled Analgesia;Pharmaceutical Preparations;Pharmacotherapy;Plasma;Polymers;Polystyrenes;Production;Reaction Time;Regimen;Research Personnel;Role;Safety;Security;Skin;Smoker;Solutions;Solvents;System;Therapeutic;Transdermal substance administration;Withdrawal;aqueous;base;biomaterial compatibility;carboxylate;chronic pain;cost;craving;dosage;flexibility;improved;in vivo;irritation;programs;prototype;skin irritation;smoking cessation;success;voltage


application_id: 8505432
project_number: 5R01DA012964-13
project_title: Novelty Dopamine and Response to Amphetamine
administering_ic: NIDA
award_notice_date: 2013-06-19
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DA
serial_number: 012964
program_official: LYNCH, MINDA
project_start_date: 2000-03-01
project_end_date: 2016-06-30
study_section: Neurobiology of Motivated Behavior Study Section[NMB]
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): There has been considerable emphasis on research aimed at determining the genetic factors responsible for phenotypic expression of increased drug abuse vulnerability. Identification of the multiple genetic factors that determine vulnerability is critically important and currently feasible with modern molecular technology. However significant efforts also need to be directed at understanding the impact of intervening environmental factors that modify the trajectory of an individual's genetic vulnerability. In this competitive renewal application we will investigate the effects of environmental enrichment during development on drug abuse vulnerability during adulthood. Evidence to date indicates that repeated exposure to novel stimuli (i.e. the "enriched" condition; EC) during the periadolescent period produces profound changes in response to novelty and response to drugs of abuse later in life. We have found that EC rats display less motivation for sucrose and for visual novelty as well as less impulsivity for obtaining sucrose reward compared to rats raised in an "impoverished" condition (IC). EC rats also show a reduction in amphetamine self-administration compared to IC rats when tested with low unit doses. These enrichment-induced behavioral changes are accompanied by a reduction in uptake and metabolism of dopamine (DA) in presynaptic terminals in medial prefrontal cortex (mPFC) a brain region known to be involved in both drug reward and behavioral inhibition perhaps via a modulatory influence on DA activity in the nucleus accumbens (NAcc) and other related components of the motivational circuitry. The overall working hypothesis of this application is that exposure to novel environmental stimulation during development protects against stimulant abuse because there is a decrease in the incentive value of positive reinforcers and a concomitant increase in behavioral inhibition with each of these processes being associated with changes in corticolimbic activity. The specific aims are to determine if environmental enrichment: 1. protects against escalating stimulant intake across long access sessions; 2. alters behavioral inhibition following stimulant exposure; 3. alters patterns of neuronal activity in corticolimbic and striatal regions involved in reward and inhibition; and 4. alters monoamine transporter function in corticolimbic and striatal regions involved in reward and inhibition. It is not clear how the environment determines the trajectory of drug abuse among adolescents. The current basic research will determine the behavioral and neurobiological consequences of raising adolescent rats in different environments. Results obtained thus far indicate that environmental enrichment protects against drug abuse vulnerability.

project_terms:
Adolescent;Adult;Amphetamines;Basic Science;Behavior;Behavioral;Behavioral inhibition;Brain region;Corpus striatum structure;Development;Dopamine;Dose;Drug Addiction;Drug abuse;Environment;Environmental Risk Factor;Exposure to;Genetic;Genetic Predisposition to Disease;Health;Impulsivity;Incentives;Individual;Intake;Intervention;Life;Medial;Metabolism;Modeling;Molecular;Motivation;Neurobiology;Nucleus Accumbens;Play;Positive Reinforcer;Prefrontal Cortex;Presynaptic Terminals;Procedures;Process;Rattus;Research;Rewards;Risk;Role;Self Administration;Serotonin;Stimulus;Sucrose;System;Technology;Testing;Visual;Work;base;design;drug of abuse;drug reward;environmental enrichment for laboratory animals;insight;monoamine;neurobehavioral;neuronal patterning;novel;protective effect;response;stimulant abuse;uptake;young adult

public_health_relevance:
It is not clear how the environment determines the trajectory of drug abuse among adolescents. The currentbasic research will determine the behavioral and neurobiological consequences of raising adolescent rats indifferent environments. Results obtained thus far indicate that environmental enrichment protects against drugabuse vulnerability.


application_id: 8505378
project_number: 5R01AR060964-02
project_title: Modulating Inflammation and Fibrosis to Control Scarring in Muscle Wounds
administering_ic: NIAMS
award_notice_date: 2013-07-25
opportunity_number: PA-10-009
application_type: 5
activity_code: R01
ic: AR
serial_number: 060964
program_official: BOYCE, AMANDA T
project_start_date: 2012-08-01
project_end_date: 2016-07-31
study_section: Musculoskeletal Tissue Engineering Study Section[MTE]
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 (provided by applicant): Muscle injuries occurring recreationally as well as in the workplace and home are among the most common musculoskeletal conditions in the U.S. Satellite cells provide muscle with the potential for regeneration but for large defects slow healing and excessive proliferation of fibroblasts frequently results in fibrosis and scarring that
can create a mechanical barrier that delays or restricts myofibers from bridging the injury gap. Recent findings have begun to elucidate differences between inflammatory processes that promote muscle repair and regeneration following injury and those that disrupt muscle homeostasis. In light of the multiple demands needed for preventing fibrotic scarring a multidisciplinary team has been assembled to apply a proactive strategy in which multiple biomolecules are delivered in a site-specific and temporally orchestrated manner to treat different aspects of the inflammatory and wound healing processes. Aim 1 will develop and characterize a mechanically flexible controlled release system for localized delivery of anti- inflammatory anti-oxidant pro-resolution and anti-fibrotic biomolecules. With respect to this Aim it is hypothesized that the devices can be tailored to deliver anti-inflammatory anti-oxidant pro-resolution and anti-fibrotic molecules with discrete profiles that roughly follow the kineticsof the wound healing process. Aim 2 will determine the efficacy of controlled localized sequential release of anti-inflammatory anti- oxidant pro-resolution and anti-fibrotic components to enhance structural/histological biochemical and functional properties in vivo in a rodent skeletal muscle defect model. The working hypothesis is that sequential treatment devices i.e. materials that resolve inflammation and then prevent fibrosis will not only enhance muscle regeneration but these films will be more effective than those releasing only one of the components or that deliver them without regard to the sequence of events during wound healing. Furthermore the methods may be applicable not only to repair of skeletal muscle defects but also for treatment of many other diseases in which control of inflammation and subsequent wound healing processes is needed.

project_terms:
Adhesions;Affect;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Biochemical;Biocompatible Materials;Biological Response Modifier Therapy;Chronic;Cicatrix;Contracture;Data;Defect;Devices;Disease;Event;Excision;Fibroblasts;Fibrosis;Film;Gel;Generations;Goals;Healed;Home environment;Homeostasis;Inflammation;Inflammation Mediators;Inflammatory;Injury;Killings;Kinetics;Laceration;Lead;Light;Location;Mechanics;Membrane;Methods;MicroRNAs;Military Personnel;Modeling;Muscle;Musculoskeletal;Natural regeneration;Operative Surgical Procedures;Outcome;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Polymers;Process;Property;Recovery;Resolution;Rodent;Sequential Treatment;Site;Skeletal muscle structure;Surface;System;Testing;Tissues;Trauma;Ursidae Family;Vent;Work;Workplace;Wound Healing;base;combat;controlled release;design;experience;flexibility;healing;in vivo;microorganism;multidisciplinary;muscle regeneration;prevent;public health relevance;repaired;response;satellite cell;stem cell population;tissue regeneration;tissue repair;vehicular accident;wound

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Muscle injuries occurring recreationally as well as in the workplace and home are among the most common musculoskeletal conditions in the U.S. Although muscle has the potential to regenerate slow healing of large defects frequently results in scarring and incomplete recovery. This project will develop bioerodible films that control different phases of wound healing to enhance muscle regeneration.


application_id: 8505322
project_number: 5R01AG019223-09
project_title: Ceramide and acute phase protein elevation during aging
administering_ic: NIA
award_notice_date: 2013-07-29
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AG
serial_number: 019223
program_official: GUO, MAX
project_start_date: 2002-08-01
project_end_date: 2016-05-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 6730250
contact_pi: NIKOLOVA-KARAKASHIAN, MARIANA N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Our lab has a long standing interest in the mechanisms leading to the state of chronic low-grade inflammation which is an intrinsic component of the aging process and many aging-associated diseases. In the past we reported that the hepatic response to Interleukin 12 (IL-12) a major mediator of systemic inflammation is augmented during aging leading to excessive production of IGFBP1 a protein that is secreted by the liver binds to the Insulin-like Growth Factor 1 (IGF1) and neutralizes its bioactivity. Hepatic IL-12 hyperresponsiveness is caused by the intrinsic activation of an evolutionary conserved cellular stress response pathway involving neutral sphingomyelinase and its product ceramide.  Here we hypothesize that this IL-12 hyperresponsiveness impairs the insulin signaling pathway in liver. First we will investigate how aging-associated IL-12 hyperresponsiveness affects the insulin pathway and will study the interactions between key molecules in the two cascades PI3K Akt-1 and Foxo1 (for insulin) and ceramide IRAK-1 and JNK (for IL-12). Studies will be done in isolated hepatocytes in vitro and in animals in vivo. Young aged and aged calorie restricted rats will be used. The regulation of IGFBP1 mRNA transcription by the two pathways will be investigated. These molecular studies will be complemented by assays of insulin- and IGFBP1-dependent functions in vivo which include tests of IGF1 bioactivity muscle functions and glucose regulation. Throughout the experiments cause and effect relations will be tested by overexpression and silencing approach using adenovirus-mediated gene transfer. These studies may help to elucidate the cellular and molecular pathways responsible for muscle waste frailty and glucose dysregulation in the elderly. They may also reveal a novel mechanism for integration of inflammatory and metabolic signaling pathways and how aging affects these interactions. )

project_terms:
Acute-Phase Proteins;Adenoviruses;Affect;Aging;Aging-Related Process;American;Animals;Arthritis;Attenuated;Binding (Molecular Function);Biological Assay;Caloric Restriction;Cell membrane;Cells;Cellular Stress Response;Ceramides;Chronic;Complement;Disease;Dose;EMSA;Effectiveness;Elderly;Environment;Event;Exhibits;Funding;Gene Transfer;Genetic Transcription;Glucose;Goals;Health;Hepatic;Hepatocyte;IGF1 gene;Immune response;Impairment;In Vitro;Indium;Inflammation;Inflammatory;Insulin;Insulin Signaling Pathway;Insulin-Like Growth Factor I;Insulin-Like Growth-Factor Binding Protein 1;Interleukin-12;Interleukins;Life;Link;Lipids;Liver;Longevity;Luciferases;MAPK8 gene;Mammals;Mediating;Mediator of activation protein;Messenger RNA;Metabolic;Molecular;Monitor;Muscle;Muscle function;Non-Insulin-Dependent Diabetes Mellitus;Organism;Pathway interactions;Phosphoenolpyruvate Carboxylase;Phosphorylation;Phosphotransferases;Play;Production;Promotor (Genetics);Protein Binding;Proteins;Rattus;Regulation;Reporting;Role;Serum;Signal Pathway;Signal Transduction;Sphingomyelinase;Testing;Tissues;Ubiquitination;Up-Regulation (Physiology);Work;aged;blood glucose regulation;cytokine;drug metabolism;frailty;glucose tolerance;improved;in vivo;insulin sensitivity;insulin signaling;interest;juvenile animal;liver function;novel;overexpression;receptor;research study;response;sarcopenia;small hairpin RNA;success;tissue repair;transcription factor;wasting

public_health_relevance:
Understanding the mechanisms that dysregulate liver functions during aging is very important for improving the health of older Americans because liver plays critical role in many functions including glucose homeostasis innate immune response drug metabolism etc.).


application_id: 8504030
project_number: 1R01AG042419-01A1
project_title: Modulation of microRNA pathways by gemfibrozil in predementia Alzheimer disease
administering_ic: NIA
award_notice_date: 2013-07-12
opportunity_number: PAR-11-100
application_type: 1
activity_code: R01
ic: AG
serial_number: 042419
suffix: A1
program_official: RYAN, LAURIE M
project_start_date: 2013-07-15
project_end_date: 2016-06-30
study_section: Special Emphasis Panel[ZRG1 BBBP-V (55)]
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: NELSON, PETER T.
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
5 year old;Adult;Adverse event;Age;Agonist;Alzheimer disease prevention;Alzheimer's Disease;Amyloid;Animal Model;Area;Attenuated;Biological Markers;Cells;Clinical;Clinical Trials;Clinical Trials Design;Cognition;Cognitive;Cohort Studies;Data;Dementia;Developed Countries;Developing Countries;Development;Disease;Disease Progression;Double-Blind Method;Elderly;Enzymes;Epidemic;Evaluation;FDA approved;Fibrates;Foundations;Frequencies (time pattern);Future;Gemfibrozil;Glucose;Health Priorities;Hepatotoxicity;Human;Hyperlipidemia;Impaired cognition;Individual;Intervention;Lipids;Measurement;Measures;Metabolic;Metabolism;MicroRNAs;Monitor;Mus;Outcome Measure;Pathogenesis;Pathology;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Pharmacotherapy;Phase;Placebo Control;Placebos;Plasma;Play;Population;Primary Prevention;Production;Property;Proteins;Publishing;Randomized;Regulation;Research;Role;Safety;Secondary Prevention;Staging;Target Populations;Testing;Visit;Work;aged;base;beta-site APP cleaving enzyme 1;cost;design;drug discovery;human subject;mild cognitive impairment;novel;peptide A;placebo controlled study;pre-clinical;primary outcome;public health relevance;secondary outcome;tau Proteins

public_health_relevance:
Widespread recognition of the current and projected impact of the AD epidemic has spurred research into novel drug discovery efforts. This proposal seeks to further progress in this area investigating the novel actions of PPAR agonists as a disease modifying therapy in AD through their modulation of novel miRNA pathways that influence A production repurposing an existing drug therapy. As such the proposed study represents a cutting-edge data-driven low-cost exploration of a novel disease relevant pathway that may hold promise for our global efforts targeting this major health priority among developing and developed nations.


application_id: 8502185
project_number: 5R01GM094155-04
project_title: Mechanism of Neuropilin Dependent Angiogenesis
administering_ic: NIGMS
award_notice_date: 2013-07-05
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 094155
program_official: DUNSMORE, SARAH
project_start_date: 2010-09-06
project_end_date: 2015-06-30
study_section: Macromolecular Structure and Function C Study Section[MSFC]
contact_pi_person_id: 9627039
contact_pi: VANDER KOOI, CRAIG
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):  Angiogenesis the production of new blood vessels from existing vasculature is required for normal development wound repair and vascular homeostasis. Neuropilin is an essential mammalian cell surface receptor for one of the most potent pro-angiogenic molecules vascular endothelial growth factor (VEGF) and functions in synchrony with VEGFR receptor tyrosine kinases. Neuropilin is of particular medical importance because it is critical to the pathology of VEGF dependent hyper-vascularization in tumor angiogenesis.  We propose a series of parallel and complementary structural and functional studies to understand the physical interactions and receptor coupling at the heart of the VEGF signaling complex. Unlike many other kinase systems VEGF binding to VEGFR in the absence of neuropilin is insufficient to induce angiogenesis. We seek to first understand the molecular mechanism(s) underlying neuropilin's unique role in VEGF dependant angiogenesis. In Aim 1 we will determine the basis for competitive binding of ligands to neuropilin and the role that this competition plays in regulating angiogenesis. In Aim 2 we will explore the structural and conformational changes that neuropilin undergoes in its transition from inactive monomer to activated dimer. More globally we seek to define the physical basis for the coordinated action of VEGF neuropilin and VEGFR. Aim 3 is focused on utilizing multiple structural and biochemical tools coupled with endothelial cell signaling assays to determine the physical interactions and conformational changes necessary to couple extracellular ligand binding to receptor activation. Taken together these studies will provide a molecular understanding of the physical mechanisms underlying the critical first step connecting VEGF ligand binding to receptor activation.

