# projects

application_id: 8080667
project_number: 3R25HL084695-05S1
project_title: Summer Undergraduate Experiences In Biomedical Research
administering_ic: NHLBI
award_notice_date: 2010-06-03
opportunity_number: RFA-HL-05-018
application_type: 3
activity_code: R25
ic: HL
serial_number: 084695
suffix: S1
program_official: COMMARATO, MICHAEL
project_start_date: 2006-04-07
project_end_date: 2012-03-31
study_section: ZHL1-CSR-B(F1)
contact_pi_person_id: 1917399
contact_pi: JOSHUA, IRVING G
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
project_abstract:
The primary goal of this program is to provide minority and disadvantaged undergraduate students with aninitial exposure to basic science and clinical researchers and their areas of cardiovascular research at theUniversity of Louisville School of Medicine. It is anticipated that significant number of minority undergraduatestudents will elect to enter into graduate research programs at either this university or others around thecountry as a results of the experiences in our program. We also expect a limited number of medical studentsto participate in this program. It is hoped that these students will either pursue a research experience duringtheir residency or in a few cases pursue a combined degree in medicine and research (Ph.D. or M.S.). Specifically the program will emphasize the following: a. To develop an appreciation for the scientific method of investigation. Emphasis will be placed onexposing students to literature-based hypothesis generation proper experimental design and appropriatedata analysis procedures.b. Exposure to a biomedical research environment that emphasizes collaboration between basic scienceand clinical researchers and that clearly demonstrates the clinical relevance of cardiovascular research thatis being conducted at this university.c. To provide an accurate perception of the importance of animal research with emphasis on proper use ofanimals and an initial exposure to ethics in the conducting of these types of research studies;

project_terms:
Animal Experimentation;Animals;Area;Basic Science;Biomedical Research;Cardiovascular system;Clinical;Collaborations;Country;Data Analyses;Disadvantaged;Doctor of Philosophy;Environment;Ethics;Experimental Designs;Exposure to;Generations;Goals;Investigation;Literature;Medical Students;Medicine;Methods;Minority;Perception;Procedures;Research;Research Personnel;Residencies;Students;Universities;base;clinically relevant;experience;medical schools;programs;research study


application_id: 8079910
project_number: 1R01NS073584-01
project_title: ER stress and oligodendrocyte survival after spinal cord injury
administering_ic: NINDS
award_notice_date: 2011-01-31
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: NS
serial_number: 073584
program_official: KLEITMAN, NAOMI
project_start_date: 2011-02-01
project_end_date: 2016-01-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: HETMAN, MICHAL
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The endoplasmic reticulum (ER) is the intracellular organelle in which secretory and membrane proteins are synthesized and folded by resident chaperone proteins. The ER stress response (ERSR) is an evolutionarily conserved cell defense mechanism that protects against excessive accumulation of malfolded proteins in the ER. These malfolded proteins are translocated to the cytoplasm by the machinery of the ER- associated degredation (ERAD) where they are degraded. The ERSR is initiated after multiple cellular stresses including hypoxia inflammation trauma excitotoxicity and oxidative damage. The ERSR is initially protective but if malfolded proteins cannot be cleared apoptotic cell death initiates. The 3 pathways involved in the ERSR involve PERK IRE1/XBP-1 and ATF6 signaling. Preliminary data demonstrate upregulation of all 3 ERSR pathways following SCI. Mice null for CHOP a pro-apoptotic transcription factor that is downstream of PERK and activated during ERSR showed enhanced functional recovery after SCI and we identified oligodendrocytes as highly vulnerable to ER stress. We hypothesize that enhancing the protective or inhibiting the apoptotic aspects of the ERSR will enhance functional recovery after SCI. In Aim 1 we will potentiate the protective effectors of ERSR and in Aim 2 suppress those that initiate oligodendrocyte apoptosis. We will use a combination of pharmacological agents constitutive and conditional null mice as well as cell culture studies using wild type (WT) and available null oligodendrocyte precursor cells (OPCs) and/or siRNAs to address these questions.  
  
PUBLIC HEALTH RELEVANCE: Spinal cord injury (SCI) is a devastating injury for both patients and their families and at present there is no effective treatment either acutely or for chronic patients. This grant examines the role of the endoplasmic reticulum stress response a cellular defense mechanism induced in every spinal cord cell after SCI in mediating survival or death of myelinating oligodendrocytes after SCI. We expect to identify new acute therapeutic targets that will hopefully extend beyond SCI to other CNS trauma and neurological disease treatment.

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

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


application_id: 8079709
project_number: 5R01CA131075-02
project_title: The role of Mc1r in melanocytic UV-induced DNA damage and repair responses
administering_ic: NCI
award_notice_date: 2011-03-18
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 131075
program_official: OKANO, PAUL
project_start_date: 2010-07-01
project_end_date: 2015-04-30
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 8508402
contact_pi: D'ORAZIO, JOHN A
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): We seek to understand the molecular responses that occur when skin is exposed to UV radiation in order to devise novel strategies to protect against damage and carcinogenesis. In this proposal we will examine two major risk factors for skin cancer: UV radiation and pigment (melanin) phenotype. Our studies focus on the melanocyte and its cell surface receptor the melanocortin-1 receptor (Mc1r) which regulates melanin synthesis. We hypothesize that Mc1r protects melanocytes against UV-mediated mutagenesis and transformation by modulating melanization and recovery from UV-mediated cellular injury. Loss-of-function polymorphisms in Mc1r correlate with fair skin and a high incidence of melanoma while robust Mc1r function correlates with darker skin and UV resistance. We have developed a novel genetically-matched murine model of human skin as well as a protocol for growing primary melanocytes from these mice. These isogenic melanocytes span eumelanotic pheomelanotic and amelanotic melanin composition will serve a unique and potent tool to delineate the role of Mc1r function in response to UV. Using our unique animal model and primary melanocytes derived thereof we propose the following aims: Aim 1. Characterize the mechanism of Mc1r-mediated enhancement of nucleotide excision repair (NER); Aim 2. Determine whether Mc1r signaling protects against UV-mediated oxidative damage; and Aim 3. Determine the ability of pharmacologic Mc1r rescue to protect against UV damage. With respect to Aim 1 we will examine the role of Mc1r in the repair of UV-induced photolesions by southwestern and flow cytometric analysis and determine the influence of Mc1r on cellular levels of nucleotide excision repair enzymes by qRT-PCR and Western analysis. We will investigate a molecular link between Mc1r signaling and enhanced repair enzyme levels by examining expression of the NER enzymes basally and in the setting of UV irradiation and by investigating the ability of cAMP-responsive transcription factors downstream of Mc1r signaling (namely Mitf and CREB) to bind to and induce transcription of NER enzyme promoters. In Aim 2 we will study whether pheomelanin which is produced as a result of low Mc1r function promotes oxidative damage in melanocytes by complementary measures of oxidative load (DCF-mediated fluorescence flow cytometry Southwestern blotting hOGG1-adapted Comet assay TBARS assay and direct quantification of oxidative DNA adducts by GC/MS). Importantly we will directly test whether  
pheomelanin functions as a pro-carcinogen by an HPRT-based forward mutagenesis approach in primary melanocytes. Finally we will directly test the ability of forskolin an activator of adenylyl cyclase to bypass defective Mc1r function to enhance recovery from UV-mediated DNA damage and to rescue UV protection in melanocytes and in whole skin. Together these studies will lay the foundation for future translational studies designed to develop novel small molecule-based approaches for UV and cancer protection to prevent many cases of melanoma.  
  
PUBLIC HEALTH RELEVANCE:  Though it has long been known that people with functional defects of the melanocortin 1 receptor (Mc1r) protein are at high risk of developing melanoma the way(s) in which Mc1r protects against melanoma are not understood. Using pigment cells known as melanocytes we will study how the Mc1r protein influences UV- mediated DNA and cellular damage in melanocytes and contributes to melanoma resistance. Our goal is to develop the strategy of pharmacologic Mc1r rescue toward translational applicability so that many cases of melanoma can be prevented.


application_id: 8079690
project_number: 5R01CA115801-05
project_title: Redox Modulation of Prostate Cancer
administering_ic: NCI
award_notice_date: 2011-04-14
application_type: 5
activity_code: R01
ic: CA
serial_number: 115801
program_official: BERNHARD, ERIC J
project_start_date: 2007-08-01
project_end_date: 2012-11-30
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 1941793
contact_pi: ST CLAIR, WILLIAM H
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-06-01
project_abstract:
DESCRIPTION (provided by applicant):  The nuclear factor kappa beta (NF-kB) a redox-sensitive transcription factor is well established as a regulator of genes coding for both proapoptosis and prosurvival proteins. It has been shown that hormone-independent prostate cancer has a high constitutive level of NF-kB and activation of NF-kB by cancer therapeutic agents can blunt the activity of these agents to cause cancer cell death. The goal of this project is to gain insight into an NF-kB mediated mechanism leading to intrinsic radiation resistance and to identify novel approaches that can be used to improve the treatment of prostate cancer. Our initial data demonstrate that androgen-independent prostate cancer has high levels of selected members of the NF-kB family and its prosurvival NF-kB target gene products including the primary antioxidant enzyme manganese superoxide dismutase and the antiapoptotic protein BclXL. We also found that radiation induced activation of NF-kB in a two-wave pattern. We hypothesize that tumor cells with high levels of constitutive NF-kB will be sensitive to inhibition of the NF-kB mediated cytoprotective pathway and modulation of this pathway can improve the radiation response of aggressive prostate cancer. Parental PC-3 and its NF-kB mutant derived cell lines will be used as models for androgen-independent prostate cancer cells. Parental LNCaP and its corresponding derivatives will be used as models for androgen-dependent prostate cancer cells. Well characterized PC-3 derived as well as LNCaP derived prostate cancer cell lines will be studied in vitro and in vivo. Five-weeks-old male athymic nude mice will be used as hosts of human prostate cancer cells by orthotopic implantation in the prostate glands. Specific aim 1 is designed to identify specific members of the NF-kB family that play an important role in high intrinsic radioresistance of aggressive prostate cancer cells. Specific aim 2 is designed to test the concept that selective modulation of NF-kB or redox-based intervention can be used to enhance radiation sensitivity. Specific aim 3 is designed to validate the results from Specific aim 2 in an experimental therapeutic setting. Accomplishment of this study will enhance our understanding of the mechanisms by which members of the NF-kB family participate in cell survival. This information can serve as a rationale for the development of selective approaches that might eventually translate into significant clinical benefit.

project_terms:
Androgens;Antioxidants;Binding Sites;Cancer Etiology;Cell Death;Cell Line;Cell Survival;Cells;Cessation of life;Clinical;Clinical Treatment;Code;Data;Development;Dominant-Negative Mutation;Dose;Enhancer Elements (Genetics);Enzymes;Family;Family member;Free Radicals;Gene Targeting;Genes;Genetic Transcription;Goals;Growth;Hormones;Human;Implant;In Vitro;Interruption;Intervention;LNCaP;Location;Malignant Neoplasms;Malignant neoplasm of prostate;Manganese Superoxide Dismutase;Mediating;Modeling;Monitor;Mus;NF-kappa B;Nature;Nude Mice;Oxidation-Reduction;Oxidative Stress;PC3 cell line;Pathway interactions;Pattern;Play;Process;Promotor (Genetics);Prostate;Proteins;RNA;Radiation;Radiation Tolerance;Reactive Oxygen Species;Regulator Genes;Resistance;Role;Signal Transduction;Testing;Therapeutic;Therapeutic Agents;Time;Translating;Tumor Necrosis Factor Ligand Superfamily Member 6;androgen independent prostate cancer;base;cancer cell;design;direct application;implantation;improved;in vitro Model;in vivo;in vivo Model;inhibitor/antagonist;insight;male;member;men;mutant;neoplastic cell;novel strategies;overexpression;prevent;radiation effect;radiation resistance;research study;response;survivin;transcription factor;tumor


application_id: 8079641
project_number: 5R42HD055009-03
project_title: A device containing an immobilized chelator to remove aluminum from total parente
administering_ic: NICHD
award_notice_date: 2011-06-10
opportunity_number: PA-09-081
application_type: 5
activity_code: R42
ic: HD
serial_number: 055009
program_official: RAITEN, DANIEL J
project_start_date: 2008-03-01
project_end_date: 2015-05-31
study_section: Special Emphasis Panel[ZRG1-EMNR-E(10)B]
contact_pi_person_id: 7876821
contact_pi: YOKEL, ROBERT ALLEN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 623014201
duns_number: 623014201
fips: US
organization_id: 10008312
organization_name: ALKYMOS, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405173808
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-06-01
budget_end_date: 2015-05-31
project_abstract:
DESCRIPTION (provided by applicant): A high percentage of the ~ 500000 children born prematurely each year in the US require intravenous feeding after birth because they do not tolerate oral feeding. This is accomplished with a total parenteral nutrition (TPN) solution which is prepared from component solutions: small and large volume parenterals (SVPs and LVPs). Aluminum (Al) is a common contaminant in some SVPs particularly calcium gluconate solution. Excessive Al can produce toxicity to the skeletal system and brain and perhaps the liver. The potential for Al toxicity is significantly greater in humans such as premature infants who have reduced renal function; because the kidneys excrete Al. Medical personnel who care for neonates have suggested for decades that the Al in these solutions needs to be greatly decreased to avoid Al-induced toxicity. The FDA implemented a labeling requirement for these component solutions that sets a maximum Al concentration in LVPs and requires a statement of the maximum Al concentration in SVPs at expiry. This merely documents estimated maximum Al concentration. It is not the actual Al concentration nor does this reduce the Al in SVPs. Based on prior work to develop new chemicals that bind Al (chelators) the long- term objective is to develop a flow-through filter device containing a chelator that is immobilized on small polymer beads to remove Al from solutions. Based on results obtained using computational chemistry which predicted the strength of binding of novel immobilized chelators with Al and results obtained before and during the Phase I award from novel chelators we have synthesized it is proposed to advance the lead resin (a chelator immobilized on a resin bead) and develop prototype devices containing the lead resin and test these devices for their efficacy to remove Al from calcium gluconate solution and their safety. We will then assess the safety and efficacy of the resultant optimized device in a pre-clinical proof- of-principle piglet model of the neonate receiving TPN. The results will position this project to advance to Phase III in which the resin and device will be manufactured under cGMP conditions and the device tested in a clinical proof-of-principle study in neonates receiving TPN in a neonatal intensive care unit.  
  
PUBLIC HEALTH RELEVANCE: The proposed work will advance the lead resin (immobilized chelator) and develop and test prototype devices to contain the resin to create a medical device to remove a toxic contaminant aluminum (Al) from intravenous solutions. This device will be tested in a pre- clinical proof-of-principle study in an animal model of the neonate receiving intravenous feeding. This will remove the potential for Al to produce toxicity to premature infants and other patients who are exposed to Al through intravenous fluids solving a decades-old problem that has escaped resolution to date.

project_terms:
Address;Adult;Advocacy;Aluminum;Alzheimer's Disease;Animal Model;Award;Binding (Molecular Function);Birth;Brain;Businesses;Calcium;Calcium Gluconate;Caliber;Caring;Chelating Agents;Child;Childhood;Cholestasis;Clinical;Cyclic GMP;Development;Devices;Encephalopathies;Endotoxins;European;Excision;Filtration;Goals;Guidelines;HDPE;Health Personnel;Hemodialysis;Housing;Human;IV Fluid;Infant;Infant formula;Injection of therapeutic agent;Intake;Intravenous;Intravenous Feeding;Kentucky;Kidney;Label;Lead;Ligand Binding;Liver;Marketing;Medical Device;Membrane;Metabolic Bone Diseases;Metals;Methods;Modeling;Neonatal;Neonatal Intensive Care Units;Oral;Particulate Matter;Patients;Pharmacopoeias;Pharmacy facility;Phase;Plant Resins;Plastics;Polymers;Positioning Attribute;Premature Infant;Preparation;Price;Process;Production;Property;Pyrogens;Recommendation;Renal function;Research;Research Institute;Residual state;Resolution;Respondent;Risk;Safety;Skeletal system;Small Business Technology Transfer Research;Sodium Chloride;Solutions;Solvents;Stage 5 renal failure;Staging;Sterility;Stress;Surveys;Testing;Total Parenteral Nutrition;Toxic effect;United States;Universities;Variant;Work;base;chemical binding;chemical release;computational chemistry;design;drinking water;feeding;fluid flow;gluconate;meetings;mental development;neonate;novel;phase 2 study;pre-clinical;pressure;prototype;public health relevance;safety study

public_health_relevance:
The proposed work will advance the lead resin (immobilized chelator) and develop and testprototype devices to contain the resin to create a medical device to remove a toxiccontaminant aluminum (Al) from intravenous solutions. This device will be tested in a pre-clinical proof-of-principle study in an animal model of the neonate receiving intravenousfeeding. This will remove the potential for Al to produce toxicity to premature infants andother patients who are exposed to Al through intravenous fluids solving a decades-oldproblem that has escaped resolution to date.


application_id: 8079484
project_number: 5R03AG032099-02
project_title: Voxel Based Relaxometry Analysis of ADNI Images
administering_ic: NIA
award_notice_date: 2011-06-09
opportunity_number: PA-06-240
application_type: 5
activity_code: R03
ic: AG
serial_number: 032099
program_official: HSIAO, JOHN
project_start_date: 2010-06-01
project_end_date: 2013-11-30
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 6727688
contact_pi: HARDY, PETER 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): Alzheimer's disease is a neurodegenerative disease causing a progressive decline in the memory language and motor abilities of individuals affected leaving them increasingly debilitated and dependent. The high incidence of Alzheimer's Disease is predicted to have a dramatic increase in its prevalence and a commensurate increase in the costs to society. This situation requires the development of improved methods of early detection and identification of subjects likely to progress to full AD so that they might be properly triaged to appropriate therapy. Additionally new techniques for evaluating potential therapies to slow AD progression are urgently needed so that the most promising therapies are moved rapidly through clinical trials into public use. To study a potential non-invasive imaging method for the detection of the pathological changes occurring in the brains of patients who might develop Alzheimer's disease this project will test the hypothesis that individuals with mild cognitive impairment (MCI) and with AD will have a shorter T2 in the GM regions of the brain and higher T2 in WM regions of the brain compared with age and education-matched cognitively normal (CN) individuals. Our broad long-term goal is to develop image acquisition and analysis tools to measure physiological changes occurring in neurodegenerative diseases. Using image and psychometric data obtained on a large group of individuals followed as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI) the project will accomplish three specific aims: (1) To correlate the relaxation time T2 measured from images acquired at 1.5T on a voxel-by-voxel basis across the entire brain with the subject's cognitive status. (2) To correlate the increase in the relaxation rate 1/T2 with magnetic field strength B0 with the subject's cognitive status. (3) To test the power of T2 to predict the probability of conversion from MCI to AD. By comparing the relaxation times and rates of change of subjects who convert to AD with those who remain stable we will build a model relating initial and rates of change of T2 to the probability of conversion to AD. The results of the project will demonstrate that physiological changes in the brain occurring with the progression of Alzheimer's disease can be detected through MRI independently and potentially earlier than brain atrophy is detectable on MR images. Such a non-invasive and sensitive imaging technique will have widespread application in the management and investigation of AD.  
  
PUBLIC HEALTH RELEVANCE: This project makes use of a valuable collection of magnetic resonance images and clinical data on a large (800) group of elderly subjects acquired as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). The ADNI subjects are grouped into three categories cognitively normal mild cognitively impaired or Alzheimer's diseased and are followed for up to three years using MR imaging and clinical testing. ADNI is the most comprehensive effort to date to identify neuroimaging and other biomarkers of the changes associated with Mild Cognitive Impairment and Alzheimer's Disease. This proposed project will analyze the fast spin echo images acquired on the subjects at each of five study points and on two magnet field strengths to generate images sensitive to iron accumulation and axonal loss. The images will be analyzed using Voxel Based Relaxometry to determine brain sites associated with these physiological changes which accompany the progression of Alzheimer's disease. The research will make particular use of the unique information available from images of the same subjects acquired at two field strengths which will increase the likelihood of detecting an association between iron accumulation and the progression of Alzheimer's disease. The work will stimulate further exploration into the development and application of imaging techniques to provide independent information about the likelihood of Alzheimer's disease progression.

project_terms:
Affect;Age;Alzheimer's Disease;American;Area;Basal Ganglia;Brain;Brain region;Categories;Clinical;Clinical Data;Clinical Trials;Cognitive;Collection;Data;Degenerative Disorder;Deposition;Detection;Deterioration;Development;Diagnostic;Disabled Persons;Disease;Disease Progression;Early Diagnosis;Early identification;Educational aspects;Elderly;Ferritin;Fiber;Future;Goals;Image;Imaging Techniques;Impaired cognition;Incidence;Individual;Intervention;Investigation;Iron;Language;Left;Liquid substance;Magnetic Resonance Imaging;Measurement;Measures;Medial;Memory;Methods;Modeling;Motor;Neocortex;Nerve Degeneration;Neurodegenerative Disorders;Pathologic Processes;Pathology;Patients;Physiological;Population;Prevalence;Probability;Psychometrics;Relaxation;Research;Resolution;Risk;Senile Plaques;Site;Societies;Techniques;Temporal Lobe;Testing;Time;Triage;United States;Work;base;biomarker;cerebral atrophy;cost;effectiveness measure;imaging modality;improved;magnetic field;mild cognitive impairment;neuroimaging;public health relevance;research clinical testing;tool;white matter;white matter change

public_health_relevance:
NarrativeThis project makes use of a valuable collection of magnetic resonance images and clinical data on a large(800) group of elderly subjects acquired as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). TheADNI subjects are grouped into three categories cognitively normal mild cognitively impaired or Alzheimer'sdiseased and are followed for up to three years using MR imaging and clinical testing. ADNI is the mostcomprehensive effort to date to identify neuroimaging and other biomarkers of the changes associated withMild Cognitive Impairment and Alzheimer's Disease. This proposed project will analyze the fast spin echoimages acquired on the subjects at each of five study points and on two magnet field strengths to generateimages sensitive to iron accumulation and axonal loss. The images will be analyzed using Voxel BasedRelaxometry to determine brain sites associated with these physiological changes which accompany theprogression of Alzheimer's disease. The research will make particular use of the unique information availablefrom images of the same subjects acquired at two field strengths which will increase the likelihood of detectingan association between iron accumulation and the progression of Alzheimer's disease. The work will stimulatefurther exploration into the development and application of imaging techniques to provide independentinformation about the likelihood of Alzheimer's disease progression.


application_id: 8079447
project_number: 2R01MH072567-05
project_title: HIV-1 and amyloid beta interactions at the blood-brain barrier
administering_ic: NIMH
award_notice_date: 2011-06-21
opportunity_number: PA-07-089
application_type: 2
activity_code: R01
ic: MH
serial_number: 072567
program_official: RAO, VASUDEV RAMACHANDRA
project_start_date: 2005-09-20
project_end_date: 2012-03-31
study_section: Special Emphasis Panel[ZRG1 AARR-C (02)]
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
other_pis: Not Applicable
congressional_district: 06
department: NEUROSURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): A new element of HIV-1 epidemiology is an increase in the older population infected with HIV-1. This phenomenon is of significant concern because the increasing age may have a detrimental effect on their cognitive functions and facilitate and enhance the development of neurodegenerative diseases in HIV-infected patients. The present application is based on our recent observations that exposure to HIV-1 results in a significant increase in amyloid beta (A2) levels in human brain microvascular endothelial cells. These findings are consistent with strong clinical evidence that indicates increased amyloid deposition in the brain of HIV-1-infected patients. Because blood-borne A2 is the main source of amyloid deposition in the brain we formed the central hypothesis of the present proposal that HIV-1-induced specific alterations of transporter activities in brain endothelial cells results in intracellular A2 accumulation and its transendothelial passage. We identified that HIV-1-induced activity of the receptor for advanced glycation end products (RAGE) and alterations of ABC efflux transporters (namely P-glycoprotein [Pgp] and breast cancer resistance protein [BCRP]) may be involved in these processes. It is striking to note that these transporters are associated with cell membrane lipid rafts or their specific subset called caveolae. In addition expression of these transporters appears to be regulated by small GTPases such as the Ras and Rho pathways that are also localized in lipid rafts/caveolae. Therefore we propose that functional lipid rafts and caveolae provide the signaling platform that is detrimental for HIV-1-induced vascular mechanisms leading to A2 accumulation in the CNS.   
Data arising from our proposal will be critical for a better understanding of the molecular mechanisms underlying HIV-1-related cerebrovascular injury in older HIV-1-infected individuals. The results generated by the proposed research are also likely to be relevant to other neurodegenerative diseases that have significant cerebrovascular components and are associated with amyloid accumulation such as Alzheimer's disease.  
  