project_terms:
Angiogenesis Inhibitors;Arginine;Binding (Molecular Function);Biochemical;Biological Assay;Blood Vessels;Breast;C-terminal;Cardiovascular system;Cell Surface Receptors;Colon;Competitive Binding;Complex;Coupled;Coupling;Development;Dimerization;Disease;Electron Microscopy;Endothelial Cells;Extracellular Structure;Family;Goals;Growth;Growth Factor;Growth Factor Interaction;Heparin;Homeostasis;Ligand Binding;Ligands;Mammalian Cell;Mediating;Medical;Membrane;Molecular;Nature;Neuropilins;Nutrient;Pathology;Pathway interactions;Peptide Hydrolases;Phosphotransferases;Pituitary Gland;Play;Production;Prostate;Proteolytic Processing;Publishing;Receptor Activation;Receptor Protein-Tyrosine Kinases;Resolution;Role;Semaphorins;Series;Signal Pathway;Signal Transduction;Solid Neoplasm;Structure;System;Techniques;Tumor Angiogenesis;Vascular Endothelial Growth Factor Receptor;Vascular Endothelial Growth Factors;Vascularization;Work;Wound Healing;angiogenesis;antiangiogenesis therapy;axon guidance;base;cytokine;dimer;extracellular;glucosaminoglycans;member;monomer;novel;public health relevance;receptor;receptor coupling;tool;tumor

public_health_relevance:
Neuropilin is an essential receptor needed for the formation of new blood vessels. New blood vessels are critical during normal development and wound repair but also provide a tumor with critical nutrients for its growth. Understanding how neuropilin works in the formation of new blood vessels will help us understand how this pathway normally functions and how we can block its activity in tumors and related diseases.


application_id: 8501465
project_number: 5F30ES017730-05
project_title: Y-family DNA polymerases and cellular responses to benzo[a]pyrene
administering_ic: NIEHS
award_notice_date: 2013-06-24
opportunity_number: PA-05-151
application_type: 5
activity_code: F30
ic: ES
serial_number: 017730
program_official: REINLIB, LESLIE J
project_start_date: 2009-07-01
project_end_date: 2015-06-30
study_section: Special Emphasis Panel[ZRG1-F10-S(21)L]
contact_pi_person_id: 9713011
contact_pi: KLARER, ALDEN C
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): Recent advances implicate error-prone DNA polymerases in the generation of virtually all mutations induced by environmental carcinogens in higher eukaryotic cells. These data have supported the promise of cancer chemoprevention based on the selective modulation of the activity of these proteins based on the assumption that reducing the mutant frequency will reduce the incidence of cancer. However carcinogenesis studies using newly-developed mouse models in which one or another of these polymerases is deficient have yielded unexpected results. Specifically deficiency in individual polymerases may result in greatly enhanced cancer incidence in the face of reduced mutation frequencies. This unexpected result is not consistent with the somatic mutation hypothesis of carcinogenesis and highlights the fact that there are critical gaps in our knowledge of the cellular function of this universe of polymerases. These studies have been done with ultraviolet radiation and the role of these enzymes in mutagenesis and carcinogenesis by chemical mutagens remains largely unexplored. This application proposes to examine the hypothesis that mutagenic translesion synthesis past adducts induced in DNA by the activated form of the environmental carcinogen benzo[a]pyrene (i.e. BPDE) is dependent on the Y-family DNA polymerases eta and/or iota. This will be examined in three Specific Aims: Aim 1 To determine the frequency and spectrum of mutations induced by BPDE in the endogenous hprt gene of fibroblasts derived from isogenic strains of excision repair-deficient mice that are wild-type or combinatorially deficient in pol eta and/or iota. Aim 2 To examine the effect of polymerase deficiency on BPDE-induced cell cycle checkpoints apoptosis and gene expression in these same cells. Aim 3 To examine the incidence and multiplicity of lung adenomas/adenocarcinomas induced by B[a]P in the isogenic polymerase-deficient mice. This proposal will fill critical gaps in our knowledge of how cancer is initiated by a common environmental carcinogen. The public health implication of this work is that mutations induced by chemical carcinogens are implicated in the development of cancer particularly lung cancer. The ultimate goal of this research is to understand how these chemicals cause cancer in order to design strategies to prevent the disease.

project_terms:
78-Dihydro-78-dihydroxybenzo(a)pyrene 910-oxide;Adenocarcinoma;Apoptosis;Base Pairing;Benzo(a)pyrene;Bypass;Cancer Etiology;Carcinogens;Cell Cycle Checkpoint;Cell physiology;Cells;Chemicals;Complex;DNA;DNA biosynthesis;DNA-Directed DNA Polymerase;Data;Development;Disease;Environmental Carcinogens;Enzymes;Eukaryotic Cell;Excision Repair;Family;Fibroblasts;Frequencies (time pattern);Gene Expression;Generations;Genes;Goals;In Vitro;Incidence;Individual;Induced Mutation;Knowledge;Lesion;Lung Adenoma;Malignant Neoplasms;Malignant neoplasm of lung;Mammalian Cell;Molecular;Mus;Mutagenesis;Mutagens;Mutation;Mutation Spectra;Nucleotide Excision Repair;Pathway interactions;Polymerase;Proteins;Rad30 protein;Research;Role;Somatic Mutation;Tumor Suppressor Proteins;Ultraviolet Rays;Wild Type Mouse;Work;adduct;base;cancer chemoprevention;carcinogenesis;chemical carcinogen;chemical carcinogenesis;design;insight;mouse model;mutant;prevent;public health medicine (field);response


application_id: 8500419
project_number: 5T32HL076138-10
project_title: Training Program in Transplantation
project_terms: Training Programs;Transplantation
administering_ic: NHLBI
award_notice_date: 2013-07-11
opportunity_number: PA-08-226
application_type: 5
activity_code: T32
ic: HL
serial_number: 076138
program_official: CHANG, HENRY
project_start_date: 2004-04-01
project_end_date: 2015-07-31
study_section: NHLBI Institutional Training Mechanism Study Section[NITM]
contact_pi_person_id: 1878929
contact_pi: ILDSTAD, SUZANNE T
other_pis: SHIRWAN, HAVAL
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
project_abstract:
DESCRIPTION (provided by applicant): This is a resubmission of a competing renewal for a highly successful training program in transplantation immunology and stem cell biology. Over the past 11 years a dynamic group of internationally recognized investigators in transplantation and stem cell biology were strategically recruited to the University of Louisville which is increasingly recognized for its comprehensive translational research in composite tissue allotransplantation tolerance and stem cell-mediated regenerative medicine. This training program directly addresses the mission of the NIH training grant program to help ensure that a diverse and highly trained workforce is available to assume leadership roles related to the nation's biomedical research agenda. All positions have been filled with outstanding applicants to date including six women (one minority) thereby addressing the major concern of all three reviewers. Applicants must have a Ph.D. D.V.M. or M.D. They are required to submit a CV publication list three letters of recommendation and a statement of the specific research proposed. An Executive Training Committee comprised of the program Director and senior trainers selects the trainees. Trainees assemble a program and undertake basic research with one trainer and one or more co-mentors. Evaluation of the Training Program occurs on several levels including manuscript and abstract submissions; oral presentations and participation at research seminar series; and completion and submission of an NRSA postdoctoral individual training grant or equivalent (AHA JDRF ASH or other foundation or society fellowships) within the second year of training. The overall progress of this Training Program is assessed by an External Advisory Board through semiannual meetings and feedback. The External Advisory Board also assists in minority recruitment. The faculty in this training program has the expertise and breadth of background to successfully train fellows in well-equipped centrally-located laboratories it is our goal that our trainees will be qualified to assume leadership positions related to transplantation and stem cell biology in industry academia and biotechnology. Our established track record demonstrates that we are well on our way to achieving this goal.


application_id: 8499513
project_number: 3R01AI051517-09S1
project_title: Paramyxovirus F protein mediated membrane fusion
administering_ic: NIAID
award_notice_date: 2012-07-10
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: AI
serial_number: 051517
suffix: S1
program_official: CASSETTI, CRISTINA
project_start_date: 2002-05-15
project_end_date: 2014-01-31
study_section: Special Emphasis Panel[ZRG1-IDM-S(02)S]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Membrane fusion a process critical for viral entry is promoted by the paramyxovirus fusion (F) proteins. All F proteins contain a number of common features that play fundamental roles in fusion. However significant variations exist between F proteins related to protein activation and promotion of membrane fusion and many critical questions remain concerning the mechanism by which fusion is promoted by these important viral proteins. The long-term objective of our research is to understand the precise mechanism(s) of paramyxovirus F protein-promoted membrane fusion. Our overall hypothesis is that the function of domains critical for fusion promotion will be conserved in diverse F proteins but that interactions in these domains will modulate triggering mechanisms. To address this important hypothesis we will pursue the following specific aims: 1.) We will build on our exciting preliminary data which demonstrates trimer formation of isolated Hendra F transmembrane (TM) domains to define the role of TM-TM interactions in glycoprotein folding and fusion. We will therefore delineate the residues critical for TM-TM interactions and evaluate the role of this interaction in Hendra F folding trafficking and fusion; analyze the effect of HRB or cytoplasmic-tail additions on stability of TM-TM interactions; compare TM-TM interactions for the PIV5 and HMPV F proteins to those observed for the Hendra F TM; and determine if TM domains from paramyxovirus attachment proteins interact with themselves or with the F protein TM domains; 2.) We will define the role of low pH and endocytosis in HMPV viral entry and delineate the role of electrostatic repulsion in the HRB linker region in HMPV F low pH-induced conformational changes and entry of recombinant viruses and; 3.) We will analyze the role of stabilizing interactions between HRA and a conserved region of F2 which our studies of PIV5 F indicate can play a role in triggering by defining key interactions in this domain in PIV5 F assessing the stage of fusion which is affected analyzing the effect of mutations in this region on viral entry and analyzing the effect of mutations to this region in other F proteins. Accomplishing these goals will provide crucial information on the regions that control the molecular events involved in the F protein-promoted membrane fusion process and potentially identify new targets for antiviral therapy. PUBLIC HEALTH RELEVANCE The paramyxovirus family contains both established human pathogens such as measles virus and respiratory syncytial virus and newly emerged human pathogens including the highly pathogenic Hendra and Nipah viruses and the recently identified human metapneumovirus (HMPV). A detailed understanding of the fusion mechanism could lead to development of new antiviral reagents.

project_terms:
Address;Affect;Alanine;Antiviral Agents;Antiviral Therapy;Cathepsin L;Cell fusion;Cell membrane;Cells;Charge;Chimeric Proteins;Cleaved cell;Cysteine;Cytoplasmic Tail;Data;Development;Electrostatics;Endocytosis;Event;Family;Family member;Funding;Glycine;Glycoproteins;Goals;Health;Hendra Virus;Human;Human Metapneumovirus;Human respiratory syncytial virus;Integral Membrane Protein;Kinetics;Lead;Measles virus;Mediating;Membrane Fusion;Molecular;Mutation;Nipah Virus;Paramyxovirus;Peptide Hydrolases;Peptides;Play;Positioning Attribute;Process;Proline;Proteins;Reagent;Recombinants;Recycling;Research;Respiratory syncytial virus;Role;Route;Scanning;Staging;Structure;System;Transmembrane Domain;Variant;Viral;Viral Proteins;Virus;insight;mutant;novel;parainfluenza virus;pathogen;protein activation;protein folding;recombinant virus;trafficking

public_health_relevance:
Relevance: The paramyxovirus family contains both established human pathogens suchas measles virus and respiratory syncytial virus and newly emerged human pathogensincluding the highly pathogenic Hendra and Nipah viruses and the recently identifiedhuman metapneumovirus (HMPV). A detailed understanding of the fusion mechanismcould lead to development of new antiviral reagents.


application_id: 8499435
project_number: 5R01NS062993-05
project_title: Cyclophilin D as a Therapeutic Target following Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2013-06-19
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 062993
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2009-07-15
project_end_date: 2015-06-30
study_section: Special Emphasis Panel[ZRG1-BDCN-T(03)M]
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W.
other_pis: SULLIVAN, PATRICK G
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The goal of this research is to minimize the secondary cell death and resultant morbidity following traumatic brain injury (TBI). Clinical interventions to improve outcome following TBI are extremely limited. Mitochondrial dysfunction is a pivotal link in the neuropathological sequalae of traumatic brain injury (TBI). TBI-induced increases in mitochondrial Ca2+ cycling/overload ultimately lead to opening of the mitochondrial permeability transition pore (mPTP). This pore located on the inner mitochondrial membrane opens in response to elevated Ca2+ and oxidative stress and is gated by the mitochondrial protein cyclophilin D (CypD). When prolonged mPTP opening is catastrophic as a result of the loss of mitochondrial membrane potential and the release of calcium and death-related proteins from mitochondria. The goal of this research is to minimize the secondary cell death and resultant morbidity following TBI by limiting mPTP opening. The immunosuppressant Cyclosporin A (CsA) inhibits mPTP opening by binding to CypD. We and others previously demonstrated that CsA reduces the extent of tissue damage when administered following experimental TBI. Unfortunately CsA is toxic at high concentrations resulting from its inhibition of calcineurin. Recently we have demonstrated that CypD levels in primary neurons are approximately double the levels found in astrocytes and that CypD levels are also significantly higher in synaptic mitochondria (neuronal origin) compared to non-synaptic mitochondria (predominately non-neuronal origin). As a result of their high CypD content we hypothesize that neuronal mitochondria are more vulnerable to mPTP opening and also require greater CsA levels to inhibit mPTP opening. To test this hypothesis we propose to use genetic and newer pharmacologic approaches to inhibit CypD following neuronal injury. Specifically we will use CypD knockout mice and a CsA derivative NIM811 which does not bind to or inhibit calcineurin. The specific aims are: 1: To evaluate the hypothesis that the high CypD content of neuronal mitochondria enhances vulnerability to mPTP opening following insults that result in elevated intracellular Ca2+ and oxidative stress. 2: To evaluate the hypothesis that the levels of the CypD inhibitor NIM811 required to protect neurons from excitotoxic insult is proportional to their CypD content. 3: To examine the hypothesis that mitochondrial CypD levels modulate the neuropathologic and functional outcome following TBI in mice. 4: To examine the hypothesis that CypD inhibitor NIM811 reduces tissue damage and improves functional outcome following TBI. Based on the results of these studies we anticipate that NIM811 will exhibit strong potential as novel therapy for TBI.