PUBLIC HEALTH RELEVANCE: We propose that exposure to HIV-1 can increase amyloid beta levels in the CNS by alterations of expression and activity of selected transporters at the level of the blood-brain barrier (BBB). Specifically we will explore the link between HIV-1-induced alterations of lipid rafts/caveolae-associated signaling differential regulation of the BBB transporters and accumulation of amyloid beta in brain endothelial cells followed by its transendothelial passage. In addition we will evaluate the protective effects of statins in these events. Data arising from our proposal will be critical for a better understanding of the molecular mechanisms underlying HIV-1-related cerebrovascular injury in older HIV-1-infected individuals. The results generated by the proposed research are also likely to be relevant to other neurodegenerative diseases that have significant cerebrovascular components and are associated with amyloid accumulation such as Alzheimer's disease.

project_terms:
AIDS neuropathy;ATP-Binding Cassette Transporters;Abbreviations;Address;Advanced Glycosylation End Products;Age;Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Amyloid deposition;Attenuated;Basic Science;Blood;Blood - brain barrier anatomy;Blood Circulation;Blood Vessels;Brain;Caveolae;Cells;Clinical;Data;Dependency (Psychology);Deposition;Development;Elements;Employee Strikes;Endothelial Cells;Epidemiology;Event;Excision;Exposure to;Family;HIV;HIV-1;Human;Individual;Injury;Link;Mediating;Membrane Microdomains;Molecular;Monomeric GTP-Binding Proteins;Movement;Neurodegenerative Disorders;Older Population;P-Glycoprotein;Pathology;Pathway interactions;Patients;Process;Production;Regulation;Research;Role;Signal Pathway;Signal Transduction;Source;Text;Therapeutic Agents;Transgenic Mice;abeta accumulation;amyloid formation;base;cerebrovascular;cognitive function;design;human ABCG2 protein;interest;member;migration;novel;protective effect;receptor;receptor function;receptor upregulation;rho

public_health_relevance:
We propose that exposure to HIV-1 can increase amyloid beta levels in the CNS by alterations of expression and activity of selected transporters at the level of the blood-brain barrier (BBB). Specifically we will explore the link between HIV-1-induced alterations of lipid rafts/caveolae-associated signaling differential regulation of the BBB transporters and accumulation of amyloid beta in brain endothelial cells followed by its transendothelial passage. In addition we will evaluate the protective effects of statins in these events. Data arising from our proposal will be critical for a better understanding of the molecular mechanisms underlying HIV-1-related cerebrovascular injury in older HIV-1-infected individuals. The results generated by the proposed research are also likely to be relevant to other neurodegenerative diseases that have significant cerebrovascular components and are associated with amyloid accumulation such as Alzheimer's disease.


application_id: 8079078
project_number: 5R01DA027068-03
project_title: Efficacy of Extended Release Tramadol for Treating Prescription Opioid Withdrawal
administering_ic: NIDA
award_notice_date: 2011-05-23
opportunity_number: RFA-DA-09-005
application_type: 5
activity_code: R01
ic: DA
serial_number: 027068
program_official: HAMPSON, AIDAN
project_start_date: 2009-08-15
project_end_date: 2013-07-31
study_section: ZDA1-EXL-T(06)
contact_pi_person_id: 8887956
contact_pi: LOFWALL, MICHELLE RENEE
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: 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): Approximately 1.7 million people in the United States met diagnostic criteria for prescription opioid abuse or dependence in 2007 and more than 2 million people initiated misuse of these medications in the last three years of the National Survey of Drug Use and Health. Given that opioid addiction is known to be chronic and relapsing and cause individual and societal public health problems (individual morbidity and mortality increased transmission of infectious diseases and crime) more efficacious treatment options for this disorder are needed. Currently approved maintenance medications for opioid dependence while efficacious have been hampered by limited patient acceptance (naltrexone) limited availability (methadone) and concerns about diversion (methadone and buprenorphine). Tramadol an atypical analgesic with opioid agonist activity that is uncontrolled by the Controlled Substances Act has reduced abuse potential relative to other full mu- opioid agonists and may be an effective treatment for opioid dependence. This two-week randomized placebo-controlled inpatient study has two phases each with one primary aim. Phase 1 (Days 1-7) will evaluate the withdrawal suppression efficacy of extended release (ER) tramadol for treatment of short-acting prescription opioid withdrawal. Phase 2 (Days 8-14) will assess the characteristics and severity of withdrawal from acute cessation of ER tramadol dosing and will provide further information about the strength of opioid agonist effects and dependence potential produced by tramadol. Persons age 18-55 years old with a positive observed opioid urine specimen self-report of use of a short-acting opioid at least 21 out of the last 30 days meeting diagnostic criteria for prescription opioid dependence (otherwise healthy) will be eligible for inpatient admission to the residential research unit. After the first overnight stay (to ensure a period of opioid abstinence) participants showing observable signs of opioid withdrawal will be randomized to one of three double-blind treatments: placebo or ER tramadol (400 or 800 mg daily given as two divided doses of matched capsules). Stratification will occur based on three levels of objective opioid withdrawal severity (low medium and high) as assessed by trained staff immediately prior to randomization. Twelve subjects will be needed to complete each treatment arm (n=36). Tramadol doses will be escalated over the first 24 hours to decrease chance of side effects. Ancillary medications are available to all groups to treat breakthrough withdrawal. Primary outcome measures include the participant-rated Opioid Adjectives Questionnaire Withdrawal Scale and amount of ancillary medication used for breakthrough opioid withdrawal during each Phase of the study. Numerous secondary outcome measures will be collected. The data gathered from this study will provide novel and important information regarding the dose-related withdrawal suppression efficacy of ER tramadol and determine whether tramadol produces a withdrawal syndrome after acute cessation. These results will be used to determine if a larger-scale evaluation of tramadol for prescription opioid dependence is warranted.  
  
PUBLIC HEALTH RELEVANCE: Prescription opioid addiction is a growing public health problem and more pharmacologic treatments are needed because current approved medications have had limited patient acceptance (naltrexone) limited availability (methadone) and concerns about misuse and diversion (methadone and buprenorphine). Tramadol is a currently approved medication used to treat moderate-severe pain and initial studies demonstrate that it may be useful for treatment of the uncomfortable syndrome of opioid withdrawal without producing euphoric effects. This study will determine whether two different doses of extended release tramadol can treat opioid withdrawal and whether tramadol itself produces withdrawal after it is no longer taken.

project_terms:
12 year old;Abstinence;Acute;Admission activity;Adverse effects;Age;Agonist;Analgesics;Buprenorphine;Cessation of life;Characteristics;Chronic;Cognition;Cognitive;Communicable Diseases;Crime;Data;Dependence;Diabetes Mellitus;Diagnostic;Disease;Dose;Double-Blind Method;Drug usage;Enrollment;Ensure;Evaluation;FDA approved;Health;Hepatic;Heroin;Hour;Hypertension;Illicit Drugs;Individual;Inpatients;Intravenous;Kentucky;Licensing;Life;Mainstreaming (Education);Maintenance;Measures;Medical;Methadone;Moods;Morbidity - disease rate;Morphine;Mortality Vital Statistics;Naltrexone;Opiate Addiction;Opioid;Oral;Outcome Measure;Pain;Parents;Participant;Patient Self-Report;Patients;Persons;Pharmaceutical Preparations;Phase;Physical Dependence;Pilot Projects;Placebo Control;Placebos;Population;Provider;Questionnaires;Randomized;Randomized Controlled Trials;Relapse;Relative (related person);Reporting;Research;Route;Safety;Schedule;Screening procedure;Severities;Societies;Specimen;Stratification;Substance Withdrawal Syndrome;Surveys;Syndrome;Task Performances;Time;Training;Tramadol;United States;Universities;Urine;Variant;Withdrawal;addiction;arm;base;capsule (pharmacologic);design;disease transmission;drug craving;effective therapy;epidemiologic data;meetings;monoamine;novel;opioid withdrawal;prescription opioid;prescription opioid abuse;primary outcome;public health medicine (field);public health relevance;reuptake;secondary outcome;volunteer

public_health_relevance:
PROJECT NARRATIVEPrescription opioid addiction is a growing public health problem and more pharmacologic treatments areneeded because current approved medications have had limited patient acceptance (naltrexone) limitedavailability (methadone) and concerns about misuse and diversion (methadone and buprenorphine).Tramadol is a currently approved medication used to treat moderate-severe pain and initial studiesdemonstrate that it may be useful for treatment of the uncomfortable syndrome of opioid withdrawal withoutproducing euphoric effects. This study will determine whether two different doses of extended releasetramadol can treat opioid withdrawal and whether tramadol itself produces withdrawal after it is no longertaken.


application_id: 8078922
project_number: 5P20RR016481-11
project_title: KY IDeA Networks of Biomedical Research Excellence
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
program_official: CANTO, MARIA TERESA
project_start_date: 2001-09-30
project_end_date: 2014-04-30
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:
DESCRIPTION (provided by applicant): 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 support 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.  
  
PUBLIC HEALTH RELEVANCE (provided by applicant): 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: 8078566
project_number: 2T35ES014559-06
project_title: Summer Environmental Health Sciences Training Program
administering_ic: NIEHS
award_notice_date: 2011-05-18
opportunity_number: PA-10-037
application_type: 2
activity_code: T35
ic: ES
serial_number: 014559
program_official: SHREFFLER, CAROL A
project_start_date: 2006-04-01
project_end_date: 2016-03-31
study_section: Environmental Health Sciences Review Committee[EHS (TK)]
contact_pi_person_id: 1886009
contact_pi: PROUGH, RUSSELL ALLEN
other_pis: MCCLAIN, CRAIG J.;SRIVASTAVA, SANJAY
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)   
  
 This NIEHS Short-Term Institutional Training Grant (5T35ES014559) application is to request support for 6 medical student trainees for the next 5 years. The overarching scientific theme of research that links the faculty to this T35 Training Grant is the common interest in research training of medical students in their laboratories in elucidating the health outcomes of exposure of obese individuals to various environmental or common chemicals in the environment. The faculty mentors involved come from the Department of Biochemistry & Molecular Biology (Klinge Prough and Ramos) Department of Medicine Division of Cardiovascular Medicine (Bhatnagar Conklin Prabhu and Srivastava) Division of Pulmonary Medicine (Roman Chair of Medicine) and Division of Gasteroenterology (Barve Cave Joshi-Barve and McClain) Department of Pharmacology & Toxicology (Arteel Hein and States) Department of Occupational and Environmental Health Sciences School of Public Health and Information Sciences (Hoyle and Tollerud) and Molecular Cellular & Craniofacial Biology Birth Defects Research Center School of Dentistry (Pisano).  Most are funded from the NIEHS or grants that support research directly relevant to environmental health sciences. The NIEHS Center directed by Ken Ramos encourages faculty to compete for more NIEHS grants through career development and pilot project grants to the junior and senior faculty respectively. The proposal contains two specific aims.    
  
Specific aim 1: To provide hands-on training in basic and clinical environmental health sciences- based research to medical students in a structured mentored environment.    
  
Specific Aim 2: To provide an interactive educational experience that introduces medical students the fundamental skills necessary for basic translational and clinical environmental health sciences-based research.    
  
The principal objectives of the Summer Environmental Health Sciences Research Training Program are to provide research experience for medical students and to stimulate interest among medical students in becoming clinical research scientists. Students who engage in research activities with faculty members will participate in projects germane to the field of environmental health and the health concerns of this country. The program includes didactic instruction (Syllabus for the "Summer Environmental Health Sciences Research Training Seminar Series"; Syllabus for the "Bench to Bedside Course") as well as a hands-on- research experience directed by experienced scientists interested in environmental medicine.


application_id: 8077960
project_number: 5R01CA091901-09
project_title: Novel Aureolic Acid-Type Antitumor Agents
administering_ic: NCI
award_notice_date: 2011-05-20
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 091901
program_official: FU, YALI
project_start_date: 2001-06-01
project_end_date: 2013-05-31
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 2257319
contact_pi: ROHR, JURGEN T
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Aureolic acid-type anticancer agents such as mithramycin (MTM) or chromomycin (CMM) are potent anticancer drugs with a unique mode-of-action. They inhibit the growth of cancer cells by cross-linking GC-rich DNA thereby shutting down specificity-protein (Sp)-dependent pathways towards various proto-oncogenes including c-myc and c-src the latter being associated with the unique hypocalcemic activity found for these drugs. Particularly MTM is important and has become a popular biochemical tool to study Sp-dependent signal transduction pathways but  due to its toxic side effects  is rarely used as anticancer agent except for the treatment of tumor hypercalcemia refractory to other chemotherapy. However MTM was recently identified as a potential lead drug against neurological diseases arthritis and for the treatment of hematologic disorders. All these new applications require only very small less toxic concentrations of the drug although the mode-of- action in these contexts remains obscure. MTM's biosynthesis has been studied intensely during the previous funding period of this research project and consequently pursued combinatorial biosynthetic efforts revealed various biosynthetic intermediates and new MTM-analogues. Two of these analogues MTM SK and MTM SDK showed a much better anticancer activity profile with a greatly improved therapeutic index than MTM itself. These new drugs deserve further investigations. During the previous biosynthetic studies biosynthetic intriguing and interesting key enzymes were discovered which need to be further investigated particularly oxygenase MtmOIV Ketoreductase MtmW glycosyltransferases MtmGIV MtmGIII MtmGII MtmGI and other early acting post-polyketide synthase tailoring oxygenases and reductases. The goal is to understand the role and mechanisms of these enzymes in the MTM biosynthesis and to optimize them for the engineering of novel MTM derivatives. It is planned to (a) further investigate unclear biosynthetic steps and mechanisms of the MTM and CMM pathways and to generate new MTM analogues applying combinatorial biosynthesis (b) to analyze intriguing oxygenases and reductases (c) to investigate and improve the substrate specificity of glycosyltransferases (d) to study in vitro and in vivo MTM SK MTM SDK and other promising MTM analogues developed during the project.   
  
PUBLIC HEALTH RELEVANCE: The proposed work aims to develop and refine a new generation of aureolic acid type natural product analogues with significantly diminished toxicity that will be useful mainly as anticancer drugs but also as drugs to treat neurological diseases arthritis and hematologic disorders. To enable the production of these fine-tuned drugs through combinatorial biosynthesis in-depth research of the biosynthetic machinery including key enzymes will be explored.

project_terms:
Address;Adverse effects;Anabolism;Antineoplastic Agents;Arthritis;Biochemical;Biological Factors;Cancer Cell Growth;Chromomycin A3;Chromomycins;DNA;Disease;Engineering;Enzymes;Funding;Generations;Goals;Hypercalcemia;In Vitro;Investigation;Lead;Methods;Oxidoreductase;Oxygenases;Pathway interactions;Pattern;Pharmaceutical Preparations;Plicamycin;Process;Production;Property;Proteins;Proto-Oncogenes;Refractory;Research;Research Project Grants;Role;SRC gene;Signal Transduction Pathway;Specificity;Substrate Specificity;Therapeutic Index;Toxic effect;Work;analog;anticancer activity;antitumor agent;c-myc Genes;chemotherapy;chromomycin;combinatorial;crosslink;design;enzyme mechanism;glycosyltransferase;improved;in vivo;interest;nervous system disorder;novel;olivomycin A;polyketide synthase;protein structure;public health relevance;research study;sugar;tool;tumor


application_id: 8077945
project_number: 5R01CA149274-02
project_title: Diffuse Optical Monitoring of Head and Neck Tumor Therapy
administering_ic: NCI
award_notice_date: 2011-05-23
opportunity_number: PA-07-279
application_type: 5
activity_code: R01
ic: CA
serial_number: 149274
program_official: BAKER, HOUSTON
project_start_date: 2010-07-01
project_end_date: 2015-04-30
study_section: Biomedical Imaging Technology Study Section[BMIT]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
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): Treatment with radiation or chemo-radiotherapy is the standard therapy for head and neck cancers but this treatment is well known to be less efficacious in patients with hypoxic tumors. Furthermore cancer therapy may alter tumor physiological status thus impacting treatment efficacy. Factors that modulate tumor oxygenation include blood flow blood oxygenation oxygen metabolism and nicotine levels (i.e. tobacco use). Tumor hemodynamics and metabolism however are not routinely measured during cancer therapy due to the lack of appropriate technologies. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are the best currently available and reproducible methods to measure target lesions selected for objective response assessment but these modalities require large and costly instrumentation that severely limits their routine use in clinics. The capabilities of diffuse optics for continuously monitoring tumor hemodynamics and metabolism during therapy at the clinical bedside have recently been demonstrated in our preliminary studies. The objective of this project is to develop and optimize a noninvasive versatile multi-modality clinical optical instrument to aid in evaluating and predicting tumor responses at the most early stage possible. More specifically this optical instrument will monitor and predict hemodynamic and metabolic responses to chemo- radiotherapy in head and neck tumors. We hypothesize that functional assessment of tumor physiological status and dynamic changes during therapy will provide information for early prediction of long-term treatment outcomes thus enabling clinicians to optimize therapy for each patient in a time sensitive fashion. To achieve this goal we will assemble a hybrid flow and oxygen system that combines a newly developed diffuse correlation spectroscopy (DCS) flowmeter with a commercial tissue-oximeter for simultaneous measurement of tumor blood flow oxygenation and oxygen metabolism (derived from the flow and oxygenation data). The instrument including optical probes and a software platform will be tested and optimized for continuous and longitudinal monitoring of tumor physiological status and hemodynamic/metabolic changes before during and after therapy in patients including smokers and nonsmokers (n=125). It is anticipated that significant correlations will be observed between therapy outcomes (e.g. tumor volume change tumor toxicity time to disease recurrence survival) and tumor physiological status and changes as well as nicotine levels. Different types of physiological parameters may show different sensitivities to cancer therapy in each patient which could reveal the primary factor(s) affecting individual therapy outcomes. Our novel hybrid optical system will provide hemodynamic and metabolic imaging contrasts complementary to those of CT and MRI and holds unique potential for early evaluating and predicting cancer therapy responses. Our long-term goal is to develop robust scientific collaborations to optimize and individualize cancer therapy at early stages with noninvasive optical technologies.  
  
PUBLIC HEALTH RELEVANCE: Treatment with radiation alone or in combination with chemotherapy is standard therapy for the head and neck cancers but this treatment is well known to be less efficacious in patients with poorly-vascularized/hypoxic tumors. The objective of this project is to develop and test a low-cost clinical-level optical instrument that can quickly assess tumor hemodynamic and metabolic status and responses to cancer therapy in the early stages. This in depth assessment of tumor hemodynamic and metabolic properties will provide essential information for the early prediction and evaluation of treatment outcomes thus enabling clinicians to optimize individual treatment.

project_terms:
Accounting;Acute;Affect;Aftercare;Blood;Blood Volume;Blood flow;Cessation of life;Clinic;Clinical;Collaborations;Computer software;Cotinine;Data;Data Analyses;Data Collection;Devices;Diffuse;Disease;Drug Delivery Systems;Evaluation;Exhibits;Fiber Optics;Flowmeters;Forearm;Goals;Head and Neck Cancer;Head and Neck Neoplasms;Hybrids;Hypoxia;Image;Individual;Lesion;Location;Magnetic Resonance Imaging;Malignant Neoplasms;Measurement;Measures;Metabolic;Metabolism;Methods;Modality;Monitor;Muscle;Nicotine;Non-smoker;Optical Instrument;Optical Methods;Optics;Outcome;Oxygen;Patient Care;Patients;Physiological;Progressive Disease;Property;Radiation;Radiation therapy;Recurrence;Reporting;Research;Roentgen Rays;Scanning;Serum;Smoker;Smoking;Spectrum Analysis;Stable Disease;Staging;System;Technology;Testing;Time;Tissues;Tobacco use;Toxic effect;Treatment Efficacy;Treatment outcome;Tumor Oxygenation;Tumor Volume;Ultrasonography;Withdrawal;X-Ray Computed Tomography;base;blood flow measurement;cancer therapy;chemotherapy;cost;design;follow-up;hemodynamics;improved;insight;instrument;instrumentation;novel;prognostic;prototype;public health relevance;response;simulation;therapy outcome;tissue phantom;tool;treatment duration;treatment planning;tumor


application_id: 8077285
project_number: 5R01HL085777-04
project_title: Engineered Early Embryonic Cardiac Tissue
administering_ic: NHLBI
award_notice_date: 2011-06-29
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 085777
program_official: SCHRAMM, CHARLENE A
project_start_date: 2008-07-01
project_end_date: 2013-05-31
study_section: Cardiovascular Differentiation and Development Study Section[CDD]
contact_pi_person_id: 1902498
contact_pi: KELLER, BRADLEY BARTH
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): We developed an Engineered Early Embryonic Cardiac Tissue termed EEECT using embryonic rat cardiac cells isolated during the period of cardiac morphogenesis in order to investigate the regulation of immature cardiomyocyte (CM) proliferation and differentiation and to generate implantable tissues with optimal properties for cardiac repair. Our EEECT construct preserves the unique proliferative and contractile properties of immature CM including a proliferative response to cyclic mechanical stretch. With prolonged culture EEECT acquires a post-natal phenotype (reduced proliferation and increased force production). Preliminary data show that EEECT implanted onto injured adult rat LV survive and improve LV diastolic and systolic function. In this revised R01-A2 proposal we identify molecular pathways that regulate EEECT CM proliferation and test our paradigm that EEECT is an optimal CM-rich tissue construct for cardiac repair. Specific Aim 1: Define molecular pathways that regulate EEECT CM proliferation during the transition from fetal to post-natal CM phenotype. We hypothesize that the regulation of CM proliferation and growth involves 2 concurrent processes: (1) CM proliferation to expand myocardial mass via p38 mitogen-activatedprotein kinase (p38MAPK) and Akt; and (2) CM sarcomere maturation and growth of non-proliferating CM via integrin-linked kinase (ILK) p38MAPK and Akt. We will use our in vitro EEECT model (generated from ED 14 embryonic rat cardiac cells) to define the impact of (1) cyclic mechanical loading; (2) stimulation or blockade of ILK p38MAPK and Akt; and (3) thyroid hormone treatment on CM proliferation and the phenotypic transition. Post-treatment characterization of EEECT will include: (1) histologic measures of CM proliferation differentiation and apoptosis; (2) biomechanical properties; (3) protein content and kinase activities; and (4) genome-wide changes in RNA transcript expression patterns. Specific Aim 2: Determine the fate of EEECT following implantation onto injured adult myocardium and the contribution of EEECT to recipient myocardial functional recovery and remodeling. We hypothesize implanted EEECT (1) display sustained CM proliferation and limited cell death; (2) positively contribute to the diastolic and systolic functional recovery of infarcted myocardium; and (3) become vascularized. We implant GFP+ transgenic rat EEECTs onto syngenic rat LV 2 weeks following myocardial infarction. Outcome assays at 3 days 2 weeks and 8 weeks include LV functional assay and histologic characterization of cell proliferation cell phenotype cell-cell coupling and vascularization. We further hypothesize that in vitro treatments that increase EEECT CM proliferation will increase in vivo EEECT CM survival and functional recovery. PUBLIC HEALTH RELEVANCE: Our proposed experiments first identify pathways that regulate cardiomyocyte proliferation and maturation within an Engineered Early Embryonic Cardiac Tissue (EEECT) generated using tissue culture and immature cardiac cells. We then evaluate the success of EEECT implantation onto the surface of the injured adult heart (myocardial infarction) as part of a cardiac repair and regeneration strategy.

project_terms:
Adrenergic Agents;Adult;Aftercare;Allogenic;Animals;Apoptosis;Autologous;Biological Assay;Biology;Biomechanics;Birth;Calcium;Cardiac;Cardiac Myocytes;Cardiomyoplasty;Cell Death;Cell Proliferation;Cell Proliferation Regulation;Cell Survival;Cell Therapy;Cell Transplants;Cells;Cicatrix;Clinical;Coupling;Data;Dimensions;Echocardiography;Embryo;Embryonic Development;Engineering;Environment;Extracellular Matrix;Failure (biologic function);Goals;Growth;Health;Heart;Heart Transplantation;Histologic;Human;Hypertrophy;Hypoxia;Implant;In Vitro;Infarction;Injury;Left ventricular structure;MAPK14 gene;Measures;Mechanics;Mitogens;Molecular;Molecular Genetics;Morphogenesis;Myocardial;Myocardial Infarction;Myocardium;Natural regeneration;Outcome;Pathway interactions;Pattern;Phenotype;Phosphotransferases;Population;Process;Production;Proliferating;Property;Proteins;Published Comment;RNA;Rattus;Recovery;Recovery of Function;Regulation;Sarcomeres;Signal Pathway;Stimulus;Stretching;Surface;Testing;Thyroid Hormones;Tissue Model;Tissues;Transcript;Transgenic Organisms;Translating;Transplantation;Treatment Protocols;Vascularization;adrenergic;extracellular;fetal;genome-wide;human MAPK14 protein;implantation;improved;in vivo;injured;insight;integrin-linked kinase;neovascularization;pressure;repaired;research study;response;response to injury;success;tissue culture

public_health_relevance:
Our proposed experiments first identify pathways that regulate cardiomyocyte proliferation and maturationwithin an Engineered Early Embryonic Cardiac Tissue (EEECT) generated using tissue culture and immaturecardiac cells. We then evaluate the success of EEECT implantation onto the surface of the injured adult heart(myocardial infarction) as part of a cardiac repair and regeneration strategy.


application_id: 8077273
project_number: 5K01DA021309-05
project_title: Rural Drug Abuse Treatment: Organizations Counselors and Client Outcomes
administering_ic: NIDA
award_notice_date: 2011-06-06
opportunity_number: PA-06-001
application_type: 5
activity_code: K01
ic: DA
serial_number: 021309
program_official: JONES, DIONNE
project_start_date: 2007-07-15
project_end_date: 2014-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 6264981
contact_pi: OSER, CARRIE BETH
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The primary goal of this revised K01 application is to further develop a productive independent research career in substance abuse treatment. The major changes in this revised application include the addition of an ecological theoretical framework supplementary didactic and experiential qualitative training as well as improved recruitment and analytic strategies. Additional training will enhance Dr. Carrie Oser's experience in organizational-level models to encompass a multi-level perspective and broaden her research focus to rural areas. The proposed training goals will provide additional instruction in: (1) the cultural nuances of rural communities (2) qualitative research methods (3) advanced statistical training specific to multi-level modeling (e.g. HLM SEM) and (4) the conduct of ethical research. Dr. Carrie Oser will be sponsored by Dr. Carl Leukefeld who has experience in rural substance abuse research. The overall goal of this revised research plan is to better understand counselor contextual and organizational contributions to rural treatment outcomes in public treatment facilities. The specific aims are: (1) to describe the characteristics of rural clients as compared to urban clients; (2) to examine the characteristics and treatment practices of rural counselors as compared to those employed in urban facilities; (3) to identify the organizational characteristics of state-funded treatment facilities in rural counties as compared to urban utilizing a PDA-based data collection methodology; (4) to develop two-level hierarchical linear models from an ecological perspective to predict rural treatment outcomes and urban treatment outcomes; (5) to separately examine the proportional contributions of client-level factors counselor contextual factors and organizational factors to rural treatment outcomes and urban treatment outcomes using an ecological theoretical framework. This project will significantly contribute to understanding community treatment and client outcomes in rural and urban counties. The focus on treatment outcomes within rural public treatment facilities is a logical transition from Dr. Oser's graduate work on the adoption of innovative pharmacological treatments within privately funded treatment organizations. This proposed project will allow for a practical application of the substantive knowledge and analytical skills acquired from the K01 training activities and will ultimately culminate in the development of future investigator initiated NIDA grant applications.

project_terms:
Administrator;Adoption;Age;Alcohol or Other Drugs use;Applications Grants;Area;Attention;Belief;Censuses;Characteristics;Client;Climate;Clinical;Commit;Communities;County;Criminal Justice;Development;Drug abuse;Educational aspects;Emotional;Employment;Employment Status;Environment;Ethics;Evaluation Studies;Funding;Future;Goals;Instruction;Intention;Knowledge;Lateral;Linear Models;Literature;Mental Health;Modeling;Motivation;National Institute of Drug Abuse;Organizational Change;Outcome;Patient Self-Report;Perception;Pharmaceutical Preparations;Pharmacological Treatment;Principal Investigator;Professional Education;Professional counselor;Qualitative Research;Recording of previous events;Recovery;Reporting;Research;Research Methodology;Research Personnel;Resources;Rural;Rural Community;Services;Site;Structure;Substance abuse problem;Substance of Abuse;System;Techniques;Therapeutic;Training;Training Activity;Training and Education;Treatment outcome;Work;base;career;contextual factors;data collection methodology;demographics;exhaustion;experience;follow-up;health care service utilization;improved;innovation;metropolitan;organizational climate;organizational structure;practical application;pressure;programs;psychologic;rural area;skills;substance abuse treatment;treatment as usual;treatment organization;treatment program;urban area


application_id: 8077261
project_number: 5R01EY017594-04
project_title: The Role of CaMKII in Cell Death and Survival Responses of Retinal Ganglion Cells
administering_ic: NEI
award_notice_date: 2011-05-18
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 017594
program_official: GREENWELL, THOMAS
project_start_date: 2008-06-01
project_end_date: 2013-05-31
study_section: Biology and Diseases of the Posterior Eye Study Section[BDPE]
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:
DESCRIPTION (provided by applicant): The signal transduction and gene regulatory events which occur downstream of the precipitating causes of retinal diseases is largely unknown. Yet these downstream sites would be excellent targets for interventional therapies. The long term goal of the proposed research is to define the role of calmodulin dependent protein kinase II (CaMKII) which is likely downstream of the initiating events in eye diseases like retinal ischemia. CaMKII is upstream of the cell death and survival pathways in retinal ganglion cells (RGCs). We know that when challenged with glutamate receptor agonists: 1) retinal cytoplasmic CaMKII1 becomes autophosphorylated; 2) there is an increase in the alternatively spliced nuclear transcript CaMKII1B; 3) caspase-3 becomes activated and 4) cells in the inner nuclear and ganglion cell layers die. We have demonstrated that the specific inhibitor of CaMKII autocamtide inhibitory peptide (AIP) blocks these changes (1 3 and 4) and protects all cells from cell death. Pilot data with the aid of a cell line indicates that the AIP promotes the secretion of brain derived neurotrophic factor (BDNF) which may aid the survival of challenged cells. We also know that an elevated level of CaMKII1B (2) is associated with enhanced transcription of BDNF. Since glutamate is implicated in retinal ischemia and CaMKII1 is also activated in this condition we hypothesize that CaMKII1 plays an important role in pathways involved in the death and survival responses of RGCs during retinal ischemia. This will be tested with methods which include RNA- interference for the CaMKII1B transcript. We will use a rat retinal ischemia-reperfusion model as well as primary cultured rat RGCs and ex vivo retinal explants. Aim 1 will determine the time frame in which AIP protects RGCs during/after ischemia. Aim 2 will explore the role of cytoplasmic CaMKII in regulating caspase-3 activation NF:B translocation and BDNF release in RGC/retinas. Aim 3 will explore the role of nuclear CaMKII1 in cell death/survival and the underlying mechanisms. The results of these studies will provide important insights into the signal transduction pathways and gene regulatory networks that control death and survival responses of RGCs which will be of relevance to retinal ischemia. PUBLIC HEALTH RELEVANCE: Retinal ischemia a common clinical entity that has been widely studied because of its proposed role in for example retinal and choroidal vessel occlusion anterior ischemic optic neuropathy glaucoma and diabetic retinopathy etc remains a common cause of blindness in the developed world due to relatively ineffective treatment. We propose to explore the signal transduction pathways linked to gene regulatory networks which control cell death and survival processes in rat retinal ganglion cells whose death is a major contributing factor for visual impairment in these diseases. Knowledge of such pathways and networks is important for the development of practical therapeutic interventions.

project_terms:
Acute;Affect;Agonist;Animal Model;Anterior Ischemic Optic Neuropathy;Blindness;Brain-Derived Neurotrophic Factor;Calcium/calmodulin-dependent protein kinase;Cell Death;Cell Line;Cell Survival;Cells;Cessation of life;Clinical;Data;Development;Diabetic Retinopathy;Disease;Equilibrium;Event;Eye diseases;Ganglion Cell Layer;Gene Targeting;Genes;Genetic Transcription;Glaucoma;Glutamate Receptor;Glutamates;Goals;Health;In Vitro;Injection of therapeutic agent;Intraperitoneal Injections;Ischemia;Knowledge;Laboratories;Link;Mediating;Methods;Modeling;N-Methylaspartate;Nuclear;Pathway interactions;Patients;Peptides;Phosphotransferases;Play;Process;Protein Isoforms;RNA Interference;RNA Splicing;Rattus;Regulator Genes;Reperfusion Therapy;Research;Retinal;Retinal Diseases;Retinal Ganglion Cells;Role;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Site;Testing;Therapeutic Intervention;Time;Transcript;Transduction Gene;Visual impairment;autocrine;calmodulin-dependent protein kinase II;caspase;caspase-3;inhibitor/antagonist;insight;neuroprotection;paracrine;prospective;response;retinal ischemia;retinal neuron;transcription factor


application_id: 8077237
project_number: 5R01DC008168-05
project_title: Perceptual processing of indirect sound
administering_ic: NIDCD
award_notice_date: 2011-06-10
application_type: 5
activity_code: R01
ic: DC
serial_number: 008168
program_official: KING, KELLY ANNE
project_start_date: 2007-07-01
project_end_date: 2013-06-30
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 1908853
contact_pi: ZAHORIK, PAVEL A
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: 2011-07-01
project_abstract:
DESCRIPTION (provided by applicant):  The processes by which we hear auditory events in most everyday acoustic environments that produce ndirect sound (e.g. echoes reflections reverberation) are complex and not well understood. Under certain circumstances indirect sound can facilitate speech communication and certain aspects of sound localization n other circumstances however indirect sound can produce deficits in these and other abilities that can be particularly large for individuals with hearing impairment. Recent results have demonstrated that some aspects of indirect sound processing appear to be affected by previous exposure to the acoustic environment which suggests a form of perceptual adaptation. Although these adaptation effects can be substantial for situations with a single echo the effects have not been evaluated in more realistic acoustic environments with complex patterns of indirect sound resulting from multiple echoes and reverberation. The ong-term goal of this project is a complete understanding of the mechanisms and the potentially adaptive processes that subserve auditory localization and communication in everyday acoustic environments with complex patterns of indirect sound and the potential impact of hearing loss on these processes. This goal will be addressed by the following Specific Aims: Specific Aim 1: Demonstrate and quantify environment- adaptation effects on sound localization and speech intelligibility for a single realistic acoustical environment configuration. Specific Aim 2: Determine the sensitivity of environment-adaptation effects to particular environments and source/listener configurations. Specific Aim 3: Quantify the time course of environment- adaptation effects. Specific Aim 4: Quantify the effects of source or listener motion on environment- adaptation effects. The research proposed to address these aims uses state-of-the-art virtual acoustic environment simulation techniques for auditory stimulus control that enable testing of listening situations that would not be possible in real environments. Knowledge gained from these studies will lead to an improved understanding of a significant public health problem: the impairment of communication and localization in acoustically reflective or reverberant environments resulting from hearing loss. This knowledge may facilitate improvements in both assistive technologies (signal processing algorithms within hearing aids and cochlear implants) and the acoustical design of listening environments. KEYWORDS: Sound Localization Spatial Hearing Speech Intelligibility Room Acoustics Adaptation Virtual Auditory Space.

project_terms:
Acoustics;Address;Affect;Algorithms;Auditory;Auditory system;Brain;Brain Stem;Cochlear Implants;Communication;Communication impairment;Complex;Dependence;Ear structure;Environment;Event;Exposure to;Goals;Hearing;Hearing Aids;Human;Individual;Knowledge;Lead;Mediating;Motion;Pattern;Performance;Positioning Attribute;Process;Property;Recording of previous events;Research;Research Personnel;Research Support;Role;Self-Help Devices;Sound Localization;Source;Speech;Speech Intelligibility;Stimulus;Surface;Techniques;Testing;Time;Travel;Work;auditory stimulus;base;computerized data processing;design;environmental adaptation;experience;hearing impairment;improved;interest;loss of function;precedence effect;programs;public health medicine (field);research study;simulation;sound;virtual


application_id: 8076171
project_number: 5R01NS051568-05
project_title: Mechanisms of Cerebral Vascular Remodeling
administering_ic: NINDS
award_notice_date: 2011-05-30
opportunity_number: PAS-04-072
application_type: 5
activity_code: R01
ic: NS
serial_number: 051568
program_official: CORRIVEAU, RODERICK A
project_start_date: 2007-06-01
project_end_date: 2013-05-31
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  High levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) are associated with cerebral- vascular disease dementia stroke and Alzheimer's disease. The ?-amino butyric acid (GABA) stimulates the inhibitory neurotransmitter GABA-A receptor and decreases vascular dementia and stroke. The novelty of this proposal is that Hcy specifically competes with the GABA-A receptors and acts as an excitotoxic neurotransmitter. Hcy activates cerebral vascular matrix metalloproteinases (MMPs) by inducing redox stress and reactive oxygen species (ROS): The long-term goal of this proposal is to understand the mechanisms of cerebral vascular remodeling in HHcy. The hypothesis of this proposal is that Hcy induces MMPs and suppresses tissue inhibitors of metalloproteinase (TIMPs) in part by inhibiting the GABA-A receptor. This leads to degradation of the matrix and disruption of the blood brain barrier We will test this hypothesis by three specific aims: Specific aim #1: To determine whether Hcy increases levels of NADH oxidase and ROS and decreases levels of thioredoxin and peroxiredoxin by attenuating the GABA-A receptor. Levels of NADH oxidase activity and thioredoxin in brain cortex of transgenic mouse model of HHcy (cystathionine  synthetase CBS -/+) and GABA-A receptor null mice treated with and without muscimol (GABA-A receptor agonist) will be measured. The mRNA levels will be measured by Q-RT-PCR. Specific aim #2: To determine whether Hcy increases metalloproteinase activity and decreases TIMP activity by antagonizing the GABA-A receptor. Levels of MMP-2 -9 -13 and TIMP-1 -2 -3 and -4 will be measured by innovative 2-D zymography functional proteome Western blots and Q-RT-PCR analyses. Specific aim #3: To determine whether Hcy alters brain microvascular reactivity and increases permeability of brain microvessels by augmenting GABA-A receptor. Brain microvascular permeability will be measured by in vivo video fluorography using fluorescence-labeled albumin. The vascular reactivity will be measured by a topical application of vasoactive agents. These studies will demonstrate a novel mechanism in which brain microvascular permeability changes during HHcy and vascular dementias and will have therapeutic ramifications for microvascular disease in Alzheimer's patients.

project_terms:
2266-tetramethyl-4-piperidinol-N-oxyl;Abbreviations;Adenosine Diphosphate;Agonist;Albumins;Alteplase;Alzheimer's Disease;Antioxidants;Arginine;Attenuated;Basement membrane;Blood - brain barrier anatomy;Blood Vessels;Brain;Butyric Acids;Caliber;Cerebrum;Collagen;Cystathionine;Dementia;Diabetic Angiopathies;Disintegrins;Endothelial Cells;Extracellular Matrix;Extravasation;Fluorescence;Functional disorder;GABA-A Receptor;Gelatinase A;Gelatinase B;Goals;Heterozygote;Homocysteine;Homocystine;Hydrolase;Hyperhomocysteinemia;Knock-out;Knockout Mice;Label;Ligase;MTHFR gene;Matrix Metalloproteinases;Measures;Mediating;Messenger RNA;Metalloproteases;Methionine;Methylenetetrahydrofolate reductase (NADPH);Microvascular Permeability;Muscimol;N-Methylaspartate;NADH oxidase;NADP;Neurotransmitters;Niacinamide;Nitric Oxide Synthase;Norepinephrine;Oxidation-Reduction;Patients;Permeability;Plasma;Polymerase Chain Reaction;Process;Proteome;Reactive Nitrogen Species;Reactive Oxygen Species;Research Personnel;Reverse Transcriptase Polymerase Chain Reaction;Secondary to;Seizures;Stress;Structure of thyroid parafollicular cell;Testing;Therapeutic;Thioredoxin;Time;Tissue Inhibitor of Metalloproteinase-1;Tissue Inhibitor of Metalloproteinases;Topical application;Transgenic Mice;Vascular Dementia;Vascular Diseases;Vascular remodeling;Western Blotting;Wild Type Mouse;cerebrovascular;constriction;gamma-Aminobutyric Acid;human NOS3 protein;in vivo;innovation;micrography;mouse model;novel;peroxiredoxin;programs;receptor;relating to nervous system;stroke;tetrahydrobiopterin;tissue inhibitor of metalloproteinase 4;vasoactive agent


application_id: 8075560
project_number: 5R01DE019243-04
project_title: Mathematical Model of Parotid Acinar Differentiation
administering_ic: NIDCR
award_notice_date: 2011-06-01
opportunity_number: RFA-DE-08-001
application_type: 5
activity_code: R01
ic: DE
serial_number: 019243
program_official: BURGOON, PENNY W
project_start_date: 2008-09-16
project_end_date: 2013-05-31
study_section: ZDE1-RW(17)
contact_pi_person_id: 1878918
contact_pi: DARLING, DOUGLAS S
other_pis: REMPALA, GRZEGORZ A
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long term goal of the proposed project is to define the development of signaling networks that induce differentiation of cells into mature salivary serous acinar cells to allow gene therapy approaches to regenerating or replacing salivary tissue in patients. Millions of patients suffer loss of salivary gland function due to Sj"gren's syndrome or radiation therapy. Understanding the differentiation of salivary cells is a necessary step to enable the restoration of diseased or destroyed parotid salivary tissue. Previous work has described terminal differentiation of acinar cells histologically and by characterizing the expression of markers of differentiation but has not used genomics-level approaches or mathematical models to define regulatory pathways. The primary goal of the current application is to develop formal mathematical and statistical models that will identify networks which cause terminal differentiation of parotid acinar cells. The dynamic mathematical models will serve to generate hypotheses which will be tested and the model will be repeatedly refined by the incorporation of new data. This application is in response to the RFA "A Systems Approach to Salivary Gland Biology." Our overall hypothesis for these studies is that a mathematical model can identify key regulatory pathways that control parotid acinar cell differentiation. Specific Aim 1 will use Laser Capture Microdissection (LCM) to obtain RNA from embryonic and newborn rat parotid acinar cells for microarray analysis of the patterns of gene expression across the period of differentiation. A coupled Ordinary Differential Equation (ODE) model will be created to describe the hypothetical interactions that direct the process of differentiation. The hypotheses will be tested and the ODE model refined by a combination of RT-PCR IHC and Western blots. Since microRNAs are important regulators of development Specific Aim 2 will define the expression of microRNAs in acinar cells and the pattern of changes during differentiation. There are currently no publications describing microRNAs in the parotid tissue. The results will be used to revise the mathematical model of differentiation. Specific Aim 3 will create a statistical algorithm to validate and revise the ODE model by defining the sources of bias and variation as well as by assessing the model's predictive power overall and in its various sub-modules. This will allow confidence intervals to be associated with different pathways within the ODE model. Specific Aim 4 will use the ODE model to make hypotheses about specific pathways regulating gene expression in the parotid acinar cells. These hypotheses will be tested by transfection and transduction experiments and the results shall be used to refine and validate the mathematical model. This systems biology approach should identify molecular pathways that drive cytodifferentiation of parotid acinar cells. Project Narrative: The overall goal of this research is to define the molecular mechanisms which control differentiation of cells into secretory salivary acinar cells. This addresses the needs of millions of Americans who suffer from salivary gland dysfunction due to Sj"gren's Syndrome radiation therapy or xerostomia due to essential medications. This research is a necessary foundation for developing new technologies such as gene transfer therapy and biologics for treating or alleviating the oral symptoms of xerostomia.

project_terms:
Acinar Cell;Address;Algorithms;American;Biological Response Modifier Therapy;Biology;Cell Differentiation process;Complementary DNA;Computing Methodologies;Confidence Intervals;Coupled;Data;Development;Differentiation Antigens;Embryo;Equation;Foundations;Functional disorder;Gene Expression;Gene Proteins;Gene Targeting;Gene Transfer;Genes;Genomics;Goals;Histologic;MicroRNAs;Microarray Analysis;Modeling;Molecular;Muscle;Natural regeneration;Neurons;Newborn Infant;Oral;Output;Parotid Gland;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Procedures;Process;Publications;RNA;Radiation therapy;Rattus;Regulation;Regulatory Pathway;Research;Reverse Transcriptase Polymerase Chain Reaction;Salivary;Salivary Glands;Serous;Signal Pathway;Signal Transduction;Sjogren's Syndrome;Small Interfering RNA;Source;Statistical Models;Symptoms;Syndrome;System;Systems Biology;Testing;Time;Tissues;Transfection;Validation;Variant;Western Blotting;Work;Xerostomia;cell type;expectation;gene therapy;laser capture microdissection;mathematical model;new technology;parotid cell;predictive modeling;prototype;research study;response;restoration;salivary acinar cell;salivary cell;transcription factor


application_id: 8074445
project_number: 5R01DK048498-17
project_title: Surgical Studies of Functional Gene Expression
administering_ic: NIDDK
award_notice_date: 2011-06-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 048498
program_official: SERRANO, JOSE
project_start_date: 1996-03-15
project_end_date: 2014-05-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
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): The mammalian intestinal mucosa is in a constant state of renewal that is characterized by active proliferation of stem cells localized in the crypts progression of these cells up the crypt villus axis with cessation of proliferation and subsequent differentiation. A delicate and precise balance of proliferation -> differentiation -> apoptosis must exist in the gut mucosa to maintain this normal intestinal homeostasis. Surgical resection of the small intestine results in an adaptive hyperplasia whereas the inability to provide enteral nutrients as occurs in certain post-operative or trauma patients results in atrophy. The major focus of our group has been the analysis of mechanisms regulating intestinal proliferation differentiation adaptation and apoptosis. With the support of this grant we have made great strides in our better understanding of the molecular mechanisms regulating intestinal homeostasis. We have shown that stimulation of PI3K/Akt increases normal intestinal proliferation. Our most recent findings have identified novel and differential roles for the mammalian target of rapamycin (mTOR) protein complex a major downstream effector of PI3K in intestinal proliferation and differentiation and intestinal cell survival. In preliminary findings we have shown that inhibition of mTORC2 but not mTORC1 enhances intestinal cell differentiation suggesting differential effects for these proteins in the gut. Also we have recently described the molecular mechanisms contributing to glutamine-mediated intestinal cell survival and proliferation; the PI3K/mTOR pathway plays an important protective role to limit apoptosis associated with cellular stress. Finally we have demonstrated a novel role for the mTOR pathway in intestinal cell autophagy following glutamine deprivation. Based on our recent published and preliminary findings we have refined our central hypothesis to state that intestinal cell proliferation and differentiation are regulated by signaling mechanisms involving the PI3K/mTOR pathway acting on critical downstream effector proteins; novel and differential effects of mTOR and Akt components exist that further add to the complex but highly regimented regulation of intestinal homeostasis. To examine this hypothesis we have planned experiments with the following Specific Aims: 1) to determine the differential effects of mTOR complexes on intestinal cell homeostasis 2) to delineate the signaling proteins that mediate the effects of mTOR in the intestine and 3) to define the role of mTOR/mTOR complexes in intestinal cell growth in vivo. The studies in the current proposal represent direct extensions of our previous findings and are designed to define in a systematic fashion the molecular mechanisms and signaling events regulating the processes of intestinal proliferation differentiation and adaptation. To achieve our goals we have assembled a multidisciplinary diverse and highly collaborative team of investigators who each bring unique expertise and background to the project.  
  