project_terms:
Abbreviations;Adenine Nucleotide Translocase;Adenine Nucleotides;Affinity;Amino Acids;Animal Model;Astrocytes;Attenuated;Binding (Molecular Function);Binding Proteins;Blood - brain barrier anatomy;Brain Injuries;Calcineurin;Calcium;Calpain;Cell Death;Cessation of life;Chemical Structure;Cleaved cell;Clinical;Clinical Trials;Cyclophilin A;Cyclophilins;Cyclosporine;Cyclosporins;Cytosol;Dose;Endoplasmic Reticulum;Event;Exhibits;Functional disorder;Generic Drugs;Genes;Genetic;Goals;Healthcare;Heterozygote;Hydrogen Peroxide;Immunosuppressive Agents;In Vitro;Injury;Inner mitochondrial membrane;Intervention;Isoleucine;Knockout Mice;Lead;Link;Liver Mitochondria;Membrane Potentials;Mitochondria;Mitochondrial Matrix;Mitochondrial Proteins;Mitochondrial Swelling;Modeling;Morbidity - disease rate;Mus;N-Methylaspartate;Names;Neuroglia;Neuronal Injury;Neurons;Nomenclature;Outcome;Oxidative Stress;Peptidylprolyl Isomerase;Performance;Permeability;Pharmaceutical Preparations;Pharmacological Treatment;Proteins;Rattus;Reactive Oxygen Species;Research;Specificity;Staging;Synapses;Synaptosomes;Testing;Tissues;Toxic effect;Traumatic Brain Injury;United States;Wallerian Degeneration;analog;apoptosis inducing factor;base;calcium green;caspase;cis-trans-Isomerases;controlled cortical impact;cyclophilin D;endonuclease G;functional outcomes;improved;in vivo;inhibitor/antagonist;leucine methyl ester;mitochondrial dysfunction;mitochondrial membrane;mitochondrial permeability transition pore;neuron loss;novel;public health relevance;response;solute;therapeutic target

public_health_relevance:
Traumatic brain injury (TBI) is a devastating healthcare problem in the United States with no pharmacological treatments currently approved for clinical intervention following injury. Improved TBI treatment options are urgently needed. This proposal examines the potential of NIM811 a derivative of CsA to limit the brain damage and dysfunction resulting from TBI.


application_id: 8499390
project_number: 5R01HL062053-14
project_title: Host Response to P. carinii in Neonatal Mice
administering_ic: NHLBI
award_notice_date: 2013-06-17
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 062053
program_official: CALER, ELISABET V
project_start_date: 1998-09-30
project_end_date: 2015-06-30
study_section: AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC]
contact_pi_person_id: 1945284
contact_pi: GARVY, BETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Pneumocystis pneumonia PCP) causes significant morbidity and mortality among HIV-infected individuals who are newly diagnosed failed retroviral therapy or do not have access to care. Infants are particularly susceptible to pulmonary infections and it has been recently appreciated that not only are individuals exposed to Pneumocystis early in life but infants appear to carry the infection as evidenced by the high incidence found in autopsy specimens from babies that died of SIDS. HIV-infected infants tend to have a more fulminant course of PCP likely because of the immature immune system along with depletion of CD4+ cells. In the previous funding period we found that in contrast to our hypothesis the delay in clearance of Pneumocystis we observed in neonatal mice was not solely due to elevated anti-inflammatory cytokines in the lungs through the first 3 weeks of life. Instead we found that alveolar macrophages from neonatal mice are intrinsically unresponsive to Pneumocystis. The goal for this funding period is to differentiate the contribution of environmental factors and intrinsic factors to neonatal alveolar macrophage function in response to Pneumocystis. Specifically we will test the hypothesis that: neonatal alveolar macrophages fail to respond to Pneumocystis due to a defect in signaling through pattern recognition receptors along with delayed second signals from proinflammatory cytokines or costimulatory molecules on T cells. To address this hypothesis we have proposed two aims. 1. We will determine whether alveolar macrophages from neonatal mice are intrinsically unresponsive to Pneumocystis. In vitro and in vivo experimental strategies will be used to determine whether neonatal alveolar macrophages can respond to stimuli through the dectin-1 ?-glucan receptor mannose receptor or TLR2. 2. We will determine whether secondary signals from T cells are required to stimulate neonatal alveolar macrophages. We will use adoptive transfer of cells and treatment with exogenous stimulatory molecules in an attempt to stimulate alveolar macrophages to respond to Pneumocystis. These studies are a logical extension of our previous funding period and will address the mechanisms responsible for neonatal unresponsiveness Pneumocystis.

project_terms:
Address;Adoptive Cell Transfers;Adult;Age;Agonist;Alveolar Macrophages;Anti-Inflammatory Agents;Anti-inflammatory;Antibodies;Autopsy;Binding (Molecular Function);CD 200;CD4 Positive T Lymphocytes;Cell physiology;Child;Cyst;Cytokine Activation;Data;Defect;Environment;Environmental Risk Factor;Epithelial Cells;Funding;Glucans;Goals;HIV;Health;Health Services Accessibility;Immune response;Immune system;In Vitro;In-Migration;Incidence;Individual;Infant;Infection;Intrinsic factor;Life;Ligation;Lung;Macrophage-1 Antigen;Mannans;Morbidity - disease rate;Mortality Vital Statistics;Mus;Neonatal;Newly Diagnosed;Pattern recognition receptor;Phagocytosis Induction;Phenotype;Pneumocystis;Pneumocystis carinii;Pneumocystis carinii Pneumonia;Production;Regulatory T-Lymphocyte;Signal Pathway;Signal Transduction;Site;Specificity;Specimen;Stimulus;Sudden infant death syndrome;T-Lymphocyte;TLR2 gene;TNFSF5 gene;Testing;Toll-Like Receptor 2;Transgenic Mice;Up-Regulation (Physiology);antiretroviral therapy;cytokine;dectin 1;in vivo;macrophage;mannose receptor;neonate;non-compliance;pup;receptor;response

public_health_relevance:
Pneumocystis pneumonia (PCP) is an AIDs defining illness that is still prevalent in newly diagnosed HIV-infected individuals and those who fail therapy are non-compliant or do not have access to antiretroviral therapy. PCP often has a worse course in children due to the immaturity of the immune system. The goal of this project is to understand the function of alveolar macrophages and CD4 T cells and their interactions in infants with PCP.


application_id: 8497123
project_number: 3R01AA018016-05S1
project_title: The Role of Alcohol in HIV Therapy Hepatotoxicity
administering_ic: NIAAA
award_notice_date: 2012-08-21
opportunity_number: RFA-AA-08-013
application_type: 3
activity_code: R01
ic: AA
serial_number: 018016
suffix: S1
program_official: WANG, JOE
project_start_date: 2008-09-30
project_end_date: 2014-08-31
study_section: ZAA1-BB(02)
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: BARVE, SHIRISH S;EATON, JOHN W
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): It is clear that alcohol abuse can alter/suppress immune function including CD4 T-lymphocyte depletion which can accelerate HIV progression. Subjects who consume alcohol may be more likely to develop certain infectious diseases which can complicate HIV examples being various types of pneumonia and tuberculosis. Moreover subjects who consume alcohol are more likely to participate in high-risk behaviors that increase the likelihood of acquiring HIV. Patients who consume alcohol also may be less compliant with their HIV therapy which can affect disease progression. The research focus of this grant is the potential impact of alcohol use/abuse as a co-factor for HIV therapy-induced hepatotoxicity. Since the introduction of highly active antiretroviral therapy (HAART) in 1996 the life expectancy of patients with HIV has increased significantly. However HAART is associated with significant hepatotoxicity. The severity of liver toxicity ranges from the absence of symptoms to liver decompensation and the reported incidence of severe liver toxicity after initiating HAART ranges from 2% to 18%. The mechanisms involved in HAART-derived hepatotoxicity are not well understood which makes its management more difficult. Some likely mechanisms of hepatotoxicity include proinflammatory cytokine production mitochondrial toxicity hypersensitivity reactions steatosis and insulin resistance immune reconstitution in HCV or HBV co-infected patients and proteasome inhibition (with dysregulated cytokine metabolism and mitochondrial and proteasome dysfunction serving as the focus of this proposal). The long-term goals of this study are to: (1) define mechanisms of hepatotoxicity induced by a combination of drug therapy and alcohol abuse in HIV patients and (2) discover potential therapeutic interventions for HAART hepatotoxicity especially for patients in whom alcohol use/abuse may be a contributing factor. Specific Aims of this proposal are to: 1. Evaluate the potential hepatotoxic interactions of alcohol and HAART medications using rapid in vitro hepatocyte screening technology; 2. Determine the effects of anti- HIV drugs (selected agents based on preliminary toxicity studies from SO#1 and clinical hepatotoxicity risk) on the development and progression of hepatotoxicity in mice and the drug interactions with chronic alcohol intake; and 3. Evaluate in a human translational component: a) mitochondrial and proteasome function and ex vivo cytokine production in subsets of HIV patients b) serial non-invasive measures of mitochondrial and proteasome function and cytokine production in patients who develop HAART hepatotoxicity and c) liver histology findings including markers of proteasome and mitochondrial function using a human translational approach from a cohort of HCV+HIV coinfected subjects enrolled in a prospective NIH study based at the University of Cincinnati. We postulate that the HAART and alcohol mediated metabolic complications of dysregulated proinflammatory cytokine production and mitochondrial and proteasome dysfunction converge on the liver in an overlapping fashion to induce hepatotoxicity. In this proposal we test that hypothesis in a novel translational approach and we evaluate unique therapeutic interventions for this hepatotoxicity.    PUBLIC HEALTH RELEVANCE: Alcohol abuse and HIV are important health problems. Liver disease is recognized as an increasingly important problem for the HIV population. Liver disease may be due to a variety of factors including co-infection with viral hepatitis alcohol abuse and antiretroviral hepatotoxicity. Liver disease is now a leading cause of death for patients with HIV. Hepatotoxicity due to HAART is also common and up to 30% of patients on HAART experience World Health Organization grade 3 liver enzyme elevations. Furthermore hepatotoxicity from antiretroviral drugs leads to adverse patient outcomes either from fulminant hepatic failure or more commonly AIDS following discontinuation of HAART. It is unknown why some but not all HIV patients develop drug induced liver injury from HAART. Relevant to this proposal alcohol/HAART interactions are emerging as critically important factors. Recent research has shown that alcohol abuse is associated with severe hepatotoxicity in patients on HAART. Importantly alcoholic liver disease and HAART induced liver injury share many potential mechanisms of injury. These include cytokine dysregulation mitochondrial dysfunction and proteasomal dysfunction. Through these and other mechanisms alcohol and antiretroviral medications converge on the liver in an overlapping fashion to produce hepatotoxicity. Here we will study hepatotoxicity due to alcohol/HAART interactions to further define disease mechanisms and create therapeutic interventions.

project_terms:
Acetaminophen;Acquired Immunodeficiency Syndrome;Acute Liver Failure;Affect;Alcohol abuse;Alcohol consumption;Alcoholic Liver Diseases;Alcohols;Anti-HIV Agents;Anti-HIV Therapy;Anti-Retroviral Agents;CD4 Positive T Lymphocytes;CYP2E1 gene;Cause of Death;Chronic;Clinical;Combination Drug Therapy;Communicable Diseases;Depressed mood;Development;Disease;Disease Progression;Drops;Drug Interactions;Enrollment;Enzymes;Fatty Liver;Functional disorder;Goals;Grant;HIV;HIV Infections;HIV therapy;Health;Hepatic;Hepatitis B;Hepatitis B Virus;Hepatitis C;Hepatitis C virus;Hepatocyte;Hepatotoxicity;Highly Active Antiretroviral Therapy;Histology;Human;Hypersensitivity;Immune;In Vitro;Incidence;Infection;Injury;Insulin Resistance;Killings;Lactic Acidosis;Life Expectancy;Lipodystrophy;Liver;Liver diseases;Lymphocyte Count;Lymphocyte Depletion;Lymphocyte Function;Measures;Mediating;Metabolic;Metabolism;Mitochondria;Morbidity - disease rate;Mortality Vital Statistics;Mus;Natural immunosuppression;Nucleosides;Opportunistic Infections;Outcome;Oxidative Stress;Patients;Pharmaceutical Preparations;Pneumonia;Population;Predisposition;Production;Protease Inhibitor;Proteasome Inhibition;Proteins;Reaction;Reporting;Research;Reverse Transcriptase Inhibitors;Risk;Role;Screening procedure;Series;Severities;Simulate;Symptoms;TNF gene;Technology;Testing;Therapeutic Intervention;Time;Toxic effect;Tuberculosis;Tumor Necrosis Factor-alpha;United States National Institutes of Health;Universities;Viral hepatitis;Work;World Health Organization;alcohol effect;base;chronic liver disease;cohort;cytokine;design;experience;feeding;high risk behavior;immune function;interest;mitochondrial dysfunction;multicatalytic endopeptidase complex;non-nucleoside reverse transcriptase inhibitors;novel;prospective;public health relevance;reconstitution;translational approach

public_health_relevance:
Alcohol abuse and HIV are important health problems. Liver disease is recognized as an increasingly important problem for the HIV population. Liver disease may be due to a variety of factors including co-infection with viral hepatitis alcohol abuse and antiretroviral hepatotoxicity. Liver disease is now a leading cause of death for patients with HIV. Hepatoxicity due to HAART is also common and up to 30% of patients on HAART experience World Health Organization grade 3 liver enzyme elevations. Furthermore hepatoxicity from antiretroviral drugs leads to adverse patient outcomes either from fulminant hepatic failure or more commonly AIDS following discontinuation of HAART. It is unknown why some but not all HIV patients develop drug induced liver injury from HAART. Relevant to this proposal alcohol/HAART interactions are emerging as critically important factors. Recent research has shown that alcohol abuse is associated with severe hepatotoxicity in patients on HAART. Importantly alcoholic liver disease and HAART induced liver injury share many potential mechanisms of injury. These include cytokine dysregulation mitochondrial dysfunction and proteasomal dysfunction. Through these and other mechanisms alcohol and antiretroviral medications converge on the liver in an overlapping fashion to produce hepatoxicity. Here we will study hepatotoxicity due to alcohol/HAART interactions to further define disease mechanisms and create therapeutic interventions.