PUBLIC HEALTH RELEVANCE: The intestinal mucosa is in a constant state of growth and renewal; the molecular pathways contributing to this critical function are poorly understood. Our recent findings have identified novel roles for components of the PI3K/Akt/mTOR signaling pathway in intestinal homeostasis. Delineating the cellular factors and signaling pathways regulating these processes is crucial to our understanding of not only normal gut development and maturation but also the effects of surgical resection and stress on intestinal adaptation and survival.

project_terms:
1-Phosphatidylinositol 3-Kinase;Alkaline Phosphatase;Apoptosis;Atrophic;Autophagocytosis;Brush Border;Cell Differentiation process;Cell Proliferation;Cell Survival;Cell physiology;Cells;Cellular Stress;Characteristics;Chemicals;Complex;Cyclin-Dependent Kinase Inhibitor;Development;Differentiated Gene;Enteral;Enterocytes;Enteroendocrine Cell;Enzymes;Epithelial Cells;Equilibrium;Event;Excision;Gene Expression;Glutamine;Glycogen Synthase Kinase 3;Goals;Goblet Cells;Grant;Growth;Homeostasis;Hyperplasia;Intestinal Mucosa;Intestinal Volvulus;Intestines;Ischemia;MAPK3 gene;MAPK8 gene;Mediating;Molecular;Mucous Membrane;Nutrient;Oligo-16-Glucosidase;Operative Surgical Procedures;PTEN gene;Paneth Cells;Pathway interactions;Patients;Pattern;Play;Postoperative Period;Process;Proliferating;Proteins;Publishing;Regulation;Research Personnel;Role;Signal Pathway;Signal Transduction;Signaling Protein;Small Intestines;Stem cells;Stress;Sucrase;Trauma;Tumor Suppressor Proteins;Villus;base;cell growth;cell type;deprivation;design;in vivo;inhibitor/antagonist;mTOR protein;multidisciplinary;novel;overexpression;protein complex;public health relevance;research study

public_health_relevance:
The intestinal mucosa is in a constant state of growth and renewal; the molecular pathways contributing to thiscritical function are poorly understood. Our recent findings have identified novel roles for components of thePI3K/Akt/mTOR signaling pathway in intestinal homeostasis. Delineating the cellular factors and signalingpathways regulating these processes is crucial to our understanding of not only normal gut development andmaturation but also the effects of surgical resection and stress on intestinal adaptation and survival.


application_id: 8073660
project_number: 5R01MH086784-03
project_title: Building a Selective Inhibitory Control Tone in Autism: An rTMS Study
administering_ic: NIMH
award_notice_date: 2011-05-24
opportunity_number: RFA-GM-09-008
application_type: 5
activity_code: R01
ic: MH
serial_number: 086784
program_official: GILOTTY, LISA
project_start_date: 2009-07-01
project_end_date: 2013-05-31
study_section: ZMH1-ERB-L(05)
contact_pi_person_id: 1905047
contact_pi: CASANOVA, MANUEL F
other_pis: Not Applicable
congressional_district: 03
department: PSYCHIATRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Autism is a pervasive developmental disorder of childhood characterized by deficits in social interaction language and stereotyped behaviors and restricted range of interests. Recent studies on postmortem tissue suggest that autism is associated with cortical cytoarchitectural abnormalities. In brief reports on independent populations have shown a reduction in the neuropil space at the periphery of the minicolumn. This is the compartment where lateral inhibition sharpens the borders of minicolumns and increases their definition. The primary source of for this inhibitory effect is derived from axon bundles of double-bouquet cells. The axons of double bouquet cells arrange themselves in essentially repeatable patterns varying between 15 ?m and 30 ?m wide perpendicular to the cortical surface. This grant attempts to preferentially strengthen the inhibitory surround of minicolumns by taking advantage of the geometry of double bouquet cells. We will use the principle of induction to induce electrical currents in double bouquet cells by applying a coil of wire energized by a capacitor (Transcranial Magnetic Stimulator or TMS) to provide a magnetic field orthogonal to the plane of the coil. Slow or low frequency TMS will enhance interneuron inhibition which in turn will enhance spatial contrast needed to optimize functional discrimination in minicolumnar units. The trial will recruit 70 autistic patients and 30 controls matched for age sex IQ and socio-economic class. Outcome measures will include behavioral and electrophysiological measures. Overall our project will link behavioral clinical and neurophysiological (qEEG ERP) responses during cognitive tests and TMS treatment outcomes with an underlying neuropathology model (minicolumnar pathology and lateral inhibition deficits) derived from investigations in our laboratory. The results of the proposed study will help understand the specific social communication and cognitive deficits associated with developmental abnormalities of functions within cortical circuitry and thereby contribute to understanding the brain substrates of behavioral dysfunctions typical for autism. The proposal represents a new development in combining TMS with functional outcome measures (cognitive ERP EEG) using TMS as a theory-guided psychiatric therapy in autism.

project_terms:
Age;Applications Grants;Asperger Syndrome;Autistic Disorder;Autopsy;Axon;Behavioral;Brain;Cells;Clinical;Cognitive;Cognitive deficits;Development;Discrimination (Psychology);Electroencephalography;Environment;Frequencies (time pattern);Functional disorder;Grant;Interneurons;Intervention;Investigation;Laboratories;Language;Lateral;Link;Magnetism;Measures;Modeling;Neuropil;Outcome Measure;Pathology;Patients;Pattern;Persons;Pervasive Child Development Disorders;Population;Psychiatric therapeutic procedure;Recruitment Activity;Reporting;Rett Syndrome;Sensory Process;Social Interaction;Source;Stereotyped Behavior;Surface;Symptoms;Testing;Therapeutic Intervention;Thinking function;Tissues;Transcranial magnetic stimulation;Treatment outcome;functional outcomes;interest;magnetic field;neuropathology;neurophysiology;response;sex;social communication;socioeconomics;theories

public_health_relevance:
Relevance In this grant proposal we describe a potential therapeutic intervention for autism using transcranialmagnetic stimulation (TMS). Therapy would not change a person's way of thinking but is aimed at specificsymptoms related to processing sensory information from the environment which have proven disabling insome patients. The intervention if proven effective for autism would also be of value to patients with Aspergersyndrome or Rett syndrome.


application_id: 8073635
project_number: 5R01DA016718-07
project_title: Licit & Illicit Opioids: Comparative Studies in Humans
administering_ic: NIDA
award_notice_date: 2011-04-29
opportunity_number: PA-08-127
application_type: 5
activity_code: R01
ic: DA
serial_number: 016718
program_official: HAMPSON, AIDAN
project_start_date: 2004-07-10
project_end_date: 2015-04-30
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: MISCELLANEOUS
primary_duns: 939017877
primary_uei: 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): While rates of heroin dependence have been fairly stable over the last several years rates of prescription opioid abuse dependence and diversion have risen significantly. The initial 5-year award focused on the emerging prescription opioid abuse epidemic by conducting a series of studies on the clinical pharmacology of the most widely abused opioids (hydrocodone oxycodone and Oxycontin(R)). These studies investigated relative abuse potential estimates relative potency effects of pain on abuse liability and pharmacokinetics and pharmacodynamics of these drugs when misused by the oral intranasal and intravenous routes. The present application extends these findings by conducting a series of studies to collect new data on opioids purported to have low abuse liability but based upon surveillance studies are emerging as new drugs of abuse including tramadol buprenorphine (Subutex(R)) and buprenorphine/naloxone (Suboxone(R)). Three studies will be conducted enrolling both sporadic opioid abusers and opioid dependent individuals to examine the relative abuse potential and reinforcing efficacy of tramadol buprenorphine and buprenorphine/naloxone when misused by various routes of administration. These studies include careful double-blind randomized placebo- controlled crossover designs and incorporate innovative methodological additions to the standard abuse liability approach including 1) concurrent evaluation of the direct reinforcing efficacy of these compounds using human self-administration procedures to assess the concordance of findings between the "gold standard" approach to a model that examines drug-taking behavior directly 2) multiple relevant comparator agents and 3) multi-dimensional outcomes of safety subjective reports observer-rating and psychomotor performance along. The three proposed inpatient studies will examine the comparative abuse liability and reinforcing efficacy of 1) oral tramadol over a range of doses in comparison to oxycodone (a high efficacy agonist) codeine (an intermediate efficacy agonist) and placebo in non-dependent opioid abusers 2) intranasal buprenorphine and buprenorphine/naloxone over a range of doses in comparison to one another and to oxycodone codeine and placebo in non-dependent opioid abusers and 3) intranasal buprenorphine and buprenorphine/naloxone over a range of doses in comparison to one another and to oxycodone naloxone and placebo in opioid-dependent subjects maintained on a short-acting pharmaceutical opioid. These studies will provide important new information on two emerging drugs of abuse- tramadol and buprenorphine- both drugs at risk for being rescheduled to more restrictive status in the U.S. It is critical that availability of these drugs be preserved for their target patient groups (i.e. pain patients and opioid dependent individuals seeking office- based treatment for drug dependence respectively) while protecting the public safety. These studies will provide empirical data on the relative abuse liability of these drugs in a relevant population and can inform and support evidence-based regulatory decision-making.  
  
PUBLIC HEALTH RELEVANCE: Prescription opioid abuse has increased dramatically in the United States and is a significant public health problem. It is important to understand the pharmacological effects of prescribed opioids in order to predict and control their abuse and other negative health consequences. These studies will provide new information on the abuse-related features of tramadol (used for pain) and buprenorphine alone and in combination with naloxone (used for treatment of opioid dependence).


application_id: 8073300
project_number: 3R01AR055246-03S1
project_title: Circadian rhythms and skeletal muscle
administering_ic: NIAMS
award_notice_date: 2010-05-19
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: AR
serial_number: 055246
suffix: S1
program_official: BOYCE, AMANDA T
project_start_date: 2010-05-20
project_end_date: 2010-09-30
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 8263548
contact_pi: ESSER, KARYN A
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project Summary:Circadian rhythms have long been known to influence behavioral and biological processes such as physicalactivity and feeding behavior. The fundamental importance of this system which works to link physiology withthe day/night cycle is underscored by its presence in every known species and the growing evidence linkingalterations in core clock function and diseases such as cancer diabetes and mental health.Recent studies from our laboratory have shown that mutations of the canonical circadian genes Clock andBmal1 dramatically disrupt muscle function. This is the first genetic evidence linking skeletal muscle functionto circadian rhythms. Expression profiling studies of skeletal muscle over 48 hours identified that MyoD is acircadian gene. Molecular experiments went on to demonstrate that the MyoD promoter is directly bound andregulated by the core clock factors CLOCK and BMAL1.The studies outlined in this proposal combine molecular cell biological and biophysical approaches tounderstand the mechanisms by which the core clock mechanism is regulated in skeletal muscle and how lossof this rhythm leads to altered MyoD expression and loss of muscle function. The hypotheses for thisproposal are 1) Synchronization of core clock gene expression in skeletal muscle requires intact innervation2) Muscle specific mutations of Bmal1 or Clock will be sufficient to cause arrhythmic MyoD expression andmuscle dysfunction 3) Loss of maximal force capacity/specific tension in muscle of circadian clock-compromised mice is due to decreased actin:myosin interaction resulting from disruption of sarcomericstructure and/or altered stoichiometry of myofilament proteins.The results of the experiments outlined in this proposal have significant implications for maintenance ofmuscle with an impact on our understanding and treatment of sarcopenia muscle wasting/cachexia andproblems associated with metabolic diseases such as insulin resistance. In addition our understanding ofcircadian regulation of skeletal muscle will have likely applications for rehabilitation therapies for spinal cordinjury patients and people that are exposed to prolonged periods of bedrest. Project NarrativeThe results of the proposed work will determine the role of the biological clock in maintainingnormal skeletal muscle structure and function. The findings have significant implications formaintenance of muscle with an impact on our understanding and treatment of sarcopeniamuscle wasting/cachexia and problems associated with metabolic diseases such as insulinresistance. In addition our understanding of circadian regulation of skeletal muscle will havelikely applications for rehabilitation therapies for spinal cord injury patients and people that areexposed to prolonged periods of bedrest.

project_terms:
Actinin;Actins;Aging;Bed rest;Behavior;Binding (Molecular Function);Biological;Biological Clocks;Biological Process;Brain;Cachexia;Cell physiology;Cells;Chronic Disease;Circadian Rhythms;Clinical;Complement;Development;Diabetes Mellitus;Disease;Down-Regulation;Electron Microscopy;Enhancers;Feedback;Feeding behaviors;Fiber;Fluorescence Microscopy;Functional disorder;Gel;Gene Expression;Gene Proteins;Gene Targeting;Genes;Genetic;Genetic Transcription;Hour;Hypothalamic structure;In Situ Hybridization;Insulin Resistance;Intrinsic drive;Knock-out;Laboratories;Lesion;Link;Liver;Maintenance;Malignant Neoplasms;Mammals;Measures;Mechanics;Mental Health;Metabolic Diseases;Microfilaments;Molecular;Molecular Profiling;Mus;Muscle;Muscle Fibers;Muscle function;Mutant Strains Mice;Mutation;Myosin ATPase;Myosin Heavy Chains;Normal Cell;Operative Surgical Procedures;Pattern;Peripheral;Physical activity;Physiology;Promotor (Genetics);Protein Isoforms;Proteins;Regulation;Rehabilitation therapy;Role;Skeletal muscle structure;Spinal cord injury patients;Structure;System;Time;Tissues;Translations;Work;behavior influence;circadian pacemaker;connectin;cryptochrome;design;extensor digitorum;mutant;nebulin;nerve supply;novel;rehabilitation strategy;research study;sarcopenia;skeletal;stoichiometry;suprachiasmatic nucleus;transcription factor;wasting


application_id: 8073074
project_number: 5R01HL091893-04
project_title: The Platelet Secretory Machinery
administering_ic: NHLBI
award_notice_date: 2011-06-20
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 091893
program_official: SARKAR, RITA
project_start_date: 2008-05-01
project_end_date: 2013-04-30
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
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): Secretion from activated platelets is thought to be a key step in hemostasis as well as in the post-thrombus sequellae of wound healing. Controlling platelet exocytosis offers a unique therapeutic opportunity to manipulate the microenvironment formed at the site of vascular damage. However our understanding of the machinery that facilitates platelet granule release is still not sufficient to identify valuable drug targets. Our proposed studies seek to rectify this by delineating the molecular events required for platelet secretion. From past reports it is clear that specific Soluble NSF Attachment Protein Receptors (v- and t-SNAREs) are required for platelet secretion. With this established our goals are now expanded to define the roles of secretion in hemostasis and to identify the mechanisms by which the exocytosis machinery is regulated. Two Specific Aims are proposed: 1) To assess the role of the v-SNARE VAMP-8 in platelet function. Our work demonstrated that VAMP-8/endobrevin is required for platelet exocytosis. Aim 1 will complete the characterization of this v-SNARE's role using specific experiments to define the in vivo and in vitro phenotypes of VAMP-8-/- platelets. Other experiments will address the sub-platelet distribution of VAMP-8 and characterize its interacting partners. 2) To identify and characterize the SNARE regulators that interact with and control the syntaxin t-SNAREs in platelets. Past studies assigned roles for SNAP-23 syntaxin 2 and 4. This aim focuses on defining roles for known t-SNAREs regulators and identifying novel ones. The syntaxin-regulators Munc18 Munc13 DOC2 and tomosyn will be studied using biochemical techniques and a permeabilized platelet secretion assay. The experiments will expand our understanding of how these proteins mediate SNARE pairing and subsequent membrane fusion. In summary the information gained from this proposal will identify new therapeutic targets to control hyperactive platelets and will provide diagnostic reagents to determine why hypoactive platelets are defective. PUBLIC HEALTH RELEVANCE: Strokes and heart attacks are major killers in the United States. In both cases the damage is caused by a loss of blood flow usually because a blood clot has formed in the wrong place. Understanding all aspects of clot formation is critical to treating this problem. This application focuses on one aspect of clot formation platelets. Specifically this application focuses on how platelets secrete components needed for clot formation. This work is of critical important because it will direct the development of future therapeutic agents needed to decrease the risk of spurious clot formation.

project_terms:
Address;Adhesions;Agonist;Alpha Granule;Atherosclerosis;Basic Science;Biochemical;Biochemistry;Biological Assay;Blood Clot;Blood Platelets;Blood Vessels;Blood coagulation;Blood flow;Categories;Cause of Death;Cell membrane;Cells;Cellular biology;Clinical;Coagulation Process;Complex;Cytoplasmic Granules;DAB2 gene;Data;Defect;Development;Diagnostic Reagent;Disease;Drug Delivery Systems;Event;Exocytosis;Family;Future;Goals;Health;Hemorrhage;Hemostatic function;In Vitro;Inflammation;Knowledge;Lead;Learning;Lysosomes;Mediating;Membrane Fusion;Membrane Proteins;Molecular;Molecular Target;Mouse Strains;Mus;Myocardial Infarction;Pathology;Pathway interactions;Phenotype;Physicians;Platelet Activation;Play;Process;Protein Secretion;Proteins;Recombinant Proteins;Regulation;Reporting;Research;Risk;Role;S-nitro-N-acetylpenicillamine;SNAP receptor;Signal Transduction;Site;Stimulus;System;Techniques;Therapeutic;Therapeutic Agents;Thrombosis;Thrombus;Time;United States;VAMP-2;Work;Wound Healing;base;design;extracellular;falls;in vivo;in vivo Model;insight;neurotransmitter release;new therapeutic target;novel;outcome forecast;programs;protein protein interaction;research study;response;soluble NSF attachment protein;stroke;syntaxin;syntaxin-2;target SNARE proteins;therapeutic target;vesicular SNARE proteins


application_id: 8072877
project_number: 3R01DK080327-03S1
project_title: Effects of fish oil on inflammation and metabolic syndrome
administering_ic: NIDDK
award_notice_date: 2010-07-19
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: DK
serial_number: 080327
suffix: S1
program_official: STATEN, MYRLENE A
project_start_date: 2010-07-20
project_end_date: 2011-06-30
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Obesity and type 2 diabetes are conditions characterized by a state of chronic low-grade inflammation due largely to an increase in adipose tissue inflammation brought about by infiltrating macrophages. Drugs such as thiazolidinediones (TZDs) improve insulin sensitivity via activation of PPAR-gamma and there is much evidence that PPAR3 agonists also have anti-inflammatory properties. In addition to their beneficial effects on serum lipids and heart disease fish oils (I-3 fatty acids) activate PPAR3 and demonstrate anti-inflammatory properties. This is a translational research study intended to examine the mechanism for many of the beneficial effects of fish oils on metabolic syndrome in humans. We plan to treat insulin resistant subjects with fish oils and the following hypotheses. Hypothesis 1. The treatment of insulin resistant subjects with fish oils will reduce adipose tissue inflammation. We plan to examine the circulating levels of cytokines as well as the levels of cytokines and macrophages in adipose tissue biopsies of subjects who are treated with 4 g/day of I-3 fatty acids for 12 weeks. We will determine whether there is evidence of macrophage apoptosis in adipose tissue and we will determine whether I-3 fatty acids increases the level or secretion of adiponectin. Hypothesis 2. Anti-inflammatory effects of fish oils are mediated by activation of PPAR3 and/or by changes in membrane composition that affect signal transduction functions. Adipose tissue and macrophages will be treated in vitro with fish oils in the presence and absence of a PPAR3 inhibitor and we will measure PPAR3 responses such as the secretion of HMW adiponectin and macrophage apoptosis. In addition we will determine whether I-3 fatty acids induce changes in recruitment of inflammatory receptors such as toll-like receptor 4 (TLR4) and TNF1 Receptor 1 (TNFR1) to membrane rafts. Hypothesis 3. Fish oils improve peripheral insulin sensitivity through a reduction in intramyocellular lipid and an improvement in muscle insulin signal transduction. Before and after treatment with fish oils insulin sensitivity will be measured along with intramyocellular lipid and genes or proteins involved in insulin action and muscle lipid oxidation.  Project Narrative: The incidence of obesity metabolic syndrome and diabetes is rising in epidemic proportions in the Western world and the resultant heart disease will likely create a generation who will not live as long as their parents. Fish oils have proven health benefits on coronary risk factors and this study aims to develop evidence for additional properties of fish oils that will greatly extend their use to subjects with insulin resistance and metabolic syndrome.

project_terms:
Adipose tissue;Anti-inflammatory;Coronary;Coronary heart disease;Development;Diabetes Mellitus;Epidemic;Fasting;Fatty Acids;Fish Oils;Inflammation;Mediator of activation protein;Metabolic syndrome;Non-Insulin-Dependent Diabetes Mellitus;Omega-3 Fatty Acids;Pharmaceutical Preparations;Process;Thiazolidinediones;Translational Research;Tumor Necrosis Factor-alpha;insulin secretion;toll-like receptor 4

public_health_relevance:
Project Narrative The incidence of obesity metabolic syndrome and diabetes is rising in epidemic proportions in the Western world and the resultant heart disease will likely create a generation who will not live as long as their parents. Fish oils have proven health benefits on coronary risk factors and this study aims to develop evidence for additional properties of fish oils that will greatly extend their use to subjects with insulin resistance and metabolic syndrome.


application_id: 8072660
project_number: 5R01DE019826-02
project_title: Tobacco-induced alterations to P. gingivalis-host interactions
administering_ic: NIDCR
award_notice_date: 2011-05-31
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DE
serial_number: 019826
program_official: LUNSFORD, DWAYNE
project_start_date: 2010-05-15
project_end_date: 2015-04-30
study_section: Special Emphasis Panel[ZRG1-MOSS-B(02)M]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Periodontitis is a destructive infectious disease that has been associated with multiple fatal and debilitating chronic systemic diseases and consumes billions of dollars in health costs annually in the US. Tobacco smokers exhibit increased susceptibility to periodontitis; are more likely to be infected with the key periodontal pathogen Porphyromonas gingivalis; and to harbor higher numbers of this bacterial species relative to non-smokers. Despite this smokers consistently exhibit reduced clinical inflammation. We show that the pro-inflammatory response of purified human monocytes is significantly suppressed when P. gingivalis is exposed to cigarette smoke extracts (CSE) and that the inflammation inducing potential of P. gingivalis is restored when cells are sub-cultured back into fresh medium without CSE. However the influence of tobacco on the regulation of genes encoding P. gingivalis virulence determinants is essentially unknown.  We hypothesize that CSE represents an environmental stress and that P. gingivalis responds by altering gene expression to adapt to this stress. We believe that this adaptive response may involve the induction of stress-related genes virulence determinants and alterations of bacterial surface components. We also hypothesize that such cigarette smoke-induced physiological changes in P. gingivalis will include altered activities of genes encoding key pathogen recognition determinants which will explain the reduced inflammatory response of smoke-exposed P. gingivalis. It is our aim to identify isolate and test CSE-altered gene products in a primary human monocyte model of inflammation.  Preliminary data generated through transcriptome analyses and the structural characterization of several microbial determinants are strongly supportive of our hypotheses. We have identified several genes gene products and bacterial structures that are dysregulated on CSE exposure that may play pivotal roles in the engagement of the innate immune system by P. gingivalis. These include fimbrial proteins LPS major outer membrane antigens and other P. gingivalis components of known inflammatory potential such as dnaJ grpE and ragA.  These studies represent a novel area of investigation and will provide some of the first information illustrating how P. gingivalis responds at the molecular level to cigarette smoke and may provide unique insights into disease pathogenesis in smokers. Thus these studies will break new ground and provide the foundation for future studies that will elucidate mechanisms explaining how tobacco influences pathogen-host response interactions.  
  