application_id: 8496581
project_number: 1R15CA170091-01A1
project_title: Identification of Proteins from Mass Spectrometry Data: A Statistical Approach
administering_ic: NCI
award_notice_date: 2013-03-04
opportunity_number: PA-12-006
application_type: 1
activity_code: R15
ic: CA
serial_number: 170091
suffix: A1
program_official: LI, JERRY
project_start_date: 2013-03-04
project_end_date: 2017-02-28
study_section: Special Emphasis Panel[ZRG1 HDM-R (90)]
contact_pi_person_id: 9599235
contact_pi: KONG, MAIYING
other_pis: Not Applicable
congressional_district: 03
department: BIOSTATISTICS & OTHER MATH SCI
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
project_abstract:
DESCRIPTION (provided by applicant):    
Clinical Proteomic Technologies for Cancer initiative of the National Cancer Institute (NCI-CPTC) concluded that mass spectrometry (MS) is one of the main platforms for monitoring biological fluids cells and tissues. Although there has been considerable progress in acquiring accurate mass spectrometers there is still a need for development of advanced quantitative algorithms and software to analyze mass spectrometry data leading to reproducible results. Additionally although it is essential to identify individual onco-proteins it is also pertinent t elucidate the interplay of these proteins. Experimental initiatives to understand the protein-protein interaction network (PIN) although valuable did not produce consistent and reproducible results in the past. Hence there continues to be a need to predict the PIN computationally. There are numerous computational prediction procedures for Yeast Two Hybrid (Y2H) data and Affinity Purification Mass Spectrometry (AP-MS) data. However these experiments are expensive. Here we propose a completely different approach of building a large scale protein co-occurrence interaction network (PCN) from a basic fragmented peptide MS/MS data. The logic behind this PCN is that if two proteins co-occur in a sample with high probability then their chance of interaction is higher. Hence this could provide computational guidelines of conducting expensive bait-prey experiments like Y2H and AP-MS for experimental validation of a protein-protein interaction. In addition we compare the differential nature of the
PCN for the diseased and the normal samples to determine the most important protein groups that are potential biomarkers or drug targets for cancer treatments. Our goals in this proposal are three-fold: 1) Propose a novel hierarchical Bayesian statistical methodology to identify proteins from MS/MS spectra obtained from fluids and tissue samples of cervical and breast cancer patients. 2) Use an expanded hierarchical Bayesian model to construct the PCN of the cancer proteome; additionally unravel the key topological features of PCNs such as hubs modules sub-networks and bottlenecks. 3) Use statistical inference to differentiate the overall structure of the PCNs for the key features of the PCNs between the diseased and control samples. We anticipate that completeness of the project will enhance our understanding of cervical and breast cancer and aid in developing novel cancer drugs. Additionally it will train doctoral students in the field of computational biomedical research of the twenty-first century.

project_terms:
Address;Advanced Development;Affinity Chromatography;Algorithms;Antineoplastic Agents;Area;Biological Markers;Biological Monitoring;Biomedical Research;Cancer Patient;Cells;Charge;Clinical;Complex;Computer software;Custom;Data;Dependence;Detection;Development;Disease;Drug Targeting;Goals;Grouping;Guidelines;Individual;Intervention;Investigation;Liquid substance;Logic;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mass Spectrum Analysis;Measures;Methodology;Modeling;National Cancer Institute;Nature;Oncogene Proteins;One-Step dentin bonding system;Pathway interactions;Patients;Peptide Fragments;Peptides;Probability;Procedures;Process;Proteins;Proteome;Proteomics;Research;Research Personnel;Sampling;Structure;Technology;Tissue Sample;Tissues;Training;Validation;Work;Yeasts;cancer therapy;doctoral student;interest;malignant breast neoplasm;mass spectrometer;neglect;novel;protein protein interaction;public health relevance;research study;therapeutic target;yeast two hybrid system

public_health_relevance:
Our proposed research will help identifying sensitive and specific proteomic biomarkers for complex diseases like cancer. Identification of the interrelationship between different proteins and peptides responsible for the disease may eventually result into clinical interventions custom made for every individual patient. This proposal will also contribute towards building trained workforce for twenty first century biomedical research.


application_id: 8495058
project_number: 5R01CA133429-06
project_title: The Role of PHLPP in Colon Cancer
administering_ic: NCI
award_notice_date: 2013-02-06
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: 2015-02-28
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:
PROJECT NARRATIVE Colorectal cancer is the second leading cause of cancer-related deaths in the United States with148000 new cases diagnosed per year and approximately 50000 deaths estimated in 2007 and among manycontributing factors aberrant protein phosphorylation resulting from hyperactivation of oncogenic signalingmediated by protein kinases such as Akt and PKC is a key cause of colorectal cancer. We recently identified anovel protein phosphatase PHLPP that directly dephosphorylates Akt and PKC and terminates the growthsignals activated by these kinases. We propose to determine the functional importance of PHLPP as a tumorsuppressor in colorectal cancer and the results from this study will provide significant insights into thedevelopment of potential cancer therapy using PHLPP as a novel target.


application_id: 8495002
project_number: 2R15GM084431-02A1
project_title: Hydroquinone derivatives as novel calcium ATPase inhibitors
administering_ic: NIGMS
award_notice_date: 2013-09-25
opportunity_number: PA-12-006
application_type: 2
activity_code: R15
ic: GM
serial_number: 084431
suffix: A1
program_official: FABIAN, MILES
project_start_date: 2009-09-30
project_end_date: 2015-08-31
study_section: Macromolecular Structure and Function A Study Section[MSFA]
contact_pi_person_id: 8527958
contact_pi: PAULA, STEFAN FRANZ
other_pis: Not Applicable
congressional_district: 04
department: CHEMISTRY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Commonly used inhibitors of the enzyme sarco/endoplasmic reticulum calcium-ATPase (SERCA) derived from the natural product thapsigargin (TG) suffer from limitations attributed to their high structural complexity which restricts their availability and makes their customization by organic synthesis challenging and cumbersome. Because of their value as powerful research tools for the study of SERCA's role in physiological processes and their potential as novel agents against prostate cancer the development of alternatives to TG-based SERCA inhibitors is highly desirable. The research outlined in this proposal is the design and the in-depth characterization of novel SERCA inhibitors based on the structure of hydroquinone (HQ). Despite their smaller size and lower complexity HQ- based inhibitors - while readily available and conveniently customized - display remarkably high potencies against SERCA activity. As an important step towards the long-term goal of obtaining a comprehensive understanding of SERCA's interaction with small inhibitory molecules the objective of this particular application is the discovery and comprehensive characterization of HQ-based inhibitors that are good candidates for the future development into research tools or anti-cancer agents. Preliminary data support the central hypothesis that the further development of HQs into a new SERCA inhibitor class is a feasible task and will likely yield novel research tools and/or anti-cancer agents. Inhibitors that are predicted to have good potencies will be synthesized or obtained by compound library screens and their potencies will then be measured in bioassays. The feasibility of attaching peptide tethers to SERCA inhibitors to convey specificity for prostate cancer cells will also be evaluated. Complementary to synthesis library screens and bioassays a selection of the most potent compounds will be characterized thoroughly by molecular dynamics (MD) simulations in order to furnish a time-dependent account of the intermolecular interactions and events in the binding site at the molecular level. Supported by some crystallographic work the MD simulations will also predict binding affinities of inhibitors for SERCA in order to help guide the synthesis of new compounds. Furthermore the ability of SERCA inhibitors to interfere with the enzyme's Ca2+ transport function in living systems will be assessed in imaging studies with healthy and cancerous cells. The proposed research is innovative because it will explore the HQ scaffold as an attractive alternative to TG-based SERCA inhibitors. Moreover its significance stems from its goal of generating fundamental information that is necessary to eventually develop HQs into valuable new research tools and into novel agents against prostate cancer. By engaging undergraduate research students in a multi-disciplinary drug design project the planned project meets the goals of the NIH AREA program.

project_terms:
Accounting;Affinity;Antineoplastic Agents;Binding (Molecular Function);Binding Sites;Biological Assay;Biological Factors;Biomedical Research;Ca(2+)-Transporting ATPase;Calcium;Cancer Etiology;Cancerous;Cells;Cessation of life;Chemicals;Chemotherapy-Oncologic Procedure;Complex;Data;Development;Docking;Drug Design;Endoplasmic Reticulum;Environment;Enzyme Inhibitor Drugs;Enzyme Inhibitors;Enzymes;Event;Free Energy;Funding;Future;Generations;Goals;Health;Human;Hydroquinones;Image;Imaging Techniques;Institution;Kentucky;Knowledge;Length;Libraries;Location;Malignant neoplasm of prostate;Measures;Mediating;Methodology;Methods;Modification;Molecular;Molecular Models;Organic Synthesis;Organism;Peptide Hydrolases;Peptides;Pharmaceutical Preparations;Physiological;Physiological Processes;Positioning Attribute;Prodrugs;Property;Publishing;Research;Role;Secure;Source;Specificity;Structure;Students;Techniques;Thapsigargin;Time;Training;United States National Institutes of Health;Universities;Work;analog;base;career;combat;design;fluorescence imaging;functional group;hydroquinone;in vitro activity;in vivo;inhibitor/antagonist;innovation;interest;intermolecular interaction;meetings;men;molecular dynamics;molecular modeling;novel;prevent;programs;prostate cancer cell;public health medicine (field);public health relevance;research study;scaffold;small molecule;stem;tool;undergraduate research;undergraduate student

public_health_relevance:
The objective of the proposed research is relevant to public health because it targets the development of a novel class of enzyme inhibitors that are valuable tools for biomedical research and promising candidates for the development of new drugs against prostate cancer. Compared to currently used compounds these new inhibitors of the physiologically important enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA) have the advantage of being structurally simple readily available and yet effective. In addition to advancing the field of SERCA inhibition by small molecules this multi-disciplinary project meets the stated objectives of the AREA program by offering undergraduate students hands-on training in modern drug design methodologies and strengthening the research environment at Northern Kentucky University.


application_id: 8492190
project_number: 5R03NS079818-02
project_title: Cavities in Choline Acetyltransferase and Neuromuscular Disorders
administering_ic: NINDS
award_notice_date: 2013-06-19
opportunity_number: PA-11-262
application_type: 5
activity_code: R03
ic: NS
serial_number: 079818
program_official: STEWART, RANDALL R
project_start_date: 2012-07-01
project_end_date: 2015-12-31
study_section: Biophysics of Neural Systems Study Section[BPNS]
contact_pi_person_id: 7875214
contact_pi: RODGERS, DAVID W
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): Our goal is to understand the effects of congenital mutations in choline acetyltransferase (ChAT) which synthesizes the prototypical neurotransmitter acetylcholine. Decreases in ChAT activity are associated with a number of neurological disease states and mutations in the enzyme cause a severe neuromuscular disorder known as congenital myasthenic syndrome with episodic apnea (CMS-EA). Our crystal structure of ChAT showed that the known congenital mutations are distributed widely over the enzyme despite their common effects on function and recent structures show that two of the mutations affect the conformation of the catalytic histidine residue. Further the core residue packing in ChAT is poor leaving an unusually large number of cavities (voids). Based on these observations we hypothesize that the large number of cavities in ChAT makes it conformationally unstable so that point mutations cause structural changes that propagate to disrupt function. We will use a combination of structural biophysical and cell biological approaches to test this hypothesis focusing on a cavity near the two congenital mutations that have been characterized structurally. Two specific aims are proposed: 1) characterize the role of an internal cavity in mediating the functional effects of two congenital mutations 2) assess how filling the cavity effects structural changes associated with the congenital mutations This work will serve as an initial test of our hypothesis regarding the role of packing defects in ChATdirectly addressing the molecular mechanism underlying a human disease and guiding future studies of ChAT and the motor disorders associated with decreases in its function.

project_terms:
Acetylcholine;Active Sites;Address;Affect;Animal Model;Apnea;Biological;Cells;Choline O-Acetyltransferase;Communication;Congenital Myasthenic Syndromes;Cultured Cells;Data;Defect;Disease;Enzymes;Future;Goals;Hereditary Disease;Histidine;Investigation;Kinetics;Lead;Left;Location;Maps;Measures;Mediating;Molecular;Molecular Conformation;Muscle;Mutate;Mutation;Nervous system structure;Neurodegenerative Disorders;Neuroglia;Neuromuscular Diseases;Neurotransmitters;Play;Point Mutation;Research;Role;Structure;System;Testing;Therapeutic;Work;base;drug candidate;effective therapy;human disease;knowledge base;motor disorder;nervous system disorder;novel therapeutics;restoration;small molecule

public_health_relevance:
The proposed research will provide an understanding of a molecular disease that disrupts communication between the nervous system and muscles. Knowledge of the basis for the disorder will provide an approach for developing effective therapies for this and similar diseases of the nervous system.


application_id: 8492149
project_number: 5P01HL078825-08
project_title: Flow Cytometry and Cell Sorting Core
administering_ic: NHLBI
award_notice_date: 2013-06-24
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
project_start_date: 2005-04-15
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7463
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
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: 2013-06-01
project_abstract:
The function of the Flow Cytometry and Cell Sorting Core (Core D) is to provide each Project with the expertise equipment and facilities required for the flow cytometric analyses and cell sorting procedures that are needed for studies of cardiac progenitor cells (CPCs). Accurate identification characterization and quantitation of cells in a complex heterogeneous population are technically demanding and require specialized and expensive equipment and personnel. One of the maior advantages of this Program Proiect is that it will make available to all four Proiects the facilities and techniques of flow cytometry and cell sorting.
which otherwise would not be affordable to any Proiect in isolation. Flow cytometry-based analysis for the identification of specific cell populations changes in cell commitment or phenotype and characterization of cell functions such as cell cycle viability signal transduction or potential will be crucial to all Projects. A central common facility that performs these technically challenging analyses is therefore indispensable to
achieve the goals of the Program Project. Besides the obvious advantages of efficiency and cost savings the Core will also enable four investigators with diverse and complementary backgrounds (Drs. Rokosh McCracken Ratajczak and O'Toole) to combine their technical and biological expertise in order to ensure that the proposed work is successfully executed.
 The Core will offer the Program Project investigators the ability to identify and characterize specific cell types from complex populations. Specifically the Core will perform analysis of marker expression in various cells including CPCs and more differentiated cells and including changes in marker expression during differentiation; detect intracellular generation of radicals (i.e. using DAFDA for NO and DCFDA for ROS); examine mitochondrial membrane integrity membrane potential and function; assess cell viability;
determine changes in cell signaling; isolate stem cells utilizing multiple markers; and quantify cells at each phase of the cell cycle. The Core is also active in identifying and characterizing novel cell markers that will be useful for the various Projects.

project_terms:
Area;Biological;Budgets;Cardiac;Cardiomyopathies;Cell Cycle;Cell Separation;Cell Survival;Cell physiology;Cells;Centers of Research Excellence;Complex;Cost Savings;Coupled;Diabetes Mellitus;Ensure;Equipment;Flow Cytometry;Foundations;Funding;Generations;Goals;Human Resources;Institutes;Maintenance;Membrane Potentials;Myocardial Ischemia;Nature;Obesity;Phase;Phenotype;Population;Population Heterogeneity;Procedures;Reperfusion Therapy;Research Personnel;Signal Transduction;Stem cells;Techniques;United States National Institutes of Health;Work;base;cell type;diacetyldichlorofluorescein;mitochondrial membrane;novel;operation;programs;stem cell biology;stem cell therapy


application_id: 8492147
project_number: 5P01HL078825-08
project_title: Surgery and Physiology Core
administering_ic: NHLBI
award_notice_date: 2013-06-24
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
project_start_date: 2005-04-15
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7461
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
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: 2013-06-01
project_abstract:
The function of the Surgery and Physiology Core (Core B) is to provide the expertise equipment and facilities needed for all of the in vivo murine studies. Specifically Core B will be responsible for all surgical procedures (coronary artery occlusion/reperfusion and CPC delivery) echocardiographic analyses invasive hemodynamic studies and maintenance and genotyping of transgenic and knockout mouse lines. Accurate physiological measurements and surgical procedures in mice represent technically demanding tasks that cannot and should not be attempted in every laboratory but rather should be performed by a group of
dedicated investigators who focus on studies in mice and thereby acquire extensive experience with this difficult model. One of the main advantages of this Program Project is that it provides all four Proiects with access to complex and technically challenging in vivo mouse models of mvocardial infarction (Ml) and ceil therapy expert physiology and surgery and state-of-the-art technigues that otherwise would not be available to these investigators. This is a major benefit to all investigators. Core B consists of a team of skilled highly-
experienced investigators who have worked together cohesively for many years focusing exclusively on murine studies (they have performed >16.000 surgical procedures in mice) have developed and perfected murine models of Ml and cell therapy utilizing state-of-the-art facilities and equipment and have collaborated extensively with the other investigators in this PPG.
 An important feature of Core B is that it will use a new technique for delivering CPCs - intracoronary infusion in the mouse which has never been used before in this species. Compared with standard intramyocardial injection intracoronary infusion is much more clinically relevant. Furthermore it enables uniform distribution of CPCs throughout the infarct and in the noninfarcted region which is not possible with intramyocardial injection and produces superior results as shown by our data. Another feature is that all
echocardiographic and hemodynamic analvses will be performed off-line by blinded observers. The capacity of the Core has been tested in the preparation of this submission. To produce the preliminary data needed for this application. Core B has operated upon >300 mice and performed 231 studies of CPC transplantation 390 echocardiographic studies and 108 hemodynamic studies. All of this has been done in the past 10 months. These numbers eloquently illustrate the research output that the Core can produce.

project_terms:
Blinded;Cell Therapy;Complex;Coronary artery;Data;Equipment;Genotype;Infarction;Infusion procedures;Injection of therapeutic agent;Knockout Mice;Laboratories;Maintenance;Measurement;Modeling;Mus;Myocardial Ischemia;National Heart Lung and Blood Institute;Operative Surgical Procedures;Output;Physiological;Physiology;Preparation;Productivity;Publications;Reperfusion Therapy;Research;Research Personnel;Techniques;Testing;Transgenic Mice;Transplantation;Work;artery occlusion;clinically relevant;experience;hemodynamics;in vivo;mouse model;pre-clinical;programs


application_id: 8492146
project_number: 5P01HL078825-08
project_title: Administrative Core
administering_ic: NHLBI
award_notice_date: 2013-06-24
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
project_start_date: 2005-04-15
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7460
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
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: 2013-06-01
project_abstract:
Core A will provide scientific budgetary administrative logistic and biostatistical oversight to all aspects of the Program Project. The Core will facilitate communication among investigators and sharing of reagents tools specimens and data; will ensure appropriate allocation of funds to each Project and appropriate use of these funds; will provide clerical support; will coordinate the Projects with subcontracted institutions; will organize regular investigator meetings; and will provide biostatistical assistance. Dr. Bolli Core Leader will be responsible for the overall coordination integration and administration of the Program Project for the appropriate utilization of the funds for compliance with institutional and federal regulations for the scientific
productivity of the Program and for any issues related to the Program. The Principal Investigator will be assisted by the other members of the Executive Committee which will be composed of the four Project Leaders and the four Core Leaders. The Principal Investigator and the executive Committee will meet on a
monthly basis to discuss the scientific progress data problems and future directions for the four Projects.
Scientific responsibilities include (1) providing leadership in maintaining the focus of the investigators (2)  providing statistical assistance and (3) weekly meetings of all Program Project Investigators. Administrative  and financial responsibilities include (1) implementing guidelines for Program Project support (2) administering the budget according to NIH guidelines (3) monitoring budgets for each Project and Core and (4) ensuring compliance with the institutional and NIH regulations. The Biostatistician working in the  Core will be Dr. Maiying Kong. She will attend the monthly meetings of the Executive Committee review the
experimental data analyze them and calculate group sizes for future studies. She will devote 10% of his/her time to this Program Project. An important aspect of this Program Project is that the investigators  performing in vivo studies of CPCs will be blinded to the treatment until the final data analysis is released by  Dr. Kong. Another important aspect is that all sample sizes will be selected before the experiments are started  (based upon power analysis by Dr. Kong) and will not be changed; the experiments will be carried out until the  predetermined sample sizes are achieved without any knowledge of interim results. After the predetermined sample sizes are achieved all data will be given to Dr. Kong where they will be unblinded and analyzed by  appropriate statistical methods. Each Project will utilize 25% of Core A.

project_terms:
Blinded;Budgets;Communication;Consult;Data;Data Analyses;Ensure;Funding;Future;Guidelines;Human Resources;Institution;Knowledge;Leadership;Logistics;Monitor;Myocardial Ischemia;Principal Investigator;Productivity;Program Research Project Grants;Reagent;Regulation;Research Personnel;Review Committee;Sample Size;Specimen;Statistical Methods;Structure;Time;United States National Institutes of Health;Work;base;in vivo;meetings;member;operation;programs;research study;tool


application_id: 8490378
project_number: 5U01ES015673-09
project_title: Novel Therapies for Chlorine-Induced Lung Injury
administering_ic: NIEHS
award_notice_date: 2013-07-02
opportunity_number: PAR-10-180
application_type: 5
activity_code: U01
ic: ES
serial_number: 015673
program_official: NADADUR, SRIKANTH
project_start_date: 2006-09-29
project_end_date: 2016-04-30
study_section: Special Emphasis Panel[ZRG1-MDCN-J(50)R]
contact_pi_person_id: 2736750
contact_pi: HOYLE, GARY W.
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent. The goal of the research proposed in this renewal application is to develop a medical countermeasure to treat lung injury induced by chlorine inhalation. During the previous U01 award a mouse model of chlorine gas inhalation was developed a detailed characterization of lung injury following chlorine exposure was performed signaling pathways representing possible targets for therapeutic intervention were investigated strategies for manipulating signaling pathways of interest were tested and compounds that significantly inhibited lung injury or inflammation in chlorine-exposed mice were identified. Rolipram a type 4 phosphodiesterase inhibitor was shown to stimulate alveolar fluid transport decrease pulmonary edema and inhibit airway hyperreactivity. Triptolide a diterpenoid anti-inflammatory compound inhibited chlorine-induced lung inflammation. In the present application formulations of rolipram and triptolide will be developed for intramuscular (i.m.) injection a preferred delivery route for potential mass casualty situations. In addition methylprednisolone an FDA-approved anti-inflammatory compound will be evaluated as an alternative to triptolide. The overall hypothesis to be tested is that i.m. injection of an encapsulated formulation of rolipram in combination with an anti-inflammatory compound will represent the most effective countermeasure for chlorine-induced lung injury. Countermeasure formulations will be tested in mice to determine efficacy against chlorine-induced acute lung injury to assess longer term effects on airway remodeling and airway hyperreactivity and to measure the length of effective post-exposure treatment window. The most effective countermeasure formulation will be evaluated in rabbits to demonstrate efficacy in a non-rodent animal model. An optimized countermeasure formulation with efficacy against chlorine-induced lung injury in mice and rabbits will be subject to additional studies necessary for progression toward regulatory approval including collection of pharmacokinetic/pharmacodynamic and toxicity data and production of the countermeasure using current good manufacturing practices.

project_terms:
Affect;Alveolar;Animal Model;Anti-Inflammatory Agents;Anti-inflammatory;Award;Breathing;Chemicals;Chlorine;Collection;Data;Development;Diterpenes;Drug Formulations;Drug Kinetics;Encapsulated;FDA approved;Gases;Goals;Human;Inflammation;Intramuscular Injections;Irritants;Length;Liquid substance;Long-Term Effects;Lung Inflammation;Lung Injury Acute;Maximum Tolerated Dose;Measures;Medical;Methylprednisolone;Mus;No-Observed-Adverse-Effect Level;Oryctolagus cuniculus;Pathway interactions;Pharmacodynamics;Phosphodiesterase Inhibitors;Poisons;Principal Investigator;Production;Pulmonary Edema;Research;Research Institute;Rodent;Rolipram;Route;Signal Pathway;Testing;Therapeutic Intervention;Toxic effect;Universities;airway hyperresponsiveness;airway remodeling;chemokine;chlorine gas;efficacy testing;interest;lung injury;mouse model;neutrophil;novel;pre-clinical;prevent;public health relevance;research study;respiratory;triptolide

public_health_relevance:
Public Health Relevance: The goal of the proposed experiments is to develop novel ways to treat acute lung injury caused by chlorine gas inhalation. The research will focus on medical countermeasures that can be easily and rapidly administered in a mass casualty situation. This type of research is important because of concerns that U.S. civilians could be adversely affected by the accidental or intentional release of highly toxic chemicals.


application_id: 8490350
project_number: 5R01DK056132-11
project_title: Neural Circuitry in the Dorsal Vagal Complex
administering_ic: NIDDK
award_notice_date: 2013-06-04
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 056132
program_official: HYDE, JAMES F
project_start_date: 2001-06-01
project_end_date: 2015-03-31
study_section: Neuroendocrinology, Neuroimmunology, and Behavior Study Section[NNB]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Neuronal communication in the dorsal vagal complex (DVC) is critical for integrating visceral afferent and other inputs and translating that integrated signal into a coordinated parasympathetic motor output via the vagus nerve. In particular GABAergic inhibition is a dominant regulator of neuronal function in the area. Despite the recognized importance of this circuitry in controlling feeding and digestion relatively little is known about local cellular interactions in the DVC. The general hypothesis of this proposal is that activity of neurons in the dorsal motor nucleus of the vagus (DMV) that control gastric function is prominently controlled by inhibitory GABAergic inputs arising from neurons in the nucleus tractus solitarius (NTS). The activity of NTS GABA neurons is regulated by both glutamatergic excitatory and GABAergic inhibitory synaptic inputs. We propose that GABAergic control of preganglionic vagal motor output is accomplished by both phasic and tonic postsynaptic GABAA receptor-mediated inhibition and that specific cellular interactions in the DVC are organized in a manner that consistent with the concept well developed in other sensory-motor systems that local inhibitory circuitry coordinates responses between functional areas of the solitary complex. Gastrointestinal and other autonomic dysfunction affects people with diabetes mellitus and hyperglycemia significantly alters central vagal motor function. We further propose that GABAA receptor-mediated currents in gastric-related DMV neurons are functionally altered in a model of type 1 diabetes mellitus. We will use a multidisciplinary approach to examine GABA-mediated synaptic transmission between neurons in the DVC focusing particularly on inhibitory synaptic control of identified GABAergic neurons in the NTS as well as on neurons in the DMV in the context of gastrointestinal control. Electrophysiological experiments will be done in vitro using brain slice preparations from mature male mice in which DMV and NTS neurons can be identified by their anatomical connection with the stomach their GABA content or both. With whole-cell patch-clamp recordings we will use photoactivation of caged glutamate to stimulate selectively the soma-dendritic regions of local neurons in order to analyze GABA-mediated connections within the solitary complex. We aim to determine: 1) the contribution of tonic GABAergic currents to neuronal activity in the DMV; 2) how identified gastric-related GABAergic neurons in the NTS are regulated by GABA input; and 3) effects of hyperglycemia on GABA currents in a model of type 1 diabetes. We will correlate electrophysiological results with pharmacological and molecular biological analyses to construct a cellular model of local GABAergic control of DMV neuron activity.

project_terms:
Affect;Amino Acids;Area;Autonomic Dysfunction;Binding (Molecular Function);Biological;Brain;Cell model;Cells;Characteristics;Chronic;Communication;Complex;Data;Diabetes Mellitus;Diabetic mouse;Digestion;Dorsal;Event;Glucose;Glutamates;Health;Hyperglycemia;In Vitro;Insulin-Dependent Diabetes Mellitus;Label;Mediating;Membrane Potentials;Messenger RNA;Metabolic;Methods;Modeling;Molecular;Motor;Motor Neurons;Motor output;Mus;Neurons;Noise;Nucleus solitarius;Output;Preparation;Proteins;Regulation;Rest;Signal Transduction;Slice;Stomach;Synapses;Synaptic Transmission;Testing;Transgenic Mice;Translating;Vagus nerve structure;Viscera;Visceral Afferents;base;cell body (neuron);dorsal motor nucleus;feeding;gamma-Aminobutyric Acid;gastrointestinal;gastrointestinal system;interdisciplinary approach;male;mind control;neural circuit;patch clamp;photoactivation;photolysis;postsynaptic;receptor;research study;response;sensorimotor system

public_health_relevance:
Inhibitory connections between neurons that regulate the gastrointestinal system are critical to feeding and digestion but how they control output to the stomach is largely unknown. We have uncovered evidence of a heretofore unstudied and powerful means of regulating how the brain controls the gut and that this mechanism is altered in a model of type 1 diabetes mellitus. The experiments here will examine the synaptic mechanisms controlling gut-related neuron activity and will point to new ways of modifying activity of the gastrointestinal system in response to specific triggers associated with feeding and under pathological conditions of metabolic dysregulation.


application_id: 8489357
project_number: 5R01NS064247-04
project_title: Modulation of CNS Proinflammatory Cytokine Production
administering_ic: NINDS
award_notice_date: 2013-05-31
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 064247
program_official: CORRIVEAU, RODERICK A
project_start_date: 2010-07-01
project_end_date: 2014-12-30
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: 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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The serine/threonine protein kinase p381 MAPK is an established therapeutic target for a number of peripheral inflammatory diseases where increased proinflammatory cytokine production contributes to pathology. In contrast much less is known about the in vivo role of p381 MAPK in CNS dysfunction and its potential as a therapeutic target. Specifically little information is available on the quantitative contribution of microglial p381 MAPK signaling in vivo to up-regulation of proinflammatory molecules that lead to disease- relevant neuropathology the importance of p381 MAPK in the beneficial reparative and remodeling responses of activated microglia or the role of neuronal p381 MAPK in CNS dysfunction responses. We hypothesize that p381 (and not the closely related p382 MAPK isoform) is a key in vivo contributor to microglial inflammatory activation cascades that culminate in detrimental proinflammatory cytokine overproduction and subsequent neuronal/synaptic damage and that suppression of p38 MAPK signaling in the microglia and/or neuron can lead to selective beneficial outcomes. The field has been limited in its ability to pursue these questions because of the lack of CNS-penetrant selective small molecule p381 MAPK inhibitors. Our development of a novel orally bioavailable brain-penetrant selective small molecule p381 MAPK inhibitor (compound 069A) that attenuates hippocampal proinflammatory cytokine overproduction and leads to improved neurologic outcomes in a mouse CNS injury model now provides the opportunity to address these critical questions about p38 MAPK and CNS dysfunction in vivo as well as in vitro or in situ. We will use this unique chemical biology tool and novel knock-out (KO) and drug-resistant knock-in (KI) mice to pursue several important mechanistic investigations. First we will test the importance of p381 MAPK and p382 MAPK in vivo through the use of microglial p381 conditional KO and p382 global KO mouse models subjected to stressor stimuli. The temporal onset and profile of microglial activation and synaptic dysfunction responses will be determined. Second we will complement these in vivo studies by using cell culture models in order to explore in more detail the relative contributions of p38 MAPK isoforms in microglia and neurons. We will utilize microglial-neuronal co-cultures combined with pharmacological and genetic knock-down approaches to determine the importance of microglial and neuronal p38 MAPK isoforms to stressor-induced responses. Successful completion of this project will provide mechanistic insight into the role of the key regulatory protein p381 MAPK in microglial activation and neuronal damage caused by stressors that induce CNS pathophysiology and the contribution of microglial vs. neuronal p381 MAPK to the CNS dysfunction responses. In addition the studies will elucidate the potential role of the highly related p38 MAPK isoform p382 in the microglial and neuronal responses. Longer term the knowledge generated by the proposed studies will provide a firmer foundation for future development of new classes of disease-modifying therapeutics and fuller interpretation of disease progression investigations.