PUBLIC HEALTH RELEVANCE:  The Gram negative anaerobic bacterium Porphyromonas gingivalis is a causative agent of chronic periodontitis a destructive tobacco-induced and/or exacerbated disease. Smokers are more likely to be infected by P. gingivalis and to harbor higher numbers of these bacterial cells than non-smokers. However smokers also exhibit reduced clinical inflammation and in keeping with this smoke-exposed P. gingivalis exhibits a reduced capacity to illicit an inflammatory response from immune cells. The mechanisms underlying this reduced inflammatory potential are entirely unknown. Therefore we will identify P. gingivalis genes that are dysregulated by tobacco exposure by microarray analysis of P. gingivalis cultured in cigarette smoke extract (CSE)-conditioned medium. We will also examine the effects of CSE on the characteristics of cellular structures known to play critical roles in the activation of innate immune cells such as LPS and fimbriae. The inflammatory potential of tobacco-altered bacterial structures and the products of CSE-dysregulated genes will be tested in freshly isolated human monocytes. This study will provide some of the first information illustrating how P. gingivalis responds at the molecular level to cigarette smoke and may provide unique insights into disease pathogenesis in smokers.

public_health_relevance:
The Gram negative anaerobic bacterium Porphyromonas gingivalis is a causative agent of chronicperiodontitis a destructive tobacco-induced and/or exacerbated disease. Smokers are more likely to beinfected by P. gingivalis and to harbor higher numbers of these bacterial cells than non-smokers. Howeversmokers also exhibit reduced clinical inflammation and in keeping with this smoke-exposed P. gingivalisexhibits a reduced capacity to illicit an inflammatory response from immune cells. The mechanisms underlyingthis reduced inflammatory potential are entirely unknown. Therefore we will identify P. gingivalis genes thatare dysregulated by tobacco exposure by microarray analysis of P. gingivalis cultured in cigarette smokeextract (CSE)-conditioned medium. We will also examine the effects of CSE on the characteristics of cellularstructures known to play critical roles in the activation of innate immune cells such as LPS and fimbriae. Theinflammatory potential of tobacco-altered bacterial structures and the products of CSE-dysregulated genes willbe tested in freshly isolated human monocytes. This study will provide some of the first information illustratinghow P. gingivalis responds at the molecular level to cigarette smoke and may provide unique insights intodisease pathogenesis in smokers.


application_id: 8072534
project_number: 5R01DK080874-03
project_title: Regulation of the ABCG5 ABCG8 Sterol Transporter
administering_ic: NIDDK
award_notice_date: 2011-06-06
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 080874
program_official: HAFT, CAROL R
project_start_date: 2009-07-01
project_end_date: 2013-05-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8553632
contact_pi: GRAF, GREGORY A
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The purpose of this project is to determine the mechanisms by which leptin regulates the ABCG5 ABCG8 (G5G8) sterol transporter and influences cholesterol metabolism in obesity. Obesity and diabetes (diabesity) are associated with increased risk of cardiovascular and gallbladder disease elevated plasma cholesterol levels and a predilection for cholesterol synthesis rather than absorption. High-fat diets induce a virtually identical phenotype in mice. In contrast mice that lack leptin (ob/ob) or its receptor (db/db) are hyperphagic obese and diabetic yet exhibit increased cholesterol absorption reduced cholesterol synthesis decreased biliary cholesterol and resistance to cholethiasis. These observations suggest that in obesity the presence or absence of a functional leptin axis profoundly impacts cholesterol metabolism with respect to absorption synthesis and hepatobiliary transport. The central hypothesis of this proposal is that hepatic leptin signaling maintains G5G8 and prevents reductions in hepatobiliary cholesterol transport by ER stress in diabesity. The Aims are to 1) determine the role of hepatic leptin receptors on G5G8 abundance activity and cholesterol metabolism in vivo 2) determine the role of ER stress on G5G8 abundance in vivo and 3) determine the molecular mechanisms for regulation of G5G8 abundance by leptin ER stress and the ISR. Leptin receptors will be selectively deleted from liver and brain to assess the role of this signaling pathway on G5G8 and cholesterol metabolism in obesity. The effects of leptin ER stress and their interaction on G5G8 abundance will be determined in vivo and in vitro. The completion of these Aims will test our central hypothesis and elucidate the mechanisms by which the leptin axis modulates G5G8 abundance hepatobiliary lipid transport and cholesterol metabolism in diabesity. Understanding the impact of this novel pathway on cholesterol metabolism will add insight to the effects of obesity on risk factors fo cardiovascular disease. PUBLIC HEALTH RELEVANCE: The ABCG5 ABCG8 sterol transporter is the principal mechanism by which the body opposes the accumulation of dietary cholesterol and other sterols from sources such as plants and shellfish. Little is known concerning the mechanisms that regulate its abundance and activity. This proposal addresses mechanisms that are responsible for reduced abundance and activity of G5G8 in mouse models of obesity and type 2 diabetes in order to gain insight into factors that contribute to the accumulation of cholesterol in obesity.

project_terms:
Acids;Address;Adenovirus Vector;Albumins;B-Lymphocytes;Bile Acids;Bile fluid;Biliary;Brain;Cardiovascular Diseases;Cells;Cholesterol;Cholesterol Homeostasis;Diabetes Mellitus;Diamond;Diet;Dietary Cholesterol;Enterocytes;Exhibits;Fatty acid glycerol esters;Gall Bladder Diseases;Health;Hepatic;Hepatobiliary;Hepatocyte;Hyperlipidemia;In Vitro;Insulin;Insulin Resistance;Intestines;Leptin;Lipids;Liver;Measures;Messenger RNA;Modeling;Molecular;Molecular Chaperones;Mus;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathway interactions;Phenotype;Phytosterols;Plants;Plasma;Play;Promotor (Genetics);Proteins;Pulmonary Surfactant-Associated Protein C;Pump;Regulation;Resistance;Risk Factors;Role;Shellfish - dietary;Signal Pathway;Signal Transduction;Solid;Source;Sterols;Synapsins;Testing;Transgenes;absorption;basal insulin;bile canaliculus structure;biological adaptation to stress;cardiovascular disorder risk;cholesterol absorption;db/db mouse;diabetic;endoplasmic reticulum stress;human FOXO1A protein;in vivo;insight;insulin signaling;leptin receptor;lipid transport;mouse model;novel;prevent;protein misfolding;receptor;recombinase;research study;response;small molecule

public_health_relevance:
7. Project NarrativeThe ABCG5 ABCG8 sterol transporter is the principal mechanism by which the body opposes theaccumulation of dietary cholesterol and other sterols from sources such as plants and shellfish. Little is knownconcerning the mechanisms that regulate its abundance and activity. This proposal addresses mechanismsthat are responsible for reduced abundance and activity of G5G8 in mouse models of obesity and type 2diabetes in order to gain insight into factors that contribute to the accumulation of cholesterol in obesity.


application_id: 8070533
project_number: 5R01GM066152-08
project_title: Synthetic Probes of Protein Prenylation
administering_ic: NIGMS
award_notice_date: 2011-03-11
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 066152
program_official: FABIAN, MILES
project_start_date: 2002-05-01
project_end_date: 2014-03-31
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 7875230
contact_pi: SPIELMANN, H PETER
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): Covalent modification by isoprenoid lipids (prenylation) is a critical post-translational event for many proteins involved in cellular signaling and cancer. The primary goal of this research program is to design and test prenyl function inhibitors and to identify and characterize proteins that are farnesylated in vivo. The studies outlined in this proposal will result in the preparation of new tools to probe the specificity of the prenyltransferases protein- farnesyltransferase (FTase) and protein-geranylgeranyltransferase (GGTase-I) enable further development of prenyl function inhibitors and identify new prenylated proteins as potential targets for therapeutic intervention. By varying the chemical structure of the prenyl lipid we are developing reagents to probe the biological function of the posttranslational modification. Taking advantage of the fact that the prenyl group forms a substantial part of the peptide substrate binding site in the prenyltransferases has allowed us to develop peptide selective inhibitors of prenyl function. These unnatural analogues may allow for the selective interference with specific prenylation targets and may provide lead compounds to alleviate the potential toxicity associated with complete inhibition of protein prenylation. In particular the unnatural analogues may be useful to obtain a more complete understanding of the role that alternative prenylation plays in Farnesyl transferase inhibitor (FTI) evasion by oncogenes such as K-Ras. Critical to understanding the clinical effects of existing and future FTIs and geranylgeranyl transferase inhibitors (GGTIs) is the identification of in vivo substrates of FTase and GGTase-I. Our innovative strategy of using unnatural transferable prenyl analogues and analogue specific monoclonal antibodies to identify prenylated cellular proteins will provide valuable information on the cellular targets of inhibitors of prenylation. We expect these studies to result in the identification of previously unknown prenylated proteins. The specific aims of this project are: 1) Synthesis of farnesyl and geranylgeranyl diphosphate analogues to study protein prenylation. 2) Screening these compounds for substrate specificity of FTase and GGTase-I and development of prenyl function inhibitors. 3) Identification of prenylated proteins in cells. The results from these studies may provide leads to new molecules to treat cancer and also identify new molecular targets to develop anti-cancer therapies.  
  
 PUBLIC HEALTH RELEVANCE Substantial evidence points to the central role of proteins normally modified by a prenyl group in cancer progression. We propose to design and test prenyl function inhibitors and to identify and characterize proteins that are modified with prenyl groups. The results from these studies may provide leads to new molecules to treat cancer and also identify new molecular targets to develop future anti-cancer therapies.

project_terms:
Active Sites;Antibodies;Binding Sites;Biochemical;Biological;Biological Assay;Biological Process;Biology;Cells;Chemical Structure;Dependence;Development;Dimethylallyltranstransferase;Discrimination (Psychology);Drug Design;Enzymes;Event;Exhibits;Farnesyl Transferase Inhibitor;Funding;Future;Goals;Growth;Immunoprecipitation;Lead;Lipids;Malignant Neoplasms;Methods;Modification;Molecular Target;Monoclonal Antibodies;Oncogenes;Pathway interactions;Peptides;Play;Post-Translational Protein Processing;Preparation;Process;Protein Isoprenylation;Proteins;Proteomics;Reagent;Research;Role;Screening procedure;Signal Transduction;Site-Directed Mutagenesis;Specificity;Substrate Specificity;Techniques;Testing;Therapeutic Intervention;Toxic effect;Transformed Cell Line;analog;cancer therapy;cellular targeting;chemical synthesis;clinical effect;cytotoxicity;design;enzyme substrate;farnesyl pyrophosphate;geranylgeranyl diphosphate;in vivo;inhibitor/antagonist;innovation;isoprenoid;lipophilicity;novel;prenyl;prenylation;programs;protein farnesyltransferase;protein function;protein geranylgeranyltransferase;public health relevance;tool;tumor progression


application_id: 8070241
project_number: 1R03MH087448-01A1
project_title: A Cell-based HTS to discover molecules that inhibit VEEV encephalitic alphavirus
administering_ic: NIMH
award_notice_date: 2010-12-28
opportunity_number: PAR-09-129
application_type: 1
activity_code: R03
ic: MH
serial_number: 087448
suffix: A1
program_official: YAO, YONG
project_start_date: 2011-01-01
project_end_date: 2012-12-31
study_section: Special Emphasis Panel[ZRG1 BST-F (50)]
contact_pi_person_id: 9658299
contact_pi: CHUNG, DONGHOON
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  This project seeks to discover small molecules active in inhibiting replication of Venezuelan Equine Encephalitis Viruses (VEEV) by utilizing a high throughput screening (HTS) campaign from the Molecular Library Program Center Network (MLPCN). VEEV an encephalitic alphavirus is listed as a select agent for its ability to cause severe disease during epidemics as well as its potential use a bioterror weapon. However there is no FDA-approved treatment or prophylaxis of VEEV-related diseases at this time. Antiviral drug discovery for select agents has been impractical due to restrictions on handling the agents. Progress has been made toward the goal of efficacious treatment by developing a robust cytopathic effect (CPE)-based assay employing an attenuated VEEV strain TC-83. The attenuated strain is not a select agent and can be handled in a BSL-2 lab. Because the attenuated strain has a significantly high homology between its genome sequence and the wild type VEEV I hypothesize that the anti-viral compounds screened through this assay would be active for wild type VEEV as well. Thus the result of achieving the specific aims will be assays that can be used as a primary screen to discover active compounds from the Molecular Libraries Small Molecule Repository (MLSMR) library and the follow-up studies to verify activities for the attenuated and wild type virus strains. The first specific aim will be to screen the MLSMR library with a verified cell-based assay measuring CPE caused by VEEV strain TC-83 as a primary HTS. The second specific aim will be to verify the selected compounds from the primary screen in two ways 1) a dose-response cytotoxicity and efficacy assay and 2) re-screening with second attenuated strain V3526 which has a higher similarity with wild types. Finally a third battery of assays will be provided those are crucial for developing and characterizing chemical probes. The selected compounds will be subsequently verified using titer reduction assays with the wild-type strain V3000. Last for the compounds selected as probes mode of action studies will be performed with reporter- based molecular and biochemical assays. The screening pathway provided here may identify novel chemical scaffolds that can be pursued as therapeutics for encephalitic alphavirus infections including Eastern or Western equine encephalitis viruses. . Hence successful outcomes from this project will benefit the public and military a goal that aligns with the MLPCN and the NIH.  
  
PUBLIC HEALTH RELEVANCE: Venezuelan Equine Encephalitis Virus (VEEV) is transmitted to humans and equine by mosquitoes and represents neuroinvasive diseasees. In general disease is rare in US however epizootic strains of VEEV infected horses and approximately 70000 ~ 100000 people in South America in last epidemics in 1995 - 1996. There have also been reports of aerosol transmission of VEEV. VEEV has been weaponized and is a CDC/NIAID category B select agent for biodefense research. Despite of the importance in medical and bioterror needs there are no treatments for VEEV infection. There is a need for new assays to identify compounds that inhibit VEEV replication. This work represents an unmet medical need for re-emerging viruses which has classified as a select agent. Of importance Western Eastern and Venezuelan equine encephalitis viruses are close in a phylogenetic analysis therefore successful outcomes from the proposed project will enlighten the way of discover potential therapeutics for important select agents which are closely related each other.

project_terms:
Aerosols;Alphavirus;Alphavirus Infections;Animal Model;Antiviral Agents;Attenuated;Base Pairing;Biochemical;Biological Assay;Categories;Cell Death;Cell Survival;Cells;Centers for Disease Control and Prevention (U.S.);Chemicals;Collaborations;Culicidae;Disease;Docking;Dose;Epidemic;Equus caballus;Escherichia coli;Evaluation;FDA approved;Genes;Goals;Human;Image;In Vitro;Inhibitory Concentration 50;Libraries;Luc Gene;Measures;Medical;Methods;Military Personnel;Modeling;Molecular;Molecular Bank;Mutation;National Institute of Allergy and Infectious Disease;Outcome;Pathway interactions;Peptide Hydrolases;Phylogenetic Analysis;Polymerase Chain Reaction;Process;Prophylactic treatment;Proteins;Reading;Reporter;Reporting;Research;Screening procedure;Series;South America;Specificity;System;Testing;Therapeutic;Time;Toxic effect;United States National Institutes of Health;Universities;Validation;Venezuelan Equine Encephalitis Virus;Viral;Viral Physiology;Viral Proteins;Viral load measurement;Virus;Virus Diseases;Virus Replication;Western Equine Encephalitis Virus;Work;anti-viral efficacy;base;biodefense;cytotoxicity;drug discovery;efficacy testing;epizootic;fluoromethyl 22-difluoro-1-(trifluoromethyl)vinyl ether;follow-up;genome sequencing;high throughput screening;in vivo;inhibitor/antagonist;luminescence;novel;programs;public health medicine (field);repository;response;scaffold;small molecule;transmission process;weapons

public_health_relevance:
Venezuelan Equine Encephalitis Virus (VEEV) is transmitted to humans and equine by mosquitoes and represents neuroinvasive diseasees. In general disease is rare in US however epizootic strains of VEEV infected horses and approximately 70000 ~ 100000 people in South America in last epidemics in 1995 - 1996. There have also been reports of aerosol transmission of VEEV. VEEV has been weaponized and is a CDC/NIAID category B select agent for biodefense research. Despite of the importance in medical and bioterror needs there are no treatments for VEEV infection. There is a need for new assays to identify compounds that inhibit VEEV replication. This work represents an unmet medical need for re-emerging viruses which has classified as a select agent. Of importance Western Eastern and Venezuelan equine encephalitis viruses are close in a phylogenetic analysis therefore successful outcomes from the proposed project will enlighten the way of discover potential therapeutics for important select agents which are closely related each other.


application_id: 8069958
project_number: 5R01GM089684-02
project_title: DNA repair mechanisms in trinucleotide repeat instability
administering_ic: NIGMS
award_notice_date: 2011-06-08
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 089684
program_official: KRASNEWICH, DONNA M
project_start_date: 2010-06-01
project_end_date: 2014-05-31
study_section: Molecular Genetics A Study Section[MGA]
contact_pi_person_id: 7875365
contact_pi: LI, GUO-MIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of the project is to understand the mechanisms by which cells maintain trinucleotide repeat (TNR) stability. Expansions of TNR sequences e.g. (CAG)n and (CTG)n are tightly associated with progression of certain human neurological and neurodegenerative diseases including Huntington's disease (HD) and myotonic dystrophy. However the mechanisms and factors that promote/prevent TNR expansions are unknown. Because CAG and CTG repeats form thermo- stable hairpins with multiple A-A and T-T mispairs in the hairpin stem respectively DNA mismatch repair (MMR) and TNR hairpin repair have been proposed to play major roles in TNR maintenance. Surprisingly previous studies in transgenic mice suggest that mismatch recognition protein MSH2- MSH3 heterodimer (also called MutS2) promotes (CAG)n expansions by binding to (CAG)n-formed hairpins and inhibiting their repair. Our recent studies have shown that human cells catalyze error-free repair of (CAG)25 and (CTG)25 hairpins in a nick-directed PCNA-dependent manner. The repair targets the nicked strand for incisions at the repeat sequences followed by repair DNA synthesis using the continuous strand as a template thereby ensuring TNR stability. However MutS2 does not inhibit stimulates (CAG)25 or (CTG)25 hairpin repair. Interestingly our preliminary studies have shown that cell lines derived from HD patients are defective in (CAG)n hairpin repair hinting possible pathogenesis for HD. In this application Specific Aim 1 is to evaluate the model that the MMR system promotes (CAG)n expansion. Human and animal cell lines with or without MutS2 overexpression will be examined for their ability to repair (CAG)n hairpins in vitro and to replicate CAG repeats in vivo. Determination of TNR hairpin repair activity and (CAG)n stability in these cells will clarify if the MMR system is responsible for (CAG)n expansions in human cells. Specific Aim 2 is to further test the hypothesis that hairpin repair defects are associated with TNR diseases by screening hairpin repair proficiency in cell lines derived from HD patients. Specific Aim 3 is to purify and characterize a protein required for (CAG)n hairpin repair but defective in an HD cell line. A successful completion of the proposed work will provide significant insight into the mechanisms of TNR expansions and the etiology of TNR expansion-associated diseases.  
  
PUBLIC HEALTH RELEVANCE: Expansion of simple nucleotide repeats in DNA is the genetic basis for more than 40 human familial neurological neurodegenerative and neuromuscular disorders including Huntington's disease myotonic dystrophy Friedreich ataxia and fragile X syndrome. The repeat expansion can occur in any part of a gene and leads to a defective gene product. However how the repeat units expand and what cellular mechanism(s) prevent such an expansion in normal population are not fully understood. This application is to identify protein components that promote or prevent repeat expansions. A successful completion of the proposed work will provide significant insight into the pathogenesis underlying diseases associated with repeat expansions and approaches to develop effective treatments for the diseases.

project_terms:
Animals;Binding (Molecular Function);Biochemical;Biological Assay;CAG repeat;Cell Line;Cells;DNA;DNA Repair;DNA biosynthesis;Defect;Disease;Ensure;Etiology;Fragile X Syndrome;Friedreich Ataxia;Generations;Genes;Genetic;Genome;Goals;Hela Cells;Human;Huntington Disease;In Vitro;Lead;Length;Link;MSH2 gene;MSH3 gene;Maintenance;Mismatch Repair;Modeling;Myotonic Dystrophy;Neurodegenerative Disorders;Neuromuscular Diseases;Nuclear Extract;Nucleotides;Pathogenesis;Pathway interactions;Patients;Play;Population;Protein Binding;Proteins;RNA Interference;Role;Screening procedure;Site;Surgical incisions;System;Testing;Transgenic Mice;Trinucleotide Repeat Expansion;Trinucleotide Repeats;Work;base;effective therapy;in vivo;insight;nervous system disorder;overexpression;prevent;public health relevance;repaired;research study;stem

public_health_relevance:
Expansion of simple nucleotide repeats in DNA is the genetic basis for more than40 human familial neurological neurodegenerative and neuromuscular disordersincluding Huntington's disease myotonic dystrophy Friedreich ataxia and fragileX syndrome. The repeat expansion can occur in any part of a gene and leads toa defective gene product. However how the repeat units expand and whatcellular mechanism(s) prevent such an expansion in normal population are notfully understood. This application is to identify protein components that promoteor prevent repeat expansions. A successful completion of the proposed work willprovide significant insight into the pathogenesis underlying diseases associatedwith repeat expansions and approaches to develop effective treatments for thediseases.


application_id: 8069300
project_number: 5R01HL074091-07
project_title: Mechanisms of Long-term Cardiac Ion Channel Regulation
administering_ic: NHLBI
award_notice_date: 2011-06-25
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 074091
program_official: PRZYWARA, DENNIS
project_start_date: 2009-06-01
project_end_date: 2014-05-31
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
contact_pi_person_id: 7875430
contact_pi: SATIN, JONATHAN
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): Ca dysregulation in cardiac myocytes contributes to heart development defects and diseases of the aging heart. The long-term objective of this proposal is to provide a molecular mechanism that explains how cardiac L-type Ca channels (LTCC) sense and transduce signals that homeostatically regulate cardiac myocytes. Cardiac myocytes present a conundrum with respect to Ca signaling to the nucleus. Cytosolic Ca amplitude varies >10-fold during each cardiac cycle yet alterations of Ca somehow are differentially decoded for longer-term transcriptional signaling. In this funding period we will test whether Ca channel activity and the cardiac L-type Ca channel itself encodes Ca signaling for long-term regulation. In the past funding period we discovered that RGK chronically inhibited ICaL (LTCC current) and this RGK inhibition of ICaL resulted in a compensatory up-regulation of CaV1.2 mRNA. This suggests that ICaL block may signal transcriptional events in the nucleus. In new studies we confirmed and extended this notion by showing that LTCC-pharmacological- block but not internal Ca in general is responsible for perturbing heart development. Along the same lines in mature heart long-term blockade of LTCC also causes a compensatory up-regulation of LTCC and ICaL. Our driving hypothesis is that signaling is not simply determined by Ca but by active Ca channels. The discovery that mobile segment of LTCC is localized to the nucleus or t-tubules coupled with the recent report that this peptide is a transcription factor drives the exciting new hypothesis that this segment of the LTCC regulates LTCC expression. We will study this aspect of long-term channel regulation in three aims: 1. We will assess nuclear translocation of a domain of the LTCC and determine the interaction between LTCC activity and sub- cellular localization; 2. We will determine the ability of LTCC to auto-regulate itself transcriptionally; and 3. We will determine the compensatory changes of SL Ca handling proteins in response to LTCC blockade. This work may provide a missing molecular link between LTCC function and downstream signaling events. PUBLIC HEALTH RELEVANCE: These studies show that widely used clinically-relevant drugs that are used to block LTCC may inadvertently exacerbate heart dysfunction by paradoxically increasing LTCC function. This proposal will lead to understanding of a new mechanism whereby ion channels that control cardiac electrical activity also may control long-term signaling pathways that are critical for maintenance of cardiac structure and function.

project_terms:
Abbreviations;Acute;Adrenergic Agents;Adult;Aging;Automobile Driving;C-terminal;Cardiac;Cardiac Myocytes;Cell Nucleus;Chronic;Coupled;Data;Defect;Disease;Down-Regulation;Drug usage;Elements;Event;Functional disorder;Funding;Growth and Development function;Health;Heart;Homeostasis;Ion Channel;L-Type Calcium Channels;Lead;Link;Maintenance;Messenger RNA;Molecular;Monomeric GTP-Binding Proteins;Muscle Cells;Nuclear;Nuclear Translocation;Pathway interactions;Peptides;Pharmaceutical Preparations;Protein Phosphatase 2A Regulatory Subunit PR53;Protein phosphatase;Proteins;Regulation;Reporting;Signal Pathway;Signal Transduction;Structure;Testing;Transducers;Up-Regulation (Physiology);Ventricular;Work;adrenergic;cardiogenesis;chromatin immunoprecipitation;clinically relevant;heart electrical activity;in vitro Model;in vivo;novel;protein expression;response;sensor;trafficking;transcription factor

public_health_relevance:
These studies show that widely used clinically-relevant drugs that are used to block LTCC mayinadvertently exacerbate heart dysfunction by paradoxically increasing LTCC function. This proposal will leadto understanding of a new mechanism whereby ion channels that control cardiac electrical activity also maycontrol long-term signaling pathways that are critical for maintenance of cardiac structure and function.


application_id: 8069190
project_number: 5R01CA120606-05
project_title: Patient Navigation for Cervical Cancer in Appalachia
administering_ic: NCI
award_notice_date: 2011-04-08
application_type: 5
activity_code: R01
ic: CA
serial_number: 120606
program_official: KOBRIN, SARAH
project_start_date: 2007-06-01
project_end_date: 2013-10-31
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-05-01
project_abstract:
DESCRIPTION (provided by applicant):  Over the past five decades mortality rates from cervical cancer have decreased by approximately 75%. This reduction is largely attributable to the Pap smear and improvements in treatment. Despite this encouraging reduction certain groups of women have not experienced significant benefits and remain at disproportionate risk of death from cervical cancer. Among these women are those living in rural areas particularly middle aged and older women who live in rural Appalachia. This population continues to have among the highest cervical cancer mortality rates and efforts to address this problem have fallen short of their objectives. To reduce the unequal and unnecessary burden from cervical cancer experienced by rural Appalachian women we propose to undertake a community-based patient navigator (PN) intervention in partnership with local public health departments. In this proposed project we intend to develop administer and evaluate a plan for effective utilization of lay health workers as PNs in local health department cervical cancer screening programs. The aims are: 1) to improve understanding of the barriers to follow-up experienced by women with abnormal Pap test results; 2) in conjunction with designated nurse case managers to recruit train and utilize lay health workers as PNs in local health departments' cervical cancer screening and follow-up treatment programs; and 3) with extensive input from women who do not follow-up after abnormal results and through the development of a PN program to increase the proportion of patients who are adherent with recommendations for timely abnormal Pap test follow-up. The project will be conducted in 26 public health departments in rural southeastern Kentucky. A lagged design will be used in which the health departments will be randomized to intervention or delayed intervention groups. A total of 858 patients will be enrolled in the project 429 in the intervention group and 429 in the delayed intervention group. Patients who do not keep scheduled follow-up appointments for abnormal Pap smear results will be eligible and referred to PNs and enrolled. Assessment will occur in face-to-face interviews at baseline and again at two points after the intervention.

project_terms:
Address;Adherence (attribute);Aftercare;Appalachian Region;Appointment;Cancer Burden;Case Management;Case Manager;Centers for Disease Control and Prevention (U.S.);Cervical;Cervical Cancer Screening;Cessation of life;Communities;County;Dependence;Development;Disease;Enrollment;Funding;Health;Health Personnel;Health Promotion;Institution;Intervention;Interview;Kentucky;Life;Literature;Malignant neoplasm of cervix uteri;Medicaid;Modeling;Mortality Vital Statistics;Nurses;Pap smear;Patients;Population;Randomized;Recommendation;Recruitment Activity;Risk;Role;Rural;Rural Population;Schedule;Screening procedure;Services;Test Result;Training;Treatment Cost;Woman;Women's Group;Work;age group;base;cancer prevention;design;experience;falls;follow-up;group intervention;high risk;improved;innovation;malignant breast neoplasm;middle age;older women;outreach program;prevent;programs;public health medicine (field);rural area;treatment program;willingness


application_id: 8069143
project_number: 5U10NS058967-05
project_title: UK NETT Clinical Site Hub
administering_ic: NINDS
award_notice_date: 2011-05-02
opportunity_number: RFA-NS-06-009
application_type: 5
activity_code: U10
ic: NS
serial_number: 058967
program_official: JANIS, SCOTT
project_start_date: 2007-05-03
project_end_date: 2012-04-30
study_section: ZNS1-SRB-K(41)
contact_pi_person_id: 8686194
contact_pi: HUMPHRIES, ROGER LOYD
other_pis: Not Applicable
congressional_district: 06
department: EMERGENCY 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): This proposal describes the establishment of a Neurological Emergencies Treatment Trials (NETT) Network Clinical Site Hub at the University of Kentucky Medical Center (UKMC) in Lexington Kentucky in response to NIH/NINDS RFA-NS-06-009. The overall goal of this proposal is to identify UKMC as an academic medical facility with regional affiliate partners adept in "the evaluation of treatments for patients with a broad spectrum of neurological emergencies." The NETT Clinical Site Hub at UKMC is founded upon an intra- institutional collaboration between physician faculty members of the Departments of Emergency Medicine Neurology and Neurosurgery. Regional affiliate medical care facilities aligned with UKMC include the Department of Veterans Affairs Medical Center/Cooper Drive Division (DVAMC/CDD) in Lexington and "spoke" community hospitals located in non-urban environments throughout Central and Eastern Kentucky. The following Specific Aims are proposed: 1) To demonstrate the existence of an infrastructure for patient recruitment in "large simple" clinical trials performed in acute-onset neurological disorders modeled by TBI drawing upon the resources of a Level 1 Trauma Center situated within a broadly-based geographical network of referring hospitals in non-urban settings and 2) To demonstrate the existence of an infrastructure for patient recruitment in clinical trials performed in acute-onset neurological disorders requiring Exception to Consent for Emergency Research.

project_terms:
Accident and Emergency department;Acute;Adult;Advanced Cardiac Life Support;Agreement;Air;Ambulances;American College of Surgeons;Brain;Caring;Cities;Clinical Trials;Collaborations;Communication;Community Hospitals;Consent;County;Disease model;Doctor of Medicine;Emergency Medicine;Emergency Situation;Emergency medical service;Emergency treatment;Enrollment;Environment;Evaluation;Faculty;Fire - disasters;Goals;Government;Head;Hospitals;Internet;Investigational Therapies;Kentucky;Medical;Medical Faculty;Medical center;Medicine;National Institute of Neurological Disorders and Stroke;Neurological emergencies;Neurology;Operative Surgical Procedures;Patient Recruitments;Patients;Physicians;Positioning Attribute;Principal Investigator;Provider;Randomized;Rehabilitation therapy;Research;Research Infrastructure;Research Personnel;Resources;Rural;Rural Population;Services;Speed (motion);Spinal Cord;Spinal cord injury;Trauma;United States National Institutes of Health;Universities;University Hospitals;Urban Hospitals;Urban Population;Veterans;base;clinical research site;college;design;experience;meetings;member;nervous system disorder;neurosurgery;professor;response;trauma centers;treatment trial


application_id: 8069083
project_number: 3R21ES015812-02S2
project_title: Transplacental Arsenic Induced Hepatic Dysfunction and Vascular Disease
administering_ic: NIEHS
award_notice_date: 2010-05-21
opportunity_number: PA-06-181
application_type: 3
activity_code: R21
ic: ES
serial_number: 015812
suffix: S2
program_official: NADADUR, SRIKANTH
project_start_date: 2009-04-01
project_end_date: 2010-08-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
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
project_abstract:
DESCRIPTION (provided by applicant): Cardiovascular disease is the major cause of death in the U.S. Chronic arsenic ingestion causes atherosclerosis and is associated with increased mortality from myocardial infarction and stroke. Early life arsenic exposure may play a significant role in development of atherosclerosis in adult life as suggested by reports of infant deaths from myocardial infarction caused by advanced arteriosclerosis in regions where mothers consumed water with high levels of arsenic. Transplacental arsenic exposure can disrupt liver DNA methylation patterns and thus alter liver gene expression. Underlying liver disease is an independent risk factor for atherosclerosis. Hence arsenic exposure induced liver disease may predispose to atherogenesis and widespread exposure to arsenic in drinking water in the U.S. likely contributes to atherogenesis and death from cardiovascular disease. Our working hypothesis is that arsenic exposure disrupts epigenetic control of hepatic gene expression predisposing the liver to inflammation that is an atherogenic trigger resulting in accelerated atherosclerosis in susceptible animals. Preliminary data indicate that atherosclerosis-prone apolipoprotein E knockout (ApoE -/-) mice transplacentally exposed to arsenic in drinking water develop overt vascular disease by 10 weeks of age without high lipid diet and that liver gene expression suggests a pro-inflammatory state. The aims of this exploratory grant application are 1) to refine and to optimize this newly developed model of transplacental arsenic induced atherogenesis by determining arsenic exposure response of arsenic blood levels in pregnant females and fetuses determining exposure/time dependence of atherosclerotic lesion formation (rate and extent of lesion formation) assessing arsenic exposure-response of changes in vascular reactivity and characterizing the nature of arterial lesions (lesion cellularity fibrosis and inflammation) in arsenic exposed mice; 2) explore transplacental arsenic-induced hepatic changes by characterizing liver pathology determining circulating biomarkers of liver dysfunction and test the hypothesis that there is a temporal correlation between hepatic changes and vascular changes. Tissues will be examined at birth and at 10 16 and 24 weeks of age to determine the course of disease and stability of molecular changes induced by in utero arsenic exposure. The goal of the proposed studies is to determine whether there is a threshold level of arsenic exposure necessary to accelerate atherogenesis using the ApoE model. The relevance of this model to human atherosclerosis is that people prenatally exposed to arsenic are likely more susceptible to dietary influences later in life. These studies will provide important information on the mechanisms of arsenic induced atherosclerosis and the role that fetal arsenic exposure plays in disease progression. This model also will be a rich resource for future research on the mechanism of arsenic induced atherosclerosis including determination of the critical stages of development for the arsenic effect and molecular studies of arsenic exposure induced changes in DNA methylation chromatin structure gene expression and genetic imprinting. PUBLIC HEALTH RELEVANCE: Exposure to arsenic drinking water is a major concern in the United States. The effect of early life arsenic exposure on adult disease progression is unknown but potentially very important. This project uses a mouse model of fetal arsenic exposure induced vascular disease to investigate effects of fetal arsenic exposure on liver development that likely cause vascular disease by young adulthood.

project_terms:
Adult;Age;Animal Model;Animals;ApoE knockout mouse;Apolipoprotein E;Applications Grants;Arsenic;Arterial Fatty Streak;Arteriosclerosis;Atherosclerosis;Birth;Blood;Blood Vessels;Cardiovascular Diseases;Cause of Death;Cellular Stress;Cellularity;Cessation of life;Cholesterol;Chromatin Structure;Chronic;DNA Methylation;Data;Dependence;Development;Diet;Digit structure;Disease;Disease Progression;Elderly;Epidemiologic Studies;Epigenetic Process;Exposure to;Fatty acid glycerol esters;Female;Fetus;Fibrosis;Functional disorder;Future;Gangrene;Gene Expression;Genetic;Genomic Imprinting;Goals;Hepatic;Hepatic Tissue;Human;Hyperlipidemia;Infant;Inflammation;Inflammatory;Inflammatory Response;Ingestion;Lesion;Life;Link;Lipids;Liver;Liver Dysfunction;Liver diseases;Modeling;Molecular;Mortality Vital Statistics;Mothers;Mus;Myocardial Infarction;Nature;Pathology;Pattern;Phenocopy;Play;Process;Reporting;Research;Resources;Risk Factors;Role;Staging;Testing;Time;Tissues;United States;Vascular Diseases;Water;Work;arterial lesion;atherogenesis;biomarker;drinking water;fetal;in utero;infant death;interest;mouse model;offspring;pregnant;prenatal;prenatal exposure;programs;public health relevance;response;stroke;young adult


application_id: 8068879
project_number: 5R01DK080327-04
project_title: Effects of Fish Oil on Inflammation and Metabolic Syndrome
administering_ic: NIDDK
award_notice_date: 2011-06-06
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 080327
program_official: GARFIELD, SANFORD A
project_start_date: 2008-05-01
project_end_date: 2013-04-30
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Obesity and type 2 diabetes are conditions characterized by a state of chronic low-grade inflammation due largely to an increase in adipose tissue inflammation brought about by infiltrating macrophages. Drugs such as thiazolidinediones (TZDs) improve insulin sensitivity via activation of PPAR-gamma and there is much evidence that PPAR3 agonists also have anti-inflammatory properties. In addition to their beneficial effects on serum lipids and heart disease fish oils (I-3 fatty acids) activate PPAR3 and demonstrate anti-inflammatory properties. This is a translational research study intended to examine the mechanism for many of the beneficial effects of fish oils on metabolic syndrome in humans. We plan to treat insulin resistant subjects with fish oils and the following hypotheses. Hypothesis 1. The treatment of insulin resistant subjects with fish oils will reduce adipose tissue inflammation. We plan to examine the circulating levels of cytokines as well as the levels of cytokines and macrophages in adipose tissue biopsies of subjects who are treated with 4 g/day of I-3 fatty acids for 12 weeks. We will determine whether there is evidence of macrophage apoptosis in adipose tissue and we will determine whether I-3 fatty acids increases the level or secretion of adiponectin. Hypothesis 2. Anti-inflammatory effects of fish oils are mediated by activation of PPAR3 and/or by changes in membrane composition that affect signal transduction functions. Adipose tissue and macrophages will be treated in vitro with fish oils in the presence and absence of a PPAR3 inhibitor and we will measure PPAR3 responses such as the secretion of HMW adiponectin and macrophage apoptosis. In addition we will determine whether I-3 fatty acids induce changes in recruitment of inflammatory receptors such as toll-like receptor 4 (TLR4) and TNF1 Receptor 1 (TNFR1) to membrane rafts. Hypothesis 3. Fish oils improve peripheral insulin sensitivity through a reduction in intramyocellular lipid and an improvement in muscle insulin signal transduction. Before and after treatment with fish oils insulin sensitivity will be measured along with intramyocellular lipid and genes or proteins involved in insulin action and muscle lipid oxidation.  Project Narrative: The incidence of obesity metabolic syndrome and diabetes is rising in epidemic proportions in the Western world and the resultant heart disease will likely create a generation who will not live as long as their parents. Fish oils have proven health benefits on coronary risk factors and this study aims to develop evidence for additional properties of fish oils that will greatly extend their use to subjects with insulin resistance and metabolic syndrome.

project_terms:
24-thiazolidinedione;Adipocytes;Adipose tissue;Affect;Aftercare;Agonist;Animal Feed;Anti-Inflammatory Agents;Anti-inflammatory;Apoptosis;Arachidonic Acids;Biopsy;Blood specimen;Cardiovascular system;Cell Adhesion Molecules;Chronic;Complex;Coronary;Coronary heart disease;Development;Diabetes Mellitus;Disease Progression;Epidemic;Event;Fasting;Fatty Acids;Fish Oils;Generations;Genes;Health Benefit;Heart Diseases;Human;Hyperglycemia;In Vitro;Incidence;Inflammation;Inflammatory;Insulin;Insulin Resistance;Interleukin-6;Life;Lipids;Literature;Measures;Mediating;Mediator of activation protein;Membrane;Metabolic syndrome;Molecular Weight;Muscle;Muscle Cells;Non-Insulin-Dependent Diabetes Mellitus;Nuclear Hormone Receptors;Obesity;Omega-3 Fatty Acids;Organ;PPAR gamma;Parents;Peripheral;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Process;Production;Property;Protein Isoforms;Proteins;Rattus;Reactive Oxygen Species;Risk Factors;Series;Serum;Signal Transduction;Source;Syndrome;TNF gene;Thiazolidinediones;Translational Research;Triglycerides;Tumor Necrosis Factor-alpha;Western World;adiponectin;carbohydrate metabolism;cytokine;feeding;high risk;immunoregulation;improved;inflammatory marker;inhibitor/antagonist;insulin secretion;insulin sensitivity;insulin signaling;lipid metabolism;macrophage;oxidation;receptor;research study;response;toll-like receptor 4

public_health_relevance:
The incidence of obesity metabolic syndrome and diabetes is rising in epidemic proportions in the Western world and the resultant heart disease will likely create a generation who will not live as long as their parents. Fish oils have proven health benefits on coronary risk factors and this study aims to develop evidence for additional properties of fish oils that will greatly extend their use to subjects with insulin resistance and metabolic syndrome.


application_id: 8068826
project_number: 5R01NS070899-02
project_title: Regulation signaling and dynamics of glucan phosphatases.
administering_ic: NINDS
award_notice_date: 2011-03-18
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 070899
program_official: STEWART, RANDALL R
project_start_date: 2010-07-01
project_end_date: 2015-04-30
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The objective of this grant is to elucidate the regulation downstream signaling and structural dynamics of the glucan phosphatase laforin. Mammalian cells store readily mobilized energy in the form of glycogen a water-soluble carbohydrate. Recessive mutations in genes encoding the E3 ubiquitin ligase malin or the dual specificity phosphatase laforin disrupt glycogen metabolism and result in a fatal neurodegenerative epilepsy called Lafora disease (LD). A hallmark of LD is poorly branched hyperphosphorylated insoluble carbohydrate accumulations called Lafora bodies (LBs) thought to be the causative agent of LD.  We established that malin is a single-subunit E3 ubiquitin ligase that ubiquitinates and triggers the degradation of multiple proteins involved in glycogen metabolism. In addition we discovered that laforin is the founding member of a unique class of phosphatases that dephosphorylate phospho-glucans. These results allowed us to propose molecular mechanisms that cause LD: 1) loss of malin results in LBs due to an imbalance in glycogen metabolism proteins i.e. protein levels are not properly maintained; 2) loss of laforin results in LBs due to glucan hyperphosphorylation that inhibits glucan branching; 3) laforin also acts as a targeting subunit for malin so that loss of laforin disrupts some malin-directed ubiquitination events. While we have made significant strides in determining the molecular mechanisms of LD we lack an understanding of how these enzymes are regulated. This proposal will elucidate the deficiencies in our current knowledge.  We recently identified novel phosphorylation and ubiquitination events on laforin. Phosphorylation and ubiquitination are post-translational modifications that direct changes in protein concentration enzymatic activity protein localization protein-protein interactions and structural dynamics. In Aim 1 we will define the in vivo conditions triggering laforin phosphorylation and characterize the functional consequences. We will utilize 1) overexpression and endogenous protein levels in tissue culture cells to monitor the status of laforin localization and modification 2) assay laforin function in vitro using purified proteins and 3) utilize a LD mouse model to verify our results. In Aim 2 we will utilize a similar strategy to determine the affects of ubiquitination on laforin function. In addition we will define the role of laforin in malin directed ubiquitination as we have recently discovered that laforin acts as a targeting protein for malin. In Aim 3 we will determine how perturbations of the structural components of glucan phosphatases contribute to LD. We will utilize Hydrogen- Deuterium exchange mass spectrometry to define the structural dynamics of laforin and x-ray crystallography to determine the structure of a glucan phosphatase. This proposal is built on our past discoveries and uses complementary approaches to advance our understanding of the intercalated events of cell metabolism neurodegeneration and epilepsy. Completion of this work will yield a better understanding of these complex events and will produce therapeutic insights for epilepsy and neurodegeneration.  
  
PUBLIC HEALTH RELEVANCE:  The focus of our work is to determine how loss of function of either of two proteins leads to the fatal neurodegenerative epilepsy called Lafora disease. Our proposal is built on our past discoveries and uses complementary approaches to advance our understanding of the intertwined events of cell metabolism neurodegeneration and epilepsy. Completion of this work will yield a better comprehension of these complex events and will produce therapeutic insights for epilepsy and neurodegeneration.


application_id: 8068505
project_number: 3R01NS054708-03S1
project_title: Genetic approaches to functional remyelination after SCI
administering_ic: NINDS
award_notice_date: 2010-04-29
opportunity_number: PAS-05-092
application_type: 3
activity_code: R01
ic: NS
serial_number: 054708
suffix: S1
program_official: KLEITMAN, NAOMI
project_start_date: 2008-01-01
project_end_date: 2011-12-31
study_section: Special Emphasis Panel[ZRG1-BDCN-J(05)M]
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Our recently work show that glial restricted precursor cells (GRPs) grafted into a demyelinating orcontusive spinal cord injury (SCI) partially restore electrophysiological conduction and hindlimb locomotorrecovery. We will build on those data and determine the potential of human embryonic stem cells (hESC) torestore function after engraftment into the damaged spinal cord. Aim 1. Using the focal VLF+DLFdemyelinating lesion and grafting D15A-GRPs (A2B5+/NG2+/O4-) we will determine whether inhibition ofBMP and Notch signaling pathways demonstrated in vitro to inhibit oligodendrocyte differentiation canenhance the remyelination capacity of the engrafted cells. We will examine a number of genetic andmolecular biological approaches to inhibiting BMP and Notch signaling. Aim 2. Determine whether deliveryof CNTF or NRG1 types I or III neurotrophic factors known to potentiate oligodendrocyte proliferation andmaturation in vitro and in vivo will enhance remyelination by engrafted GRPs. Aim 3. Using optimalparameters established in Aims 1 and 2 and the more clinically relevant contusion SCI we will ask whetherremyelination can result in enhanced recovery of function. We hypothesize that both remyelination andenhanced white matter sparing are needed for optimal recovery and will distinguish between those effects inthese animals.

project_terms:
Address;Adult;Animals;Axon;Behavioral;Biological;Brain-Derived Neurotrophic Factor;Cells;Chest;Ciliary Neurotrophic Factor;Contusions;Data;Demyelinations;Dominant-Negative Mutation;Engraftment;Environment;Failure (biologic function);Functional disorder;Gene Deletion;Genetic;Heterozygote;Hindlimb;Impairment;In Vitro;Injury;Intervention;Lentivirus Vector;Lesion;Locomotor Recovery;Magnetism;Measures;Methods;Modeling;Modification;Molecular Genetics;Monitor;Motor Evoked Potentials;Mus;NRG1 gene;Natural regeneration;Neuregulins;Notch Signaling Pathway;Oligodendroglia;Play;Publications;Publishing;Rattus;Recovery;Recovery of Function;Research Personnel;Retroviridae;Role;Signal Pathway;Signal Transduction;Small Interfering RNA;Spinal Cord;Spinal cord damage;Spinal cord injury;Stem cells;Work;cell type;clinically relevant;combinatorial;functional restoration;human embryonic stem cell;in vivo;injury prevention;insight;mouse model;myelination;neurotrophic factor;nicastrin protein;notch protein;partial recovery;precursor cell;response;success;treatment strategy;vector;white matter


application_id: 8068159
project_number: 1U01DA030916-01
project_title: NDA-Enabling Phase I Lofexidine Program
administering_ic: NIDA
award_notice_date: 2011-02-15
opportunity_number: RFA-DA-10-018
application_type: 1
activity_code: U01
ic: DA
serial_number: 030916
program_official: BISWAS, JAMIE
project_start_date: 2011-03-01
project_end_date: 2014-02-28
study_section: Special Emphasis Panel[ZDA1 JXR-D (10)]
contact_pi_person_id: 10466426
contact_pi: LONGSTRETH, JAMES ALVAN
other_pis: GORODETZKY, CHARLES W.
congressional_district: 03
department: Unavailable
primary_duns: 087875626
primary_uei: NKGSYBV5UGN1
duns_number: 087875626
uei: NKGSYBV5UGN1
fips: US
organization_id: 10003722
organization_name: US WORLDMEDS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40241
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): (Part 1: Description) the proposed research "NDA-Enabling Phase I Lofexidine Program" is aimed at characterizing the pharmacokinetic and clinical pharmacological profiles of lofexidine hydrochloride an alpha-2 adrenergic agonist under development for the treatment of acute withdrawal from short acting opioids. The research program consists of seven studies each with a particular objective that will add to the overall understanding of the pharmacology of the investigational drug. The studies include evaluation of (1) effect of food on lofexidine's bioavailability (2) pharmacokinetics in hepatically-impaired patients (3) pharmacokinetics in renally-impaired patients drug-drug pharmacokinetic interactions between lofexidine and (4) methadone (5) naltrexone and (6) buprenorphine (drugs for related indications that may be used concurrently in a clinical setting) and (7) a study of absolute bioavailability and mass balance of lofexidine. The studies will be conducted in normal healthy volunteers or special populations (as in the case of the hepatic and renal impairment studies) and will employ use of liquid chromatography tandem mass spectrometry (LC/MS/MS) methodology to detect lofexidine hydrochloride parent molecule in the urine and plasma. Additionally for one of the planned studies tracer amounts (approximately 100 nCi) of radio-labeled 14C-lofexidine will be used in an oral dose and analyzed by Accelerated Mass Spectrometry in order to follow the plasma and excretion pharmacokinetics of parent drug and to identify and quantify the excreted metabolites of lofexidine. The 14C-lofexidine dose and the appropriate AMS methods for specific identification and quantification of lofexidine metabolites is proposed to be developed as part of the research plan which will allow identification and quantification of both lofexidine and its major metabolites in the plasma and urine. Quantification of lofexidine and/or its major metabolites over time in addition to observed tolerance and evaluation of other clinical parameters in each of the planned studies will add to the overall understanding of the pharmacokinetics and pharmacodynamics of lofexidine in the body. This information is needed to allow appropriate labeling of the product for its entrance to the US market. Furthermore the planned research has been defined by the FDA as critical to complete the clinical pharmacology section requirements for a New Drug Application for lofexidine hydrochloride approval of which will allow entrance of the first non-narcotic non-addictive drug indicated for the treatment of opiate withdrawal to the US market.  
  