project_terms:
Address;Alzheimer's Disease;Attenuated;Bioavailable;Biology;Brain;Cell Culture Techniques;Chemicals;Chronic;Coculture Techniques;Complement;Cytokine Gene;Development;Disease;Disease Progression;Drug resistance;Embryo;Family;Foundations;Functional disorder;Future;Gene Expression;Genetic;Genetic Transcription;Hippocampus (Brain);Immune;In Situ;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Investigation;Knock-in Mouse;Knock-out;Knockout Mice;Knowledge;Lead;Link;MAP Kinase Gene;MAPK14 gene;Measurable;Microglia;Mitogen-Activated Protein Kinase Inhibitor;Modeling;Mus;Nature;Neurodegenerative Disorders;Neuroglia;Neurologic;Neurologic Dysfunctions;Neurological outcome;Neuronal Dysfunction;Neuronal Injury;Neurons;Outcome;Pathology;Pathway interactions;Peripheral;Phosphorylation;Physiological;Process;Production;Protein Isoforms;Protein-Serine-Threonine Kinases;Proteins;Recording of previous events;Regulation;Relative (related person);Rheumatoid Arthritis;Role;Signal Transduction;Stimulus;Synapses;Testing;Therapeutic;Tissues;Translations;Up-Regulation (Physiology);Work;age related;base;brain tissue;cell type;central nervous system injury;computerized data processing;cytokine;cytotoxicity;genetic regulatory protein;improved;in vivo;insight;interest;knock-down;macrophage;mouse model;neuropathology;novel;public health relevance;response;small molecule;stressor;therapeutic target;tool

public_health_relevance:
Successful completion of this project will provide mechanistic insight into how the key regulatory protein p381 MAPK is involved in brain pro-inflammatory responses and CNS dysfunction caused by disease- relevant stressors. In addition the results will delineate the relative importance of microglial versus neuronal p381 MAPK and p382 MAPK to the disease-relevant pathological responses. Longer term the insights and knowledge generated by the proposed studies will provide a firmer foundation for future development of new classes of disease-modifying therapeutics and fuller interpretation of disease progression investigations.


application_id: 8489308
project_number: 5P20GM103486-10
project_title: Center for Biomedical Research Excellence in the Molecular Basis of Human Disease
administering_ic: NIGMS
award_notice_date: 2013-07-01
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: GM
serial_number: 103486
program_official: ZLOTNIK, HINDA
project_start_date: 2004-09-01
project_end_date: 2015-06-30
study_section: ZRR1-RI-B(01)
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
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:
This proposal builds upon the accomplishments made during the previous funding period and requests continuing support of COBRE the Center of Biomedical Research Excellence in the Molecular Basis of Human Disease. During the four year period this COBRE grant has been active 22 junior faculty from 9 different departments were mentored of which 8 received NIH R01 funding and an additional 4 received Other forms of extramural funding. Participating in the activities of the Center has been an additional 11 faculty 11 postodctorals/research associates and 9 graduate students. The members of the Center published more than 175 research papers and made 38 presentations at scientific meetings. The Department of Molecular and Cellular Biochemistry in which the COBRE is housed rose from 28th to 12th in NIH rankings in terms of Public Medical Schools and 26th in terms of all Medical Schools during the tenure of the COBRE. This was accomplished by an increase in $5148302 of NIH grant dollars excluding the COBRE funds. The Center for Molecular Medicine was formed in 2007 as a direct consequence of the accomplishments made during the first phase of the COBRE (Aug 2004- July 2009).  In the second phase of this COBRE we propose to establish a nationally and internationally recognized research center that will continue to compete effectively for extramural research funding. To accomplish this we propose i) to expand our critical mass of investigators including the mentoring of an additional 5 promising junior investigators who are studying the molecular basis of human disease. This will include a targeted new recruit to the University. We will enhance the opportunity to translate their research to patients by facilitating interactions with clinical faculty. We will continue with the major focus in cancer diabetes and neurological diseases ii) We will expand and continue to develop our core facilities in Proteomics Chemistry Microscopy Protein characterization and Mouse Genotyping. iii) We will continue to support pilot research projects. This has been a highly effective way to enhance the research of a rather significant number of junior faculty; iv) facilitate the development of a sustainable center through the submission of program project grants and multi-PI grants. We will provide staff resource and pilot funding to enhance these activities.

project_terms:
5'-AMP-activated protein kinase;Appointment;Area;Award;Binding (Molecular Function);Biochemistry;Biophysics;CSNK2A1 gene;Cells;Centers of Research Excellence;Chemistry;Collaborations;Complement;Core Facility;Data;Development;Diabetes Mellitus;Disease;Electrophoresis Gel Two-Dimensional;Ensure;Equipment;Extramural Activities;Faculty;Family;Fatty Acids;Fee-for-Service Plans;Fluorescence;Funding;Genotype;Goals;Grant;Housing;Image;Individual;Investments;Kentucky;Life;Longevity;Malignant Neoplasms;Mass Spectrum Analysis;Medicine;Mentors;Microscopy;Molecular;Molecular Medicine;Mus;Natural Product Drug;Neurodegenerative Disorders;Neuropilins;Nursing Faculty;Organic Synthesis;Paper;Patients;Peptides;Phase;Phosphopeptides;Polymers;Positioning Attribute;Postdoctoral Fellow;Probability;Program Development;Program Research Project Grants;Proteins;Proteomics;Publications;Publishing;Recruitment Activity;Regulation;Research;Research Personnel;Research Project Grants;Research Training;Resources;Roentgen Rays;Role;Rosa;Sampling;Science;Scientist;Security;Services;Signal Transduction;Source;Spottings;Staining method;Stains;Surveys;T-Lymphocyte;Techniques;Technology;Translating;Ultracentrifugation;United States National Institutes of Health;Universities;Wages;Work;analog;base;career;college;design;graduate student;human disease;improved;instrumentation;interest;large scale production;medical schools;meetings;member;mouse model;nervous system disorder;novel;programs;success

public_health_relevance:
To enhace the competitiveness of junior faculty at the University of Kentucky throught the funding of promising junior faculty and providing state-of-the-art research cores.


application_id: 8487647
project_number: 3R42AT006639-03S1
project_title: Novel estrogen receptor ligands from plant genomics
administering_ic: NCCIH
award_notice_date: 2012-07-23
opportunity_number: PA-12-100
application_type: 3
activity_code: R42
ic: AT
serial_number: 006639
suffix: S1
program_official: HOPP, CRAIG
project_start_date: 2010-09-01
project_end_date: 2013-08-31
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Human nuclear receptor (HNR) ligands have potential value as pharmacotherapies or chemopreventive agents for many hormone-responsive cancers. The primary aim of this STTR is to transfer an "academic" plant genomics technology into drug discovery targeting HNR ligands. Estrogen receptor (ER) ligands in plants will be used for proof of application because these have clear commercial and therapeutic value in their own right. In phase1 transgenic Arabidopsis thaliana seedlings expressing a human ERalpha/GFP construct were used to screen extracts from a native plant library for ER ligands. 9 previously uninvestigated aquatic species were identified including species with agonist or antagonist activity at ERs in mammalian cell-based screens. In phase 2 representatives of these species will be investigated further using assay-guided HPLC fractionation to isolate active compounds which will be tested on breast cancer cells in vitro and in vivo. However the major aim in phase 2 is to apply the novel plant genomics technology to optimize the production of ER ligands in two plant species. In this technology transgenic hairy root cultures of a plant species are generated expressing either the ERalpha/GFP construct or a novel ERbeta/GFP construct. These cultures are then subjected to activation tagging mutagenesis (ATM) which induces random gain-of-function mutations in the genome. Now any individual mutant in which the production of ER ligands is increased should be identifiable by bright green fluorescence. This rapidly screens the "genomic capability" of the species to generate ligands for either ERalpha or ERbeta. In phase 1 proof of concept for this approach was achieved in a mutant population of transgenic A thaliana seedlings expressing ERalpha/GFP and in phase 2 we propose initially to apply this approach to hairy root cultures of Glycine max (soybean - known to contain high levels of ER ligands) and Cacalia plantaginea (a native plantain with high levels of ERalpha/beta agonist activity). Positive cultures will be characterized by their GFP expression and on the activity of culture extracts in conventional screens for ER activity. Attempts will also be made to regenerate intact mutant plants with the same over-producing phenotype and active fractions from mutant cultures or plants evaluated on breast cancer cells as above. The approach can be used with any HNR target and the major aim is to show that the technology can be transferred to anti-cancer natural product discovery.  The commercialization plan is aimed at licensing the technology or partnering with major companies to apply the technology to targets specified by the partner.  
  
PUBLIC HEALTH RELEVANCE: The technology transfer in this STTR promises to rapidly evaluate plant species for appropriate therapeutic activity at human nuclear receptors. The example chosen is for plant compounds with activity at the two types of human estrogen receptors (ERalpha and beta) which have different therapeutic implications particularly for breast cancer. This is the most common form of cancer in women and is the major cause of death for women under 60 in the USA. Many breast cancers are (initially at least) "hormone responsive" in that drugs which inhibit ERs markedly slow the growth of the cancer cells and this is a very active research area in the pharmaceutical industry. Plants are a known rich source of ligands for the ER but it has proven difficult to exploit this source because conventional plant drug discovery is often time-consuming and expensive. This technology promises to change this by applying genomics approaches to plant drug discovery in this area.

project_terms:
Agonist;Area;Binding (Molecular Function);Biological Assay;Biological Factors;Biotechnology;Breast Cancer Cell;Breast Cancer Treatment;Businesses;Cancer Cell Growth;Cause of Death;Cells;Chemopreventive Agent;Climate;Data;Development;Drug Industry;Estrogen Receptor alpha;Estrogen Receptor beta;Estrogen Receptors;Fluorescence;Fluorescence Microscopy;Foundations;Fractionation;Genome;Genomics;Glycine max;Green Fluorescent Proteins;High Pressure Liquid Chromatography;Hormone Responsive;Human;Image;In Situ;In Vitro;Individual;Intellectual Property;Legal patent;Libraries;Licensing;Ligands;Link;Malignant Neoplasms;Mammalian Cell;Marketing;Methodology;Mouse-ear Cress;Mutagenesis;Natural regeneration;Nuclear Receptor Gene;Nuclear Receptors;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Phase;Phenotype;Plant Extracts;Plant Genes;Plant Roots;Plantago;Plants;Population;Process;Production;Promotor (Genetics);Reporter Genes;Research;Screening procedure;Seedling;Small Business Technology Transfer Research;Source;Soybeans;Specific qualifier value;Specificity;Stream;Switch Genes;Technology;Technology Transfer;Testing;Therapeutic;Time;Transgenes;Transgenic Organisms;United States National Institutes of Health;Woman;base;cancer therapy;combinatorial chemistry;commercial application;commercialization;design;drug discovery;gain of function mutation;high throughput screening;in vivo;interest;malignant breast neoplasm;mutant;novel;phase 1 study;protein expression;public health relevance;research and development;success

public_health_relevance:
Project narrative (rewritten)The technology transfer in this STTR promises to rapidly evaluate plant species for appropriate therapeuticactivity at human nuclear receptors. The example chosen is for plant compounds with activity at the two typesof human estrogen receptors (ERalpha and beta) which have different therapeutic implications particularly forbreast cancer. This is the most common form of cancer in women and is the major cause of death for womenunder 60 in the USA. Many breast cancers are (initially at least) "hormone responsive" in that drugs whichinhibit ERs markedly slow the growth of the cancer cells and this is a very active research area in thepharmaceutical industry. Plants are a known rich source of ligands for the ER but it has proven difficult toexploit this source because conventional plant drug discovery is often time-consuming and expensive. Thistechnology promises to change this by applying genomics approaches to plant drug discovery in this area.


application_id: 8485697
project_number: 5R01NS072302-03
project_title: Preclinical evaluation of IGF1 therapy for traumatic brain injury
administering_ic: NINDS
award_notice_date: 2013-06-19
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: NS
serial_number: 072302
program_official: HICKS, RAMONA R
project_start_date: 2011-07-15
project_end_date: 2016-06-30
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) afflicts an estimated 1.5 million people each year in the US. Survivors often suffer persistent neurological dysfunction compromising their quality of life and productivity. Despite the expanding base of knowledge regarding the complex pathophysiology of TBI no clinically proven therapeutic interventions have been identified. TBI produces acute neurovascular damage and cell death resulting in early functional deficits. Recovery of function may be limited by the inability of the injured brain to adequately harness endogenous repair mechanisms. The central hypothesis of this proposal is that treatment with insulin-like growth factor-1 (IGF-1) will improve neurobehavioral function through the attenuation of neurovascular damage and the augmentation of posttraumatic neurogenesis and angiogenesis. We previously showed that administration of recombinant human IGF-1 (rhIGF-1) improves motor and cognitive function in brain-injured rats. However no studies have examined the neuroprotective or neurorestorative capabilities of IGF-1 in the traumatized brain. We propose to conduct the first comprehensive investigation of the multiple potentially synergistic mechanisms underlying the behavioral efficacy of IGF-1. Importantly we will evaluate the efficacy of rhIGF-1 treatment initiated within a clinically relevant therapeutic window of 8 hr and demonstrate sustained protection up to 5 weeks postinjury. In the setting of TBI IGF-1 is a promising therapeutic candidate as it has neuroprotective properties and helps to sustain or enhance myelination. Therefore after demonstrating in Aim 1 that a 7 day systemic infusion of rhIGF-1 initiated at 15 min 3 hr or 8 hr postinjury improves motor and cognitive function in mice subjected to cortical impact brain injury in Aim 2 we will test the hypothesis that IGF-1 protects against neuronal loss and axonal degeneration. IGF-1 is also known to stimulate proliferation of progenitor cells promote neuronal oligodendroglial and endothelial differentiation and increase angiogenesis in the brain. Therefore in Aim 3 we will test the hypothesis that infusion of rhIGF-1 enhances neurogenesis in the subgranular and subventricular zones. In Aim 4 we will employ novel vascular perfusion techniques to quantify densities of total and angiogenic vessels in brain- injured mice treated with rhIGF-1 or vehicle to test the hypothesis that IGF-1 effectively enhances posttraumatic angiogenesis. Finally in Aim 5 we will test the hypothesis that rhIGF-1 administration delayed 48 hr can selectively enhance neurogenesis and angiogenesis resulting in cognitive recovery in the absence of acute neuroprotection. These data will provide unique and valuable insights into the neurovascular targets for IGF-1 in the injured brain. By establishing long term (up to 5 wks postinjury) histological benefits and correlating these with behavioral responses the proposed studies have the potential for high clinical impact. Ultimately our goal is to provide a catalyst to accelerate the translation of IGF-1 therapy into clinical application in order to improve the health and well-being of individuals burdened with TBI.

project_terms:
Acute;Age;Attenuated;Axon;Behavioral;Blood Vessels;Brain;Brain Injuries;Bromodeoxyuridine;Cause of Death;Cell Death;Cells;Cerebral Ischemia;Cessation of life;Clinical;Clinical Trials;Cognition;Cognitive;Complex;Contusions;Cortical Contusions;Data;Demyelinations;Enrollment;Evaluation;Functional disorder;Goals;Health;Hippocampus (Brain);Human;IGF1 gene;Individual;Infusion procedures;Injury;Insulin-Like Growth Factor I;Investigation;Isolectin;Label;Learning;Measurement;Memory;Motor;Mus;Myelin;Nerve Degeneration;Neurologic Dysfunctions;Neurons;Outcome;Patients;Perfusion;Personal Satisfaction;Productivity;Proliferating;Property;Quality of life;Rattus;Recombinants;Recovery of Function;Research;Silver Staining;Spinal cord injury;Staining method;Stains;Stem cells;Survivors;Techniques;Testing;Therapeutic;Therapeutic Intervention;Time;Translations;Traumatic Brain Injury;angiogenesis;attenuation;axonal degeneration;brain repair;catalyst;cell injury;cell type;central nervous system injury;clinical application;clinically relevant;cognitive function;cognitive recovery;cognitive rehabilitation;controlled cortical impact;density;disability;functional outcomes;improved;injured;insight;knowledge base;myelination;neurobehavioral;neurogenesis;neuron loss;neuronal survival;neuroprotection;neurorestoration;novel;preclinical evaluation;rehabilitation strategy;repaired;response;stem;subventricular zone;tissue repair;tomato lectin


application_id: 8485634
project_number: 5R01HL078663-08
project_title: Lysolipid Signaling in Cardiovascular Disease
administering_ic: NHLBI
award_notice_date: 2013-06-12
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 078663
program_official: HASAN, AHMED A K
project_start_date: 2004-09-24
project_end_date: 2015-06-30
study_section: Special Emphasis Panel[ZRG1-VH-E(02)M]
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are essential bioactive lysolipid mediators that regulate a range of developmental and physiological processes and are emerging as targets for a new class of molecular therapeutics. In the cardiovascular system LPA is poised to serve as a mediator of atherothrombotic disease: it is abundant in atherosclerotic plaque present in the blood produced by activated platelets triggers phenotypic responses in smooth muscle cells and potentiates platelet activation. Exposure of LPA during atherosclerotic plaque rupture/erosion has been proposed as a key modulator of platelet thrombosis. We report a novel pathway for regulation of platelet LPA responses that involves recruitment of the lysophospholipase D enzyme autotaxin responsible for LPA production to activated platelets. We have also found that LPA inhibits mouse platelet function and that approximately 20% of human volunteers also lack a stimulatory response to LPA. We have evidence that this inhibitory LPA-signaling pathway confers vascular protection from thrombosis in mice and potentially from atherosclerotic disease in humans. We suggest that a therapeutic strategy directed at blocking stimulatory platelet LPA responses while promoting inhibitory ones could result in beneficial anti-thrombotic effects. Implementation of this strategy requires the molecular characterization of platelet LPA responses and proof of a role for circulating or locally produced LPA in regulating hemostasis and thrombosis. The broad goal of this proposal is to provide mechanistic insight essential for establishing LPA signaling as a viable anti-thrombotic target. We will take advantage of the differences in murine and human platelet LPA responses to identify the receptor(s) responsible for LPA signaling in mice and humans and then generate a transgenic mouse with platelet-specific expression of a stimulatory LPA receptor that phenocopies the human LPA response so that processes of relevance to human disease can be studied in a small animal mode. We are uniquely well-prepared to achieve these goals based on our expertise in bioactive lipid signaling and the tools we have amassed to study LPA in the vasculature. Completion of these studies promises to provide valuable insight into regulation of platelet function and may have exciting implications for the development of novel anti-thrombotic strategies that target LPA signaling.

project_terms:
Acute;Adenylate Cyclase;Affect;Agonist;Animal Model;Animals;Arterial Fatty Streak;Atherosclerosis;Binding (Molecular Function);Biological Models;Blood;Blood Platelets;Blood Pressure;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell physiology;Cell surface;Cells;Cyclic AMP;Data;Development;Developmental Process;Diagnosis;Dinoprostone;Disease;Dose;Enzymes;Event;Exposure to;Funding;G-Protein-Coupled Receptors;Genetic;Goals;Hemostatic function;Human;Human Volunteers;Hyperplasia;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Integrins;Investigation;Knowledge;Lipids;Lysophosphatidic Acid Receptors;Lysophospholipids;Mediator of activation protein;Molecular;Mortality Vital Statistics;Mus;Myocardial Infarction;Myocardial Ischemia;Nuclear Receptors;Pathway interactions;Peroxisome Proliferators;Phenocopy;Physiological;Physiological Processes;Physiology;Platelet Activation;Play;Positioning Attribute;Process;Production;Property;Prostaglandins;Regulation;Reporting;Research;Research Project Grants;Risk Factors;Role;Rupture;Signal Pathway;Signal Transduction;Smooth Muscle Myocytes;Surface;System;Testing;Therapeutic;Thrombosis;Transgenic Mice;United States;Vascular Diseases;Work;alkylglycerophosphoethanolamine phosphodiesterase;base;cell growth;cell motility;human disease;improved;in vitro Model;in vivo;innovation;insight;lysophosphatidic acid;novel;novel therapeutics;prevent;programs;prostaglandin EP3 receptor;public health relevance;receptor;receptor function;research study;response;sphingosine 1-phosphate;stroke;tool

public_health_relevance:
Atherothrombotic vascular disease is a leading cause of death in the United States. Blood platelets are essential for acute thrombotic events such as heart attacks and strokes and also contribute to local and systemic inflammation. This research project seeks to understand how the production of a class of pro-inflammatory lipid molecules is influenced by platelets and how the lipids affect platelet function. Completion of the work will provide new insights into pathways that could be targeted to prevent and treat arterial thrombosis.


application_id: 8485583
project_number: 5R03DE022538-02
project_title: NOVEL STATISTICAL MODELS FOR DENTAL CARIES
administering_ic: NIDCR
award_notice_date: 2013-06-12
opportunity_number: PAR-09-182
application_type: 5
activity_code: R03
ic: DE
serial_number: 022538
program_official: HARRIS, EMILY L
project_start_date: 2012-07-01
project_end_date: 2015-06-30
study_section: ZDE1-MH(03)
contact_pi_person_id: 9020729
contact_pi: DATTA, SOMNATH
other_pis: Not Applicable
congressional_district: 03
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this application is to undertake a detailed statistical examination of caries data obtained from the Iowa Fluoride Study. In this process novel statistical models will be developed for univariate and bivariate count data both longitudinally as well as cross-sectionally and marginally both at person level and tooth level.In the United States dental caries this is a major chronic childhood disease. Nevertheless our understanding of various risk factors is limited. The Iowa Fluoride Study is an ongoing study on a cohort of Iowa children that began in 1991 led by Dr. Steven Levy who is a co-I on this application. It is anticipated that through innovative and efficient statistical modeling it will e possible to mine the resulting data more fully and discover novel relationships between caries incidences/severity and various potential risk factors. We also plan to reinvestigate the issue of optimal fluoride use through joint modeling of bivariate count data of caries and fluorosis. Prior analysis using univariate approaches indicated that a recommendation of optimal dosage is problematic since the two marginal intervals for fluoride use towards caries and fluorosis prevention did not overlap on the face of subject to subject variability. Thus the following threebroad interconnected aims will be undertaken. We will develop count data models to study the dynamical changes of the various (risk) factors on caries incidence and severity including efficient computational methods for parameter estimation (Aim 1). We will develop various marginal models to understand the relationship between caries incidences and severity with various factors that are applicable across the population and evaluation periods (Aim 2). We will develop bivariate count data regression models to study the joint relationships of caries and fluorosis at comparable evaluations (Aim 3). We will compare our results to those obtained from existing approaches. Statistical software (R packages/codes) for the novel data analysis methods will be freely distributed through the Comprehensive R Archive Network.

project_terms:
Accounting;Archives;Biometry;Child;Childhood;Chronic;Code;Complex;Computer software;Computing Methodologies;Data;Data Analyses;Data Set;Dental Hygiene;Dental Research;Dental caries;Development;Disease;Evaluation;Face;Fluorides;Goals;Incidence;Individual;Intake;Investigation;Iowa;Joints;Lead;Methods;Mining;Modeling;Nature;Outcome Measure;Persons;Population;Prevention;Process;Recommendation;Regression Analysis;Research;Risk Factors;Role;Severities;Statistical Methods;Statistical Models;Tooth structure;United States;base;calcium intake;cohort;data modeling;dosage;fluorosis;innovation;novel

public_health_relevance:
The proposed research will lead to a detailed statistical examination of caries data obtained from the Iowa Fluoride Study. It will lead to novel findings regarding the role of potential risk factor for caries. In particular it will construct a predictie model for the bivariate relationships of development of caries and fluorosis that might lead to new recommendation for the optimal childhood fluoride intake. This research will not only be useful in greater understanding of dental caries but also will it add valuable contribution to biostatistics methodological research of statistical (regression) models for count data.


application_id: 8484756
project_number: 5R01HD061617-04
project_title: Function of RUNX transcription factors in COCs
administering_ic: NICHD
award_notice_date: 2013-05-31
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HD
serial_number: 061617
program_official: TAYMANS, SUSAN
project_start_date: 2010-09-24
project_end_date: 2015-05-31
study_section: Cellular, Molecular and Integrative Reproduction Study Section[CMIR]
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of the present proposal is to determine the molecular/cellular mechanism(s) involved in the maturation process of cumulus oocyte complexes (COCs). Proper maturation of the COC is critical to reproductive success in vivo and in vitro. Our lack of a complete understanding of this maturation process restricts our ability to manage fertility in vivo and hinders implementation of ART such as in vitro fertilization and in vitro maturation. Recent studies by our laboratory and others have begun to shed light on a small family of nuclear transcription factors RUNX1 and RUNX2 as key transcriptional regulators involved in COC expansion. Our preliminary data demonstrated that Runx1 and Runx2 expression is highly induced in cumulus cells of periovulatory follicles. We also found that RUNX1 and RUNX2 regulate the expression of Ptgs2 (a rate-limiting enzyme in the biosynthesis of prostaglandins) and Hapln1 (a stabilizer of cumulus matrix) in mural granulosa cells and/or cumulus cells. Both gene products are known to play crucial roles in COC expansion. Most importantly our pilot study demonstrated that over-expression of dominant negative RUNX in cumulus cells blocked COC expansion. Based on these novel findings we hypothesized that RUNX1/2 are essential transcriptional regulators necessary for the gonadotropin surge-induced COC expansion. This hypothesis will be tested by first demonstrating the functional significance of Runx1/2 expression in cumulus cells (Aim #1). Secondly we will determine the regulation action(s) of RUNX1 and RUNX2 on their target genes (Aim #2). Next we will determine the regulatory mechanism(s) of Runx1 and Runx2 expression in cumulus cells (Aim #3). These 3 Aims will be studied using rat COCs. To insure that the data obtained from rat studies is translatable to humans RUNX1/2 and their target gene expression profile will be also verified using human cumulus cells collected throughout the periovulatory period. We will also examine the correlation of the cumulus expression of RUNX1/2 and their target genes to oocyte quality fertilization and embryo development using COCs obtained from women undergoing IVF (Aim #4). These human studies will serve as a foundation for future translational/clinical application. The information obtained from the proposed studies will not only advance our understanding of the mechanism involved in COC maturation but also be instrumental for future translational/clinical application(s) thus leading to improved management of fertility in vivo and in vitro.

project_terms:
Adenoviruses;Anabolism;Animal Model;Cells;Collecting Cell;Competence;Complex;Data;Development;Dominant-Negative Mutation;Embryonic Development;Enzymes;Female;Fertility;Fertilization;Fertilization in Vitro;Foundations;Future;GDF9 gene;Gene Expression;Gene Expression Profile;Gene Targeting;Genes;Genetic Transcription;Goals;Gonadotropins;Hormonal;Human;In Vitro;Knowledge;Laboratories;Light;Link;Mediating;Mediator of activation protein;Molecular;Molecular Profiling;Mus;Nuclear Family;Oocytes;Ovarian;Ovulation;Peptides;Physiology;Pilot Projects;Play;Process;Promotor (Genetics);Prostaglandins;Proteins;RUNX1 gene;Rattus;Regulation;Role;Signal Transduction;Small Interfering RNA;Testing;Woman;base;clinical application;combinatorial;cytokine;granulosa cell;implantation;improved;in vivo;insight;novel;public health relevance;reproductive success;success;time interval;transcription factor

public_health_relevance:
Proper maturation of COCs is requisite for successful ovulation and fertilization. Appropriate COC expansion induced by the preovulatory gonadotropin surge is directly linked to oocyte quality and developmental competence. There are still huge gaps in our understanding of how the preovulatory gonadotropin surge induces the maturation process in COCs. Previous studies and our preliminary data suggest that RUNX transcription factor(s) plays a critical role in cumulus expansion by regulating the transcription of specific periovulatory cumulus genes. Building upon these findings the present proposal will determine the molecular/cellular mechanism(s) involved in COC expansion by elucidating the functional role(s) of RUNX transcription factors during maturation of COCs. Information derived from the present proposal will provide new insight into the mechanisms involved in COC maturation. Such knowledge can be applied for promoting and inhibiting this critical facet of ovarian physiology thereby allowing us to better manage fertility in vivo and in vitro.


application_id: 8484618
project_number: 4R33AI088585-03
project_title: Plant-produced Actinohivin as a Candidate HIV Microbicide
administering_ic: NIAID
award_notice_date: 2012-07-12
opportunity_number: RFA-AI-09-021
application_type: 4
activity_code: R33
ic: AI
serial_number: 088585
program_official: TURPIN, JIM A
project_start_date: 2010-06-10
project_end_date: 2015-06-30
study_section: ZAI1-EC-A(J1)
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
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):  Safe effective and inexpensive topical microbicides are urgently needed to curb the global human immunodeficiency virus type-1 (HIV-1) epidemic. Actinohivin (AH) is an actinomycete-derived lectin. This lectin specifically binds to high-mannose clusters uniquely found on the HIV-1 envelope (Env) thereby eliciting nanomolar antiviral activity against multiple HIV strains. Preliminary analyses revealed that AH has a high safety profile in human peripheral blood mononuclear cells (PBMCs) and in the rabbit vaginal irritation assay. Meanwhile a translational AH-AH fusion protein (recombinant dimer [rd] AH) was suggested to have stronger and broader anti-HIV-1 activity than the original monomer. Given these high potentials we hypothesize that rAH and/or rdAH (r/rdAH) are excellent HIV-1 microbicide candidates. This project's goal is to reveal the feasibilities of r/rdAH in terms of manufacture antiviral efficacy and safety upon use as a vaginal microbicide. In the R21 phase we will initially focus on developing a highly efficient scalable production system for r/rdAH that allows for extensive efficacy and safety studies and possible global use. We will utilize recombinant plant virus-based expression systems and various molecular biological approaches for rapid and high-level expression of high-quality r/rdAH. Upon obtaining bulk r/rdAH active pharmaceutical ingredients with high purity standards we will analyze HIV-1 neutralization effects against selected R5-type viruses in two in vitro HIV neutralization assays based on Env-pseudotyped virus-reporter gene expression and primary isolate- PBMC infection systems. Next r/rdAH' cytotoxic mitogenic and inflammatory potentials will be tested in PBMCs and/or human cervicovaginal (CV) epithelial cell lines to establish the minimal safety profile. Our success criteria in the R21 phase are: (1) establishing the bulk preparation procedure; (2) demonstrating cross- clade antiviral effects to R5 viruses; and (3) demonstrating no apparent in vitro cytotoxicity mitogenic activity or inflammatory potential at >100 times above an average anti-HIV IC50 for plant-made r/rdAH. Upon approval of our transition to the R33 phase we will comprehensively analyze anti-HIV-1 efficacy of r/rdAH for various modes of HIV-1 infection and transmission using various in vitro assay systems. In addition we will investigate potential overlap complementation synergy and antagonism of anti-HIV activities between r/rdAH and other inhibitors toward potential microbicide combination strategies. Finally we will perform extensive evaluations of r/rdAH upon vaginal application in rabbit and mouse models. We will thoroughly evaluate r/rdAH' vaginal toxicity inflammatory potential and stability. Upon determining the maximal tolerated dose of r/rdAH we will examine their potential immunogenicity and toxicity after a long-term exposure. Potential toxicity to the symbiotic vaginal commensal bacteria the Lactobacillus species will be examined. In summary the proposed studies should answer the question of whether r/rdAH is justified for advanced next-stage preclinical studies. . The proposed studies will analyze the feasibilities of the novel HIV-1-binding lectin Actinohivin and its derivative recombinant dimer as a candidate vaginal HIV-1 microbicide. The proposed studies should generate a comprehensive data set that will reveal their large-scale producibility anti-HIV-1 efficacy and broad toxicity profile upon vaginal application thereby providing criteria of whether Actinohivin and its derivative are justified for further extensive preclinical and clinical studies.