PUBLIC HEALTH RELEVANCE: (Project Summary Part 2: Relevance) Opioid abuse and dependence is a serious and growing problem in the US with an estimated 5.2 million nonmedical-related users of prescription opiate pain killers such as Lortab(R) and OxyContin(R) (SAMHSA 2008) 1 million heroin addicts in the US (National Institutes of Health 2006) and recent articles suggesting that abuse is spreading into rural and suburban areas (Archibold 2009). There is an unmet medical need in the opioid-dependent population with only two FDA-approved drugs (methadone and buprenorphine) currently available to treat opioid withdrawal. Both are opiate products that effectively operate as replacement or substitution therapies have abuse potential and are themselves controlled substances. FDA approval of lofexidine hydrochloride will enable the entrance of the first non-narcotic non-addictive product to the market for the treatment of opioid withdrawal the first hurdle in recovery from opioid dependence. The planned research is required to understand how lofexidine works in the body so that appropriate dosing meal requirements the safety of combination with other treatment drugs and safety considerations for patients with poor liver and kidney functions can be evaluated.


application_id: 8066379
project_number: 5R01CA138688-03
project_title: Convergence of MicroRNAs and p53 Signaling in Multiple Myeloma: Environmental Co
administering_ic: NCI
award_notice_date: 2011-08-05
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 138688
program_official: JOHNSON, RONALD L
project_start_date: 2009-07-01
project_end_date: 2014-04-30
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)S]
contact_pi_person_id: 8146758
contact_pi: LI, YONG
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Multiple myeloma (MM) is one of the most common hematological neoplasms. It constitutes about 1% of human cancers and 2% of all cancer deaths. Polycylic aromatic hydrocarbons such as 2378- tetrachlorodibenzo-p-dioxin (TCDD) have been closely correlated to MM by epidemiologic studies yet the biologic mechanisms of a causal relationship between TCDD exposure and MM have not been well understood. One of the unique features of MM compared to other cancers is the extremely low genetic mutation rate of the tumor protein p53 (TP53) gene. TP53 encodes the p53 tumor suppressor guardian of the human genome. Genomic instability (chromosome translocation aneuploidy and gene mutation) is widely observed in MM and reveals that the function of p53 as the guardian of the human genome is compromised in MM. We explored the molecular mechanisms of p53 inactivation in MM by a new class of noncoding small RNAs microRNAs (miRNAs) as recent reports have demonstrated that some miRNAs such as miR-34 are important players in the p53 tumor suppressor network. We hypothesize that miRNAs negatively regulate the human TP53 gene in MM. We propose three aims for this project: first we will identify miRNAs that target the human TP53 gene by a combination of mutagenesis reporter expression and immunoblotting analyses; second we will assess the pathological significance of miRNA:TP53 interactions in MM cell lines and primary MM cells by expression profiling and miRNA inhibition assays; third we will determine whether dioxin modulates p53 signaling by upregulating miRNA expression. A novel p53 inactivation mechanism by an miRNA that is upregulated by dioxin will lead to unique targets for diagnostic markers and therapeutic interventions in MM patients as well as provide a better understanding of the biological interactions between dioxin exposure and MM tumorigenesis. PUBLIC HEALTH RELEVANCE: TP53 gene alterations are rare and late events in multiple myeloma (MM) the second most common hematological malignancy constituting about 1% of all human cancers. It is critical to explore whether there are unique mechanisms that inactivate wild-type TP53 function as an early and original molecular event in MM development. The proposed research plan is to test the hypothesis that TP53 is negatively regulated by microRNAs (miRNAs) a class of newly discovered small noncoding RNAs to define whether miRNA dysregulation contributes to tumorigenesis prior to TP53 gene alterations and to determine whether dioxin modulates p53 signaling through upregulating miRNA expression.

project_terms:
101 Mouse;ARNT gene;Aneuploidy;Antisense RNA;Apoptosis;Apoptotic;Aromatic Hydrocarbons;Aromatic Polycyclic Hydrocarbons;Aryl Hydrocarbon Receptor;Benzo(a)pyrene;Binding Sites;Biological;Biological Assay;Biological Process;Bone Marrow;CDKN2A gene;Cell Aging;Cell Cycle Arrest;Cell Death;Cell Line;Cells;Cellular Assay;Cessation of life;Characteristics;Chromosomal translocation;Clinical;Code;Collaborations;Computing Methodologies;Cytoplasm;Development;Diagnosis;Diagnostic;Diagnostic Neoplasm Staging;Dioxins;Disease Progression;Double Minutes;Drug Delivery Systems;Elements;Environmental Pollution;Environmental Risk Factor;Epidemiologic Studies;Epigenetic Process;Etiology;Event;Exposure to;FDA approved;Gene Expression;Gene Library;Gene Mutation;Gene Targeting;Genes;Genome;Genomic Instability;Hematologic Neoplasms;Human;Human Genome;Immunoblotting;Immunoglobulins;Incidence;Infiltration;Laboratories;Lead;Little's Disease;MDM2 Gene Amplification;Malignant Neoplasms;Mediating;Messenger RNA;Methods;MicroRNAs;Molecular;Molecular Profiling;Monitor;Multiple Myeloma;Mus;Mutagenesis;Mutate;Mutation;Neoplasms;Neoplastic Plasma Cell;Nucleotides;Oncogene Activation;Onset of illness;Pathogenesis;Patients;Pattern;Pharmaceutical Preparations;Physiological;Plasma Cells;Process;Promotor (Genetics);Protein p53;Proteins;RNA;Regulation;Reporter;Reporting;Research;Role;Sampling;Signal Transduction;Small RNA;Specimen;TP53 gene;Testing;Tetrachlorodibenzodioxin;Therapeutic Intervention;Time;Tumor stage;Tumor-Suppressor Gene Inactivation;Universities;Untranslated RNA;Untranslated Regions;Viral Proteins;Wisconsin;antiangiogenesis therapy;base;biomarker;clinically significant;mutant;novel;overexpression;p14ARF Protein;prevent;prognostic;public health relevance;research study;response;stressor;tool;tumor;tumorigenesis;vector

public_health_relevance:
Project Narrative TP53 gene alterations are rare and late events in multiple myeloma (MM) the second most common hematological malignancy constituting about 1% of all human cancers. It is critical to explore whether there are unique mechanisms that inactivate wild-type TP53 function as an early and original molecular event in MM development. The proposed research plan is to test the hypothesis that TP53 is negatively regulated by microRNAs (miRNAs) a class of newly discovered small noncoding RNAs to define whether miRNA dysregulation contributes to tumorigenesis prior to TP53 gene alterations and to determine whether dioxin modulates p53 signaling through upregulating miRNA expression.


application_id: 8066377
project_number: 5R01MD004598-03
project_title: Does Violence Against Women result in disparities in cancer care for women with b
administering_ic: NIMHD
award_notice_date: 2011-03-23
opportunity_number: RFA-MD-09-004
application_type: 5
activity_code: R01
ic: MD
serial_number: 004598
program_official: ALVIDREZ, JENNIFER L
project_start_date: 2009-09-25
project_end_date: 2014-04-30
study_section: ZMD1-PA(R4)S
contact_pi_person_id: 1894149
contact_pi: COKER, ANN L
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 the applicant):  Violence against women (VAW) is defined by the United Nations as "any act of gender based violence that results in physical sexual or psychological harm or suffering to women." In Kentucky almost 40% of women had experienced some form of VAW in their lifetime. The frequency of VAW poses a serious public health challenge not only due to the prevalence but also the long term impact on women's health documented in an impressive body of literature. However very little research has explored the effect of lifetime VAW on cancer prevention and control. Kentucky has a high cancer burden with the highest cancer mortality rate of all US states. Incidence rates of cancer and the proportion of women diagnosed at a later stage are higher in the Appalachian region of Kentucky. VAW frequently co-occurs with social factors leading to health disparities including unemployment less education and minority race. Overall objectives of this project are to determine the extent to which VAW may explain noted disparities in cancer care based on women's race/ethnicity socioeconomic status access to health insurance or residence in high poverty and rural areas of Kentucky. Specific aims: To determine whether VAW is associated with disparities in breast cancer (aim 1) colorectal cancer (aim 2) and cervical cancer (aim 3) care outcomes to include not receiving cancer screening at recommended intervals being diagnosed with cancer at a later stage not receiving recommended cancer treatment including supportive/palliative care and poorer cancer specific survival among women diagnosed with these cancers in Kentucky and adjusting for relevant confounders including race socioeconomic status having health insurance rural residence and specific regions of high poverty (e.g. living in the Appalachian region of eastern Kentucky or the Delta region of western Kentucky). Methods: We propose a prospective cohort using the Kentucky Cancer Registry (KCR) as the source of 3150 breast cancer cases 1575 colorectal cancer cases and 525 cervical cancer cases. These 5250 women will be interviewed by phone to determine their lifetime exposure to VAW and comorbid conditions. These data will be linked with state level Medicare claims data for women completing phone surveys who are 65 or older. The Medicare claims data administered by the Center for Medicare and Medicaid Services include comprehensive coverage of medical services regardless of where the patients seek care in the nation which would allow the detailed examination of the proposed cancer care continuum: cancer screening stage at diagnosis treatment supportive or palliative care and survivorship. Both logistic regression and Cox proportional hazards modeling will be used to determine the role of VAW (by frequency duration severity and type) and socioeconomic attributes influencing disparities in cancer care. These associations will be investigated for each of the hypothesized five cancer care outcomes and by specific cancer. The mediating or moderating role of socioeconomic factors will also be explored using structural equation modeling. Relevance: This will be the first population-based cohort of the influence of VAW on the life course of cancer care in a state with high cancer burden and regions of extreme poverty. Findings will have significant public health impact in reducing disparities and improving cancer prevention and control in women.

project_terms:
Adult;Affect;Appalachian Region;Breast;Breast Cancer Treatment;Cancer Burden;Cancer Control;Cancer Patient;Caring;Censuses;Cervical;Child;Choices and Control;Clinic;Colonoscopy;Colorectal;Colorectal Cancer;Consent;Cox Proportional Hazards Models;Data;Data Analyses;Data Set;Diagnosis;Diagnostic Neoplasm Staging;Divorce;Educational aspects;Ensure;Epidemiologic Studies;Equation;Ethnicity aspects;Event;Exposure to;Family member;Fecal occult blood;Frequencies (time pattern);Funding;Gender;Geographic state;Grant;Health;Health Insurance;Healthcare;Human Papillomavirus;Incidence;Individual;Insurance Coverage;Intervention;Interview;Kentucky;Life;Life Cycle Stages;Link;Literature;Logistic Regressions;Low income;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Mammography;Measures;Mediating;Medical;Medical Surveillance;Medicare;Medicare claim;Medicare/Medicaid;Mental Health;Methods;Minority;Modeling;Mortality Vital Statistics;Neighborhoods;Occult blood screen;Outcome;Outcomes Research;Palliative Care;Pap smear;Parents;Pathway interactions;Patient Self-Report;Patients;Pattern;Physicians;Positioning Attribute;Poverty;Poverty Areas;Prevalence;Race;Recruitment Activity;Registries;Research;Research Personnel;Risk;Role;Rural;Schools;Screening for cancer;Screening procedure;Services;Severities;Smoke;Smoking Status;Socioeconomic Factors;Socioeconomic Status;Solutions;Source;Stage at Diagnosis;Staging;Supportive care;Surveys;Survivors;Telephone;Telephone Interviews;Texas;Time;Tumor stage;Unemployment;Uninsured;United Nations;United States Centers for Medicare and Medicaid Services;Violence;Woman;Women's Health;Work;base;cancer care;cancer diagnosis;cancer health disparity;cancer prevention;cancer therapy;care seeking;cohort;emotional abuse;experience;health disparity;improved;low socioeconomic status;malignant breast neoplasm;men;neoplasm registry;physical conditioning;population based;programs;prospective;psychologic;public health medicine (field);residence;rural area;social;socioeconomics;survivorship;tool;violence against women

public_health_relevance:
Determining whether violence against women influences the life course of cancer prevention andcontrol for women with breast cervical or colorectal cancer can result in an important opportunity tounderstand reasons for and potential solutions to cancer care disparities. If VAW does influence cancercare interventions can be developed to identify VAW in women with cancer and provide appropriatesupport to ensure receipt of recommended care.


application_id: 8065903
project_number: 5R01CA133257-02
project_title: Exercise-mediated protection against brain metastases
administering_ic: NCI
award_notice_date: 2011-04-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 133257
program_official: EMENAKER, NANCY J
project_start_date: 2010-07-01
project_end_date: 2011-11-01
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
other_pis: Not Applicable
congressional_district: 06
department: NEUROSURGERY
primary_duns: 939017877
primary_uei: 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): Clinical evidence indicates that moderate to vigorous exercise is a powerful means to reduce metastatic cancer incidence. However the mechanisms of this beneficial influence are not fully understood. Our present application is specially focused on the mechanisms of tumor cell extravasation into the brain. Such an emphasis on brain metastases is consistent with our interest in the blood-brain barrier physiology and pathology. In addition brain metastases are one of the leadings causes of cancer-related morbidity and mortality. The central hypothesis of the present application is that exercise protects against the development of blood- borne brain metastases by increasing antioxidant capacity and modulating redox- regulated responses in the capillary endothelium. To study this hypothesis we will employ an animal model of wheel running mice that mimics the voluntary pattern of human exercise. We will specifically focus on the exercise-mediated protection against vascular mechanisms of tumor cell extravasation via disruption of tight junction proteins of the endothelium. Tight junctions are the critical components of the brain capillaries which regulate the integrity of the blood-brain barrier. Mechanistically the main emphasis will be placed on the involvement of the Ras and Rho signaling in alterations of phosphorylation and expression of tight junction proteins.  The proposed research combines elements of exercise physiology clinical approaches (namely tumor dissemination and growth) cancer progression and molecular and vascular biology. In addition we will employ advanced systems biology approaches. Novelty and significance of the present proposal are related to our focus on the blood-brain barrier in brain metastasis as tumor extravasation occurs at the level of the cerebrovasculature endothelium and the evaluation of the protective effects of physical activity on tumor dissemination and growth. We believe that the data obtained from this proposal will provide evidence that even moderate exercise can significantly protect against the development of blood-brain metastases. Furthermore a better understanding of the pathophysiological regulation of BBB molecular and functional properties is critical in assessing brain metastasis etiology and in identifying future drug targets to develop more effective therapeutic approaches.  
  
PUBLIC HEALTH RELEVANCE:  We propose that exercise can attenuate the formation of brain tumor metastases at the level of the blood-brain barrier (BBB) via antioxidant related mechanisms. Specifically we will explore the link between exercise and the protection against disruption of tight junction proteins alterations of caveolae-associated redox signaling and transcapillary dissemination of tumor cells. We believe that the data obtained from this proposal will provide evidence that exercise can significantly protect against the development of blood-brain metastases.

project_terms:
Abbreviations;Actins;Address;Animal Model;Animals;Antioxidants;Attenuated;Biological Models;Biology;Blood;Blood - brain barrier anatomy;Blood Vessels;Blood capillaries;Brain;Brain Neoplasms;C57BL/6 Mouse;Cancer Etiology;Caveolae;Caveolins;Cell Surface Receptors;Cerebrum;Clinical;Cytoskeleton;Data;Development;Dextrans;Disseminated Malignant Neoplasm;Drug Delivery Systems;Elements;Endothelial Cells;Endothelium;Equilibrium;Etiology;Evaluation;Event;Exercise;Exercise Physiology;Extravasation;Fluorescein-5-isothiocyanate;Functional disorder;Future;GTP-Binding Proteins;Glutathione;Goals;Growth;Human;In Situ;Incidence;Injection of therapeutic agent;Integral Membrane Protein;Intercellular Junctions;Internal carotid artery structure;Label;Lewis Lung Carcinoma;Link;Malignant Epithelial Cell;Malignant Neoplasms;Manganese Superoxide Dismutase;Mediating;Membrane;Membrane Microdomains;Metastatic malignant neoplasm to brain;Modeling;Moderate Exercise;Molecular;Monomeric GTP-Binding Proteins;Morbidity - disease rate;Mortality Vital Statistics;Mus;Neoplasm Metastasis;Nuclear;Oxidases;Oxidation-Reduction;Oxidative Stress;Pathology;Pathway interactions;Pattern;Permeability;Phosphorylation;Physical activity;Physiology;Process;Property;Proteins;Proteomics;Regulation;Research;Rodent;Role;Running;Signal Pathway;Signal Transduction;Solid;Staining method;Stains;Systems Biology;Techniques;Therapeutic;Tight Junctions;Tissues;Very Light Exercise;advanced system;base;brain tissue;capillary;caveolin 1;dextran;in vivo Model;interest;junctional adhesion molecule;mitochondrial dysfunction;neoplastic cell;novel;occludin;oxidation;prevent;protective effect;protein expression;public health relevance;research study;response;rho;sedentary;tissue processing;tumor;tumor progression;zonula occludens-1 protein

public_health_relevance:
PROJECT NARRATIVE We propose that exercise can attenuate the formation of brain tumor metastases at thelevel of the blood-brain barrier (BBB) via antioxidant related mechanisms. Specifically we willexplore the link between exercise and the protection against disruption of tight junction proteinsalterations of caveolae-associated redox signaling and transcapillary dissemination of tumorcells. We believe that the data obtained from this proposal will provide evidence that exercisecan significantly protect against the development of blood-brain metastases.


application_id: 8064754
project_number: 5T32AG000242-18
project_title: Cellular and Molecular Basis of Brain Aging
project_terms: Aging;Base of the Brain;Molecular
administering_ic: NIA
award_notice_date: 2011-04-06
opportunity_number: PA-06-468
application_type: 5
activity_code: T32
ic: AG
serial_number: 000242
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 1994-09-30
project_end_date: 2014-04-30
study_section: ZAG1-ZIJ-7(J4)
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG A.
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
project_abstract:
DESCRIPTION (provided by applicant): The goal of this Training Program is to prepare promising graduate students and postdoctoral fellows for successful careers in the neurobiology of aging. We will provide broad-based training in modern concepts in the neurobiology of aging with an emphasis on cellular and molecular mechanisms underlying aging processes and possible therapeutic interventions. The unifying focus of the training faculty is our interest in understanding both normal and pathological mechanisms by which the nervous system responds to changes that occur with age and emerging concepts in therapeutic intervention. This Training Program provides the formal framework for faculty in different departments who share a common interest in the molecular- cellular basis of brain aging and translational research to provide in-depth training in aging. The emphasis of the Training Faculty complement each other: some focus on processes that occur in the brain during normal aging others emphasize the neuropathological processes of diseases and injuries that predominate in the aging brain and there is a combined interest in applying this knowledge to treating neural disorders of aging. Thus trainees will learn from faculty who utilize a broad spectrum of state-of-the-art methodological approaches to probe critical questions in aging research. Our successes attest to our abilityto identify attract train and place promising young investigators in the area of the neurobiology of aging. Now more than ever before we are particularly qualified to train graduate students and postdoctoral fellows. The national need for training new investigators in the area of aging is clear due to our changing demography and the increasing average lifespan. Normal aging or pathology of the nervous system underlies much age-associated morbidity. Only if we better understand the basic mechanisms that regulate the aging of the brain and apply this to the treatment ofthe elderly can we hope to improve the qualityof life during the latter half ofthe lifespan. Our ability to attract and train graduate students and postdoctoral fellows to meet the challenges in the area of the neurobiology of aging will be greatly enhanced by this Training Program.   
  
RELEVANCE: This Program will train the next generation of scientists to carryout research on the neurobilogy of aging. Dramatic improvements in the treatment of age-related illnesses such as Alzheimer's disease Parkinson's disease stroke epilepsy and others are need for the aging world population. Only through training of such research areas can we hope to make strides in new treatments for illnesses that cost us billions.


application_id: 8064654
project_number: 5T32HL091812-04
project_title: Clinical Scholars in Cardiovascular Science
project_terms: Cardiovascular system;Clinical;Science
administering_ic: NHLBI
award_notice_date: 2011-05-24
opportunity_number: PA-06-468
application_type: 5
activity_code: T32
ic: HL
serial_number: 091812
program_official: CARLSON, DREW E
project_start_date: 2008-06-01
project_end_date: 2013-05-31
study_section: ZHL1-CSR-M(F1)
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
project_abstract:
DESCRIPTION (provided by applicant):   
The University of Kentucky Training Program for Clinical Scholars in Cardiovascular Science is designed to prepare exceptional clinical scholars to assume leadership positions directing multidisciplinary research in the field of cardiovascular medicine. In the last several years as a consequence of substantial institutional commitment we have assembled a vertically-integrated approach of incorporating basic translational and clinical cardiovascular science in four concentrations: Thrombosis and Inflammation; Atherosclerosis and Aneurysm; Cardiac Hypertrophy and Heart Failure; and Vascular Cell Response to Stress. We propose to leverage our cardiovascular science strengths to provide a unique multidisciplinary training program that horizontally integrates trainees across the disciplines of Medicine Nursing and Pharmacy. Our goal is to increase the pipeline of clinical investigators who will bridge the gap between basic science advances and their application to clinical medicine. Specifically our aims are: 1) To provide a rigorous and solid research education in the basic sciences related to cardiovascular research 2) To prepare new researchers for translational and clinical science in a highly interdisciplinary environment 3) To provide training in the efficient and ethical conduct of high quality laboratory management and science 4) To create an environment that will incubate scholars and mentors with an innovative and nurturing structure of interlaced mentoring teams To accomplish our goal we have designed the Program to focus on clinicians (MD PharmD RN/PhD) who are at the early postdoctoral stage of their careers. The Program will combine an intensive mentored research experience that blends laboratory-based and clinically-based methods with a rigorous curriculum in cardiovascular science. A committee of experienced investigators will enhance the research experience by providing insight and oversight. Scholars will receive supplemental training in "survival skills" and be  active participants in our cardiovascular community. Upon completion of the program we anticipate that the trainees will have the experience and capabilities necessary to initiate an independent career as a patient- oriented or translational investigators.


application_id: 8064530
project_number: 2R01NS040334-09
project_title: Transgenetic studies of prion disease in cervids
administering_ic: NINDS
award_notice_date: 2010-09-20
opportunity_number: PA-10-067
application_type: 2
activity_code: R01
ic: NS
serial_number: 040334
program_official: DALEY, WILLIAM PATRICK
project_start_date: 2000-08-01
project_end_date: 2011-06-30
study_section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT]
contact_pi_person_id: 7875112
contact_pi: TELLING, GLENN C
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Prions cause fatal incurable infectious neurodegenerative diseases in animals and humans. Transmission occurs by corruption of cellular prion protein (PrPC) by the pathogenic conformation PrPSc. Prions share with nucleic acid based pathogens the ability to propagate strain information. Our overarching goal is to understand the biological and physico-chemical basis of prion strain variation and how strains mutate and acquire fitness in the absence of nucleic acids phenomena that are linked to their underlying pathogenesis and zoonotic potential. Our focus remains largely on chronic wasting disease (CWD) a burgeoning and highly contagious prion disorder of captive and wild cervids. The discoveries of distinct CWD strains and of prions in deer skeletal muscle and elk antler velvet have unmistakable relevance to human health. The currently indistinguishable PrPSc conformations and unstable transitions of CWD strains are consistent with their separation by relatively low energy barriers. Strain stability also differs between deer and elk. Our overarching hypothesis is that host PrPC primary structure influences the portfolio of thermodynamically preferred PrPSc conformations that are kinetically selected during prion propagation. The following Aims comprise our research design and methods: 1: To produce gene targeted (Gt) mice in which the mouse Prnp coding sequence is substituted by that of deer or elk. This will enable us to explore the hypothesis that residue 226 the sole difference in deer and elk PrP primary structures resides within a critical domain influencing PrP conversion and strain stability. 2: Gt mice provide a resource to precisely characterize the properties of CWD strains and to assess the contributions of PrP primary structure on strain stability. Transgenetic studies of the domain encompassing cervid residue 226 will also be extended in this Aim. 3: We will use Gt mice and existing transgenic models to assess whether CWD strains interfere or synergize during disease and to explore peripheral pathogenesis of strains which are likely factors in the unparalleled contagious transmission of CWD. 4: We will develop innovative cell culture resources for quantifying CWD prions and characterizing strain properties. We hypothesize that prion strains are subject to selective pressure and we will assess the effects of modifiers of prion replication on the formation of strain variants with altered biological and biochemical properties of cervid PrPSc. 5: Finally we hypothesize that the instabilities of CWD strains and their currently indiscernible biochemical properties reflect thermodynamic similarities between PrPSc constituting these strains. We will examine whether purified strains differ with respect to protease-sensitive PrPSc and assess the sensitivity of Conformational Dependent Immunoassay Fourier-transform infrared spectroscopy luminescent conjugated polymers and Protein Misfolding Cyclic Amplification approaches for strain discrimination. We anticipate that our work will continue to have a sustained powerful impact on this field and likely related diseases involving protein misfolding as well as clarifying many remaining enigmatic aspects of CWD biology.  
  
PUBLIC HEALTH RELEVANCE: Prions are proteinacious infectious agents causing fatal currently untreatable neurodegenerative diseases in animals and humans. The transmission of bovine prions to humans exemplifies their zoonotic potential and that the factors controlling interspecies transmission are poorly understood. The unprecedented contagious spread of chronic wasting disease (CWD) a burgeoning epidemic of cervids the discovery of distinct but unstable CWD strains and the presence of CWD prions in muscle and other animal derivatives destined for human consumption places the human species barrier to CWD prions at the forefront of public health concerns.

project_terms:
Address;Affect;Animals;Antlers;Biochemical;Biological;Biological Assay;Biology;Cattle;Cell Culture Techniques;Cells;Chemicals;Chronic Wasting Disease;Cloning;Code;Consumption;Data;Deer;Development;Discrimination (Psychology);Disease;Epidemic;Evaluation;Gene Dosage;Gene Targeting;Genetic Polymorphism;Glutamates;Goals;Health;Human;Immunoassay;Infectious Agent;Knock-out;Link;Location;Lysine;Methods;Modeling;Modification;Molecular Conformation;Mus;Muscle;Mutate;Neuraxis;Neurodegenerative Disorders;Nucleic Acids;Partner in relationship;Pathogenesis;Peptide Hydrolases;Peripheral;Phenotype;Polymers;PrP;PrPSc Proteins;Predisposition;Prion Diseases;Prions;Production;Property;Quinacrine;Research Design;Resources;Role;Route;Scrapie;Skeletal muscle structure;Spectroscopy Fourier Transform Infrared;Structure;System;Thermodynamics;Tissues;Transgenic Mice;Transgenic Model;Variant;Wild Type Mouse;Work;base;cervid;chemical property;design;disease transmission;fitness;innovation;interest;novel;pathogen;preconditioning;pressure;prion-based;protein misfolding;protein misfolding cyclic amplification;public health medicine (field);public health relevance;response;transmission process

public_health_relevance:
Prions are proteinacious infectious agents causing fatal currenltly untreatable neurodegenerative diseases inanimals and humans. The transmission of bovine prions to humans exemplifes their zoonotic potential andthat the factors controlling interspecies transmission are poorly understood. The unprecidented contagiousspread of chronic wasting disease (CWD) a burgeoning epidemic of cervids the discovery of distinct butunstable CWD strains and the presence of CWD prions in muscle and other animal derivatives destined forhuman consumption places the human species barrier to CWD prions at the forefront of public healthconcerns.


application_id: 8064503
project_number: 1R01AR060701-01
project_title: The role of satellite cells in adult skeletal muscle growth and maintenance
administering_ic: NIAMS
award_notice_date: 2010-09-16
opportunity_number: PA-10-067
application_type: 1
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)]
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;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


application_id: 8064072
project_number: 1R21AA020188-01
project_title: Alcohol the vagus nerve and multi-organ inflammation
administering_ic: NIAAA
award_notice_date: 2011-09-19
opportunity_number: RFA-AA-10-008
application_type: 1
activity_code: R21
ic: AA
serial_number: 020188
program_official: WANG, JOE
project_start_date: 2011-09-20
project_end_date: 2013-08-31
study_section: Special Emphasis Panel[ZAA1 JJ (01)]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The tenth cranial nerve the vagus is distributed throughout the body including major divisions to all parts of the gut and to the liver. This cholinergic nerve restrains inflammation in all the organs to which the vagus is distributed by the tonic release of acetylcholine (ACh) onto nicotinic receptors (nicAChRs) of the alpha7- subtype. In addition to their presence on inflammatory cells alpha7-nicAChRs are also present on cell bodies of the vagus in the CNS where they cause vagal activation and neuroprotection. Since the presence of alcohol inhibits alpha7-nicAChRs and a known chronic effect is to cause vagal neuropathy these anti-inflammatory effects of the vagus are seriously compromised during alcohol exposure. The primary hypothesis is that this reduced vagal function contributes to the chronic inflammation following oxidative stress which is a common feature of alcohol-induced damage in many organs. If correct this predicts that compounds with alpha7- nicAChR agonist properties will protect against alcohol-induced tissue damage particularly if these compounds are also anti-oxidants. The first specific aim of this proposal is to test the primary hypothesis in vitro by studying the interactions of alcohol and alpha7-nicAChR ligands on endotoxin-induced release of mediators from inflammatory cells (splenic lung and peritoneal macrophages) from wild-type and alpha7-nicAChR knock-out C57Bl/6J mice. The second specific aim is to test the hypothesis in vivo by exposing C57Bl/6J mice (wild-type vagotomized and alpha7-nicAChR knockouts) chronically to alcohol by forced consumption and then evaluating endotoxin-induced release of inflammatory mediators in vivo. As part of these studies we will evaluate the therapeutic potential of the alpha7-nicAChR agonist choline and a methylquercetagetin which acts as a partial agonist at alpha7-nicAChRs. The latter was recently discovered by screening a native plant extract library and has potent anti-oxidant activity in addition to its action at nicAChRs where it has an affinity comparable to choline. The ability of these compounds to inhibit endotoxin-induced release of inflammatory mediators following alcohol exposure will be studied in vitro and in vivo using the same methods as above. This project therefore tests a novel hypothesis for alcohol-induced organ damage based on the interaction between brain gut and liver as represented by the vagus nerve and tests a novel therapeutic approach to this.  
  
PUBLIC HEALTH RELEVANCE: Alcoholism (either dependence or abuse) affects more than 8% of the population of the US and the societal costs approach $200BN annually. About half of this sum is medical cost much of which is accrued in treating alcohol-related organ damage. Despite this there are currently no accepted approaches to preventing or reversing this damage. This application proposes a novel hypothesis as to the cause of organ damage which has profound implications for treatment. If successful the project will establish a framework for drug discovery and evaluation in relation to this largely overlooked therapeutic target.

project_terms:
Acetylcholine;Acute;Affect;Affinity;Agonist;Alcohol-Induced Disorders;Alcoholism;Alcohols;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Brain;Cell physiology;Cells;Choline;Chronic;Consumption;Dependence;Development;Drug Evaluation;Endotoxins;Exploratory/Developmental Grant;Heart Rate;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Knock-out;Knockout Mice;Libraries;Ligands;Lipopolysaccharides;Liver;Lung;Mediator of activation protein;Medical;Methods;Mus;Nerve;Neuropathy;Nicotinic Receptors;Organ;Oxidative Stress;Peritoneal Macrophages;Pharmaceutical Preparations;Physiological;Plant Extracts;Population;Process;Property;Role;Screening procedure;Sum;Telemetry;Testing;Therapeutic;Tissues;Vagus nerve structure;Variant;Wild Type Mouse;alcohol abuse therapy;alcohol effect;alcohol exposure;alcohol research;alcoholism therapy;alpha-bungarotoxin receptor;base;cell body (neuron);cell type;cholinergic;cost;drug discovery;in vivo;macrophage;neuroprotection;novel;novel therapeutic intervention;prevent;receptor;research study;response;restraint;therapeutic target

public_health_relevance:
Alcoholism (either dependence or abuse) affects more than 8% of the population of the US and the societal costs approach $200BN annually. About half of this sum is medical cost much of which is accrued in treating alcohol-related organ damage. Despite this there are currently no accepted approaches to preventing or reversing this damage. This application proposes a novel hypothesis as to the cause of organ damage which has profound implications for treatment. If successful the project will establish a framework for drug discovery and evaluation in relation to this largely overlooked therapeutic target.


application_id: 8064014
project_number: 5R01AI048850-08
project_title: Fatty Acid Binding Proteins in Macrophage Function
administering_ic: NIAID
award_notice_date: 2011-05-04
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 048850
program_official: PEYMAN, JOHN A
project_start_date: 2003-04-01
project_end_date: 2014-04-30
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 1882106
contact_pi: SUTTLES, JILL
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): Fatty acid binding proteins FABPs have been identified as central regulators of both metabolic and inflammatory pathways.  FABPs act as intracellular receptors for a variety of hydrophobic compounds enabling their diffusion within the cytoplasmic compartment.  We have shown that adipocyte FABP (A-FABP) and epithelial FABP (E-FABP) regulate macrophage cholesterol trafficking and inflammatory function in part via regulation of the activity of the peroxisome proliferator-activated receptor (PPAR-?).  Macrophages and dendritic cells (DC) from FABP- deficient mice are defective in expression of proinflammatory cytokines and are inefficient in the promotion of proinflammatory T cells responses during antigen presentation.  FABP-deficient mice are protected from development of experimental autoimmune encephalomyelitis (EAE). Overall the results of our research suggest that FABPs regulate a molecular switch between metabolic and inflammatory pathways in macrophages and DC and as a consequence regulate both innate and adaptive immune responses.  We will continue our studies of these proteins through the pursuit of the following specific aims: Specific Aim 1 is to identify the molecular mechanism(s) by which FABPs affect inflammatory cytokine gene expression in macrophages and DC.  We have found that FABP-deficiency is accompanied by elevated activity of AMP- activated protein kinase (AMPK) and that AMPK is a negative regulator of macrophage inflammatory function.  Experiments will be performed to determine the link between FABPs AMPK and PPAR-? testing the hypothesis that FABP regulation of energy stores regulates AMPK activity which in turn modulates inflammatory activity.  Specific Aim 2 is to further delineate the impact of FABP-deficiency on autoimmune disease using EAE as a model.  This aim will include an evaluation of the specific contributions of T cell priming and of the tissue environment towards the protection from EAE displayed by FABP-deficient mice.  In this aim we will also test the in vivo efficacy of inhibitors of FABPs as an anti-inflammatory therapy using the EAE model.  Specific Aim 3 is to test the hypothesis that the expression of FABPs links dietary fat intake with exacerbated inflammatory disease. We will evaluate the effects of fat intake on FABP expression in leukocyte populations and the association of diet-induced FABP expression with inflammatory responsiveness.  The completion of these studies will provide a more comprehensive understanding of how FABPs regulate immune and inflammatory responses.  
  
PUBLIC HEALTH RELEVANCE:  Fatty acid-binding proteins (FABPs) have been shown to play a role in obesity and Type 2 diabetes.  This proposal is based on studies demonstrating that FABPs also strongly promote inflammation and contribute to autoimmune inflammatory disease.  The goals of the project are to determine the mechanisms by which FABPs regulate inflammatory function in leukocytes and to test the hypothesis that FABPs constitute an accessible and effective target for treatment of inflammatory disease.  Given the recent identification of small molecule inhibitors of FABP function this project has direct relevance to human health.

project_terms:
5'-AMP-activated protein kinase;AMP-activated protein kinase kinase;Adipocytes;Adipose tissue;Affect;Anti-Inflammatory Agents;Anti-inflammatory;Antigen Presentation;Autoimmune Diseases;Autoimmune Process;Automobile Driving;Brain;Cells;Chronic;Cytokine Gene;Data;Dendritic Cells;Development;Diet;Dietary Fats;Diffusion;Disease;Environment;Epithelial;Evaluation;Exhibits;Experimental Autoimmune Encephalomyelitis;Fatty acid glycerol esters;Gene Expression;Genes;Glycogen Synthase Kinases;Goals;Health;Human;Hydroxymethylglutaryl-CoA reductase;IL2RA gene;Immune response;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Intake;Interferons;Interleukin-17;Leukocytes;Link;Lipids;Metabolic;Modeling;Molecular;Mus;Non-Insulin-Dependent Diabetes Mellitus;Nuclear;Obesity;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Play;Population;Production;Protein Deficiency;Proteins;Regulation;Research;Role;Spinal Cord;T cell response;T-Lymphocyte;Testing;Tissues;Transcriptional Activation;Wild Type Mouse;Work;base;cholesterol trafficking;cytokine;disorder risk;fatty acid-binding proteins;feeding;in vivo;inhibitor/antagonist;mTOR protein;macrophage;protein expression;protein function;public health relevance;receptor;research study;response;small molecule;transcription factor

public_health_relevance:
Project NarrativeFatty acid-binding proteins (FABPs) have been shown to play a role in obesity and Type 2diabetes.  This proposal is based on studies demonstrating that FABPs also strongly promoteinflammation and contribute to autoimmune inflammatory disease.  The goals of the project areto determine the mechanisms by which FABPs regulate inflammatory function in leukocytes andto test the hypothesis that FABPs constitute an accessible and effective target for treatment ofinflammatory disease.  Given the recent identification of small molecule inhibitors of FABPfunction this project has direct relevance to human health.


application_id: 8063590
project_number: 5R01DA002243-34
project_title: Degradation of Opioid Peptides
administering_ic: NIDA
award_notice_date: 2011-05-02
application_type: 5
activity_code: R01
ic: DA
serial_number: 002243
program_official: PUROHIT, VISHNUDUTT
project_start_date: 1978-09-30
project_end_date: 2014-04-30
study_section: Molecular Neuropharmacology and Signaling Study Section[MNPS]
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
budget_start_date: 2011-05-01
project_abstract:
DESCRIPTION (provided by applicant):  The long-range objective of this project is to develop methods to modulate peptide hormone action through the peptidases that inactivate them. The focus of this application is to understand the contribution of three metallopeptidases insulysin neprilysin neprilysin-2 and a novel plasma membrane (3-endorphin cleaving enzyme to neuropeptide metabolism. The three specific aims are: 1. To study the allosteric properties of insulysin and its contribution to modulating physiological peptide levels. Insulysin which hydrolyzes a variety of peptides including (3-endorphin insulin and amyloid (3 peptides is allosterically regulated by both substrates (homotrophic effects) and by anions such as ATP (heterotrophic effects). The heterotrophic effectors switch the preference of the enzyme from cleaving relative large peptides like insulin amyloid (3-peptide and -3-endorphin to smaller peptides such as the dynorphins. 2. To study the contribution gate the relative contributions of neprilysin and neprilysin-2 to neuropeptide metabolism in the brain. 3. To isolate and characterize a newly found plasma membrane peptidase that degrades (3-endorphin. We propose to characterize this novel peptidase determine its tissue distribution as well as its substrate specificity. Relevence: Together these studies should contribute to our understanding of the involvement of a group of peptidases in the regulation of peptide action and may lead to new ways in which to modulate these activities in pathological states. For example one of the peptidases to be studied has recently been implicated in HIV dependent dementia in elderly affected individuals.

project_terms:
Affect;Allosteric Regulation;Amyloid;Anions;Binding Sites;Biochemical;Brain;Brain region;Cell Line;Cell membrane;Cleaved cell;Dementia;Drug or chemical Tissue Distribution;Dynorphins;Elderly;Endorphins;Enzymes;Goals;HIV;Individual;Insulin;Insulinase;Knockout Mice;Lead;Membrane;Metabolism;Metalloproteases;Methods;Neprilysin;Neuropeptides;Opioid;Opioid Peptide;Peptide Hydrolases;Peptide Metabolism;Peptides;Physiological;Progress Reports;Property;Regulation;Relative (related person);Reporting;Research Project Grants;Substrate Specificity;Techniques;Testing;cell type;in vivo;insight;macrophage;membrane activity;novel;peptide hormone;preference


application_id: 8063522
project_number: 5T32DK007778-12
project_title: Training Program in Oxidative Stress and Nutrition
project_terms: Oxidative Stress;Training Programs;nutrition
administering_ic: NIDDK
award_notice_date: 2011-07-18
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: 8062287
project_number: 5K25DK072085-05
project_title: Intelligent Control Approach to Anemia Management
administering_ic: NIDDK
award_notice_date: 2011-03-22
opportunity_number: PA-06-087
application_type: 5
activity_code: K25
ic: DK
serial_number: 072085
program_official: RANKIN, TRACY L
project_start_date: 2007-04-01
project_end_date: 2012-08-31
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 8145755
contact_pi: GAWEDA, ADAM E
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):  
Management of anemia due to end-stage renal disease is a multifactorial decision process involving administration of recombinant human erythropoietin (rHuEPO) and iron as well as assessment of other factors influencing the progress of the disease. This application aims at improving the cost-effectiveness of this process through the use of state-of-the-art numerical tools from control engineering and machine learning. The specific aims are the collection of anemia management data and development of new guidelines for period of measuring hemoglobin levels if necessary development of individualized computer-assisted approach to rHuEPO dosing based on modern control engineering and machine learning approach evaluation of the developed tools through numeric simulation and assessment of the potential improvements in therapy and projected savings in rHuEPO utilization. The final aim is to provide a physical implementation and to perform a clinical evaluation of the developed methodology. The applicant Dr. Adam E. Gaweda is an Instructor of Medicine in the Department of Medicine Division of Nephrology at the University of Louisville. His original training is in the field of electrical engineering (M.Eng.) and computer science (Ph.D.). The applicant plans to develop as an independent and well established researcher in the field of biomedical engineering with focus on translation of state-of-the-art technology to heath care. To achieve this goal the applicant will enroll into the Clinical Research Epidemiology and Statistics Training (CREST) Program at the University of Louisville School of Public Health and Information Sciences

project_terms:
Adverse event;Algorithms;Anemia;Anti-Arrhythmia Agents;Artificial Intelligence;Biological Models;Biological Neural Networks;Biomedical Engineering;Blood;Blood Vessels;Caring;Chronic;Clinical;Clinical Research;Collection;Comorbidity;Complex;Computer Assisted;Computer Simulation;Computer software;Computing Methodologies;Controlled Clinical Trials;Data;Decision Support Systems;Development;Dialysis procedure;Disease;Doctor of Philosophy;Dose;Drug Prescriptions;Effectiveness;Electrical Engineering;End stage renal failure;Engineering;Enrollment;Epidemiology;Erythropoietin;Evaluation;Feedback;Frequencies (time pattern);Funding;Goals;Guidelines;Health Sciences;Hemodialysis;Hemoglobin;Hemoglobin concentration result;Human;Individual;Information Sciences;Insulin;Iron;Machine Learning;Measures;Medicine;Methodology;Methods;Nephrology;Outcome;Patient Monitoring;Patients;Pharmaceutical Preparations;Physiological;Population;Process;Protocols documentation;Research;Research Personnel;Safety;Sampling;Savings;Schools;Techniques;Technology;Testing;Training;Training Programs;Translations;Universities;Veterans;Waran;Work;base;clinical practice;computer science;cost effectiveness;data management;experience;improved;insight;instructor;mathematical algorithm;novel;patient population;primary outcome;programs;recombinant human erythropoietin;research clinical testing;response;simulation;statistics;theories;tool


application_id: 8061964
project_number: 5R37AG010885-21
project_title: Surgical Studies of Ontogeny Aging and the Gut
administering_ic: NIA
award_notice_date: 2011-06-17
application_type: 5
activity_code: R37
ic: AG
serial_number: 010885
program_official: MACCHIARINI, FRANCESCA
project_start_date: 1992-08-01
project_end_date: 2013-05-31
study_section: NSS
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
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
budget_start_date: 2011-07-01
project_abstract:
Gastrointestinal (GI) hormones regulatea numberofimportantphysiologic functions includingintestinalsecretionmotilityand digestion ofnutrients. In additioncertain intestinal hormones havebeen shown to stimulategutmucosal proliferation.Neurotensin (NT) an importantregulatory hormone localized to specialized enterocndocrine cells (Ncells) of theadultsmall bowelfacilitatesfatty acid translocationand affects gut motility secretion and mucosal growth. Our studieshaveidentified the NT gene (designated NT/N) as an excellent molecular model to help define the complex differentiationpathways leading to gut development and maturationas wellas the process of "dedifferentiation" noted incertaincoloncancers. Expression of the NT/N gene is regulated in a strict temporal- and spatial-specific patern in the GI tract.Induction of NT/N gene expression and NT peptide secretion is regulated by signaling pathways which have yet to becompletely defined. NT acting through its cell-surface receptor (NTR) activates a cascade of signaling pathwayswhich results in the proliferationof normal gut mucosa. The central hypothesis of our proposal continues to bethatNT/N gene expression is developmentallyregulatedin the gut and isdependent upon acombinationof signaling pathwaysactivation of downstream transcription factors and in certaininstancesgene methylation; NT peptide secretion may bemediated by similar signalingpathwaysthat regulate gene expression. Identifying these regulatory mechanismsarecritical to a better understanding of normal intestinal homeostasis and the function of target tissues that are affected byNT. To examine thishypothesiswe haveplannedexperiments with the following Specific Aims: 1)to further elucidatethe mechanisms contributingto NT/N expression in vivo 2) to delineate the signaling mechanisms regulating NT/Ngene induction3) to define the mechanisms contributingto NT peptide secretion 4) to further assess proliferateveeffects of NT in the gut. Understanding the factors regulating NT/N expression and NT peptide secretion will providenovel and importantinformation regarding the function of an important intestinal hormone and its effects on target tissuessuch as normal gut mucosa. The in-depth analysisof the cellular processes leading to the expression of the "model"intest;nal gene NT/N will provide a better understanding of normal gut development and function as well aspossiblydefini ngcertain cellularevents leadingto gut neoplasia.

project_terms:
Acids;Adult;Affect;Aging;Binding (Molecular Function);Cell Proliferation;Cell Surface Receptors;Cell physiology;Cells;Complex;Development;Digestion;Enteroendocrine Cell;Fatty Acids;Gastrointestinal Hormones;Gastrointestinal tract structure;Gene Expression;Genes;Growth;Homeostasis;Hormones;Human;Intestinal Hormones;Intestines;MEKs;Malignant Neoplasms;Mediating;Methylation;Modeling;Molecular Models;Mucous Membrane;Neoplasms;Neurotensin;Operative Surgical Procedures;Pathway interactions;Pattern;Peptides;Process;Promoter Regions (Genetics);Proteins;Rattus;Regulation;Signal Pathway;Signal Transduction;Small Intestines;Tissues;base;cell growth;cell motility;gene induction;in vivo;molecular modeling;neuromedin N;novel;research study;transcription factor


application_id: 8061915
project_number: 1F31NS071804-01A1
project_title: Calpastatin overexpression as a therapeutic approach to traumatic brain injury
administering_ic: NINDS
award_notice_date: 2011-01-04
opportunity_number: PA-10-108
application_type: 1
activity_code: F31
ic: NS
serial_number: 071804
suffix: A1
program_official: HICKS, RAMONA R
project_start_date: 2011-01-05
project_end_date: 2013-07-04
study_section: Special Emphasis Panel[ZRG1 F01-L (20)]
contact_pi_person_id: 9791904
contact_pi: SCHOCH, KATHLEEN MARIE
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) afflicts approximately 1.4 million individuals in the U.S. each year. Following TBI a variety of cellular mediators contribute to neuronal death and dysfunction including the cysteine proteases calpains. Prolonged activation of calpains occurs within neurons due to a rapid and sustained rise of intracellular free calcium. Although an endogenous inhibitor of calpains calpastatin is co- expressed the sustained activation of these calcium-dependent proteases suggests endogenous calpastatin levels may be insufficient. The overall hypothesis of this proposal is that overexpression of calpastatin will reduce the proteolytic activity of calpains and associated neuronal death after trauma thereby attenuating motor and cognitive deficits. Calpastatin overexpression will be induced in two ways-transgenic overexpression of human calpastatin (hCAST) (Aim 1) and calpastatin expression via lentiviral vector delivery into brain regions vulnerable to TBI (Aim 2).  Aim 1 will use a novel transgenic mouse line with human calpastatin under control of the ubiquitous prion promoter. This mouse line exhibits a 9-fold greater expression of calpastatin in the cortex and hippocampus compared to wildtype mice. hCAST transgenic and wildtype littermates will be subjected to severe controlled cortical impact (CCI) injury or sham treatment. To confirm that calpastatin overexpression decreases calpain activity cortical and hippocampal homogenates will be evaluated for calpain-mediated cytoskeletal and membrane protein breakdown via immunoblot. Both motor and cognitive functions will be assessed after injury after which mice will be euthanized for analysis of hippocampal neurodegeneration and cortical tissue damage to assess the neuroprotective actions of hCAST overexpression. The expectation is that hCAST transgenic mice will have reduced posttraumatic calpain proteolytic activity offering a neuroprotective advantage. Aim 2 establishes an alternative approach to hCAST overexpression through lentiviral vector delivery. After injection of control lentivirus or calpastatin lentivirus into the cortex or hippocampus mice will be subjected to 1.0mm CCI brain injury or sham treatment and assessed as in Aim 1. Targeting of calpastatin to vulnerable neuronal regions prior to injury should spare affected neurons and reduce behavioral deficits.  
  
PUBLIC HEALTH RELEVANCE: Given the scope of traumatic brain injury it is imperative to understand the mechanisms of neuronal damage and death in order to develop effective treatment strategies. My research aims will not only seek to establish a functional neuroprotective role for calpastatin in brain trauma but also advance translational efforts for the treatment of brain injury.

project_terms:
Address;Affect;Area;Attenuated;Behavior;Behavioral;Brain Injuries;Brain region;C-terminal;Calcium;Calpain;Cells;Cessation of life;Cleaved cell;Cognitive;Cognitive deficits;Convection;Cysteine Protease;Cytoskeletal