project_terms:
Affinity;Animal Model;Antiviral Agents;Binding (Molecular Function);Biochemical;Biological;Biological Assay;Cell Line;Cells;Clinical Research;Data Set;Dendritic Cells;Development;Dose;Drug Formulations;Drug Kinetics;Epidemic;Epithelial Cells;Evaluation;Gene Expression;Giant Cells;Goals;HIV;HIV-1;Human;Immune;In Vitro;Infection;Inflammatory;Inhibitory Concentration 50;Integration Host Factors;Lactobacillus;Lectin;Local Microbicides;Macaca;Mannose;Maximum Tolerated Dose;Methods;Modeling;Molecular;Mus;Oligosaccharides;Oryctolagus cuniculus;Peripheral Blood Mononuclear Cell;Pharmacodynamics;Pharmacologic Substance;Phase;Pilot Projects;Plant Viruses;Plants;Play;Polysaccharides;Preclinical Testing;Preparation;Procedures;Production;Proteins;Rage;Recombinant Fusion Proteins;Recombinants;Reporter Genes;Role;Safety;Seminal Plasma;Solutions;Specificity;Staging;System;T-Lymphocyte;Testing;Time;Toxic effect;Vagina;Viral;Virus;base;commensal microbes;cytotoxic;cytotoxicity;dimer;immunogenicity;improved;in vitro Assay;inhibitor/antagonist;irritation;meetings;microbicide;monomer;mouse model;novel;preclinical study;safety study;success;sugar;transmission process;vaginal microbicide

public_health_relevance:
Project Narrative. The proposed studies will analyze the feasibilities of the novel HIV-1-binding lectin Actinohivin and itsderivative recombinant dimer as a candidate vaginal HIV-1 microbicide. The proposed studies shouldgenerate a comprehensive data set that will reveal their large-scale producibility anti-HIV-1 efficacy and broadtoxicity profile upon vaginal application thereby providing criteria of whether Actinohivin and its derivative arejustified for further extensive preclinical and clinical studies.


application_id: 8484549
project_number: 1R15NR013563-01A1
project_title: Social Media Teen Moms and PPD
administering_ic: NINR
award_notice_date: 2013-06-12
opportunity_number: PA-12-006
application_type: 1
activity_code: R15
ic: NR
serial_number: 013563
suffix: A1
program_official: ROARY, MARY
project_start_date: 2013-06-15
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1 HDM-R (90)]
contact_pi_person_id: 6861568
contact_pi: LOGSDON, M. CYNTHIA
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 NURSING
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):    
Approximately 400000 live births occur to adolescents in the United States annually. Of the 50% of adolescent mothers who experience depressive symptoms less than 25% comply with referrals for depression evaluation and treatment due to lack of knowledge of depression symptoms (literacy) negative attitude towards mental health treatment perception that individuals with depression are stigmatized (subjective norms) lack of understanding of health resources that are available to her and under her control (perceived control) and lack of time. Untreated depression creates a public health problem in this vulnerable group impacting the adolescent's relationships functioning at work and school health care seeking behaviors mothering skills and development as well as the development of her child. An innovative and evidence based approach is needed that overcomes each of these barriers is feasible is acceptable to adolescent mothers and leads to greater rates of depression treatment. Social media is a promising vehicle to reach and educate adolescent mothers since most adolescent mothers use social media for communication and to search for health information. Based upon the Theory of Planned Behavior we will target 10 counties in Kentucky with a social media ad campaign that will result in adolescent mothers (n=140) from those counties enrolling in an internet based intervention related to postpartum depression. The previously tested intervention includes vignettes from other adolescent mothers questions and answers resources and an option to enroll in text message service. Before the intervention after the intervention and two weeks later the adolescent mothers will complete established questionnaires to determine if the intervention improved attitude and subjective norms towards depression and depression treatment perceived control and intention related to seeking depression treatment and the number of adolescent mothers with symptoms of depression who receive depression treatment. Data will be compared to scores on the same instruments from adolescent mothers (n=140) from the control group (10 other counties in Kentucky) that have not been targeted with the social media ad campaign or participated in the intervention. Data from the adolescent mothers in the control group will be collected in partnership with community agencies. The overall purpose of this trial is to test a cost effective and feasible method for reducing the cognitive an emotional barriers to accessing depression treatment in adolescent mothers. The specific aims are to (1) measure the extent to which a social media ad campaign is effective as a recruitment strategy; (2) test the effectiveness of an internet based social marketing intervention on both intention to seek treatment and rates of depression treatment and (3) examine the dose effect of the intervention. The innovative use of social media ads and an internet based social marketing intervention to increase rates of depression treatment in adolescent mothers has the potential to improve public health of two generations adolescent mothers and their infants and allows us to address a serious national health problem.

project_terms:
Address;Adolescent;Adopted;Adult;Area;Attitude;Behavior;Child Development;Clinical;Clinical Nursing;Cognitive;Communications Media;Communities;Community Hospitals;Control Groups;County;Data;Depression screen;Development;Discipline of Nursing;Dose;Effectiveness;Emotional;Enrollment;Evaluation;Exposure to;Generations;Health;Health Care Seeking Behavior;Health Promotion;Health Resources;Health behavior change;Healthcare;Healthcare Systems;Individual;Infant;Intention;Internet;Intervention;Intervention Studies;Kentucky;Knowledge;Live Birth;Marketing;Measures;Mental Depression;Mental Health;Methods;Mothers;Outcome;Patient Education;Pattern;Perception;Planning Theory;Policies;Postpartum Depression;Questionnaires;RQ2;Recruitment Activity;Research;Resources;Schools;Science;Services;Site;Social Change;Social Marketing;Societies;Symptoms;Teenagers;Testing;Text;Time;Underserved Population;United States;Vulnerable Populations;Work;base;behavior change;cost;cost effective;depressive symptoms;evidence base;experience;health disparity;improved;innovation;instrument;interest;intervention effect;literacy;new technology;programs;public health medicine (field);public health relevance;skills;social;teenage mother;urban area

public_health_relevance:
Fifty percent of teen mothers experience symptoms of depression but few seek or receive depression treatment. Untreated depression creates a public health problem in this vulnerable group impacting the teen's relationships her functioning at work and school healthcare seeking behaviors her mothering skills and her and her child's development. We will target teen mothers in 10 Kentucky counties with Google and Facebook ads invite them to participate in an internet intervention that encourages depression treatment and compare their rate of depression treatment to a control group of teen mothers in 10 other Kentucky counties.


application_id: 8484409
project_number: 5P20GM103436-13
project_title: KY IDeA Networks of Biomedical Research Excellence
administering_ic: NIGMS
award_notice_date: 2013-05-23
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
program_official: ARORA, KRISHAN
project_start_date: 2001-09-30
project_end_date: 2014-07-31
study_section: ZRR1-RI-4(01)
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Kentucky INBRE serves a statewide mission to build infrastructure and capacity for biomedical and health-related research and training as well as for bioinformatics. In this application the University of Louisville is partnered with the University of Kentucky Berea College Eastern Kentucky University Morehead State University Northern Kentucky University and Western Kentucky University to continue the development of our collaborative network. The goals of our network are to build competitive research and training programs in the biomedical and health sciences particularly in the fields of genomics and neuroscience as well as to build competitive bioinformatics programs. These efforts will lead to improved prospects for career development for our undergraduate and graduate students postdoctoral fellows and young faculty investigators. In this application we propose mechanisms to sustain as well as grow the competitive research component of this program as this aspect is viewed as critical to the establishment of our training and career development activities. This will include support for teaching-postdoctoral fellows and research associates for existing investigators program support for new research investigators and for the initiation of new developmental research projects. For bioinformatics we aim to support projects with the potential for development as competitive independent and/or collaborative proposals. To enhance the career development aspects for faculty postdoctoral fellows and prospective researchers in our program we will develop a mentoring team of proven investigators to provide workshops on grant writing skills and disseminate materials related to best practices. We intend to continue partial funding of our centralized microarray facility which is essential to the development of genomics-based research projects at this and other institutions and we will continue to develop initiatives in aid of our growing proteomics research base. We propose to establish a new community-based participatory research core. As a first step this core will establish web-accessible de-identified electronic health records for health care organizations in rural Kentucky. Health information gained from this activity will be used to inform the future development of our undergraduate and graduate curriculum content and our biomedical research goals. The infrastructure will also be used to enable the patient community to indicate their interest in participating in relevant clinical research trials. In summary our strategy is designed to strengthen and build our infrastructure and capacity and to build an innovative next generation network.

project_terms:
Bioinformatics;Biomedical Research;Clinical Research;Communities;Development;Educational Curriculum;Educational process of instructing;Educational workshop;Electronic Health Record;Faculty;Funding;Future;Genomics;Goals;Grant;Growth and Development function;Health;Health Sciences;Incentives;Institution;Kentucky;Lead;Mentors;Mission;Neurosciences;Patients;Postdoctoral Fellow;Proteomics;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Training;Rural;Training;Training Programs;Universities;Writing;base;career;career development;college;community based participatory research;design;graduate student;health care service organization;improved;innovation;interest;next generation;programs;prospective;skills;undergraduate student;web-accessible

public_health_relevance:
Health information gained from the development of a community-based participatory core will be used to inform the future development of our undergraduate and graduate curriculum content and our biomedical research goals. The infrastructure will also be used to enable the patient community to indicate their interest in participating in relevant clinical research trials.


application_id: 8484371
project_number: 5T32DA016176-10
project_title: Training in Drug Abuse Related Research
project_terms: Drug abuse;Research;Training
administering_ic: NIDA
award_notice_date: 2013-06-13
opportunity_number: PA-06-468
application_type: 5
activity_code: T32
ic: DA
serial_number: 016176
program_official: BABECKI, BETH
project_start_date: 2004-07-01
project_end_date: 2014-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
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:
DESCRIPTION ( provided by applicant):  This application is for renewal of a training program directed by Louis Hersh and co-directed by Linda Dwoskin and Sharon Walsh. We request continued support for four predoctoral and two postdoctoral trainees utilizing a training faculty of 15 housed in three colleges and 5 different departments within the University of Kentucky. All of the training faculty have been funded through NIDA or collaborate with NIDA funding training faculty with their research broadly focused on the molecular aspects of drug abuse. The University of Kentucky has a long history of involvement in drug abuse research and includes the Center on Drug and Alcohol Research and the Center for Drug and Alcohol Research and Translation. The goal of this training program continues to be the preparation of promising graduate students and postdoctoral fellows for careers in drug abuse research. The program provides broad-based training in modern aspects of drug abuse research with a particular emphasis on studying the cellular and molecular aspects of receptors involved in the response to drugs and the development of ligands which interact with these receptors as potential pharmacotherapy's for drug abuse. The training faculty share a common interest in understanding basic mechanisms related to drug abuse at the molecular level. The emphasis of the training faculty focus on the structure of opiate receptor ligands the effects of opiate receptor ligands on physiological processes and the structure and function of the proteins and ligands involved in opiate receptors. Trainees learn from a strong faculty who utilize state-of-the-art methodological approaches to drug abuse research. A unique aspect of this program is the interaction of trainees with other faculty and trainees involved in the behavioral aspects of drug abuse giving them a broad based understanding of drug abuse research. This unique training opportunity is hoped to fill the need for new investigators in drug abuse research who have a broad understanding of the field.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This program is designed to train graduate students and postdocs for a career in drug abuse research providing them with the tools to conduct research on the molecular aspects of drug abuse while at the same time endowing them with an understanding of the behavioral aspects of drug abuse.


application_id: 8482795
project_number: 1R01OH010425-01
project_title: Home healthcare hazard training through virtual simulation
administering_ic: NIOSH
award_notice_date: 2013-09-18
opportunity_number: PAR-10-188
application_type: 1
activity_code: R01
ic: OH
serial_number: 010425
program_official: FREDERICK, LINDA J
project_start_date: 2013-09-01
project_end_date: 2016-08-31
study_section: Safety and Occupational Health Study Section[SOH]
contact_pi_person_id: 11844758
contact_pi: POLIVKA, BARBARA J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract Healthcare provided in the home is increasing resulting in a greater number of professional caregiversproviding in-home services for ill and disabled persons. The number of home health aides is expected toincrease dramatically. The unique physical environment of each home results in challenges to worker safetyand health. Sixty percent of all injuries experienced by home health aides occurred inside patient homes andwere due to patient handling tasks medical devices equipment and other environmental factors. Given theincrease in health care provided in homes and the hazards faced by home healthcare workers it is critical thatworkers across disciplines have the ability to identify assess and respond to home hazards. The proposed project will (1) Develop a virtual simulation training system (VSTS) using aninterdisciplinary participatory design approach; (2) Assess the usability usefulness and desirability of theVSTS across multiple professional disciplines; and (3) Evaluate the efficacy of the VSTS in preparing homehealthcare professionals to recognize assess and respond to hazards in the home health environment usingappropriate risk perception and decision-making processes. The project will use an iterative participatory design approach to develop the VSTS and a randomizeddesign to determine its efficacy for training home healthcare professionals (Home Health Aides NursesOccupational Therapists and Physical Therapists). The VSTS will contain a Training Environment (TE) and anEvaluation Environment (EE). The TE will provide training in hazard identification assessment and responseas well as training in risk assessment and decision-making. The EE will allow an assessment of an individual'sability to identify assess and respond to hazards appropriately as well as an assessment of the decision-making processes used to evaluate risks in the home. To develop the VSTS we will recruit 90 participantsrepresenting seven professions involved with the provision in home healthcare (nurses home health aidesoccupational therapists physical therapists agency educators nurse managers and health and safetyexperts). These professionals will participate in focus groups interviews and ultimately VSTS testing toensure development of a relevant accessible and comprehensive training program. To test the efficacy of thetraining we will recruit 90 additional participants who will be randomly assigned to either the training (TE) orthe control condition. Differences in performance and risk assessment will be evaluated through descriptiveand inferential statistical analysis as well as qualitative "think aloud" techniques. Unique to this study is the use of virtual simulation as a training technique a participatory designapproach and the integration of decision making and risk perception measures into the training andevaluation. The impact of this work will be the development of a broadly available easily disseminated andaccessible health and safety training system for home healthcare workers across multiple disciplines.

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


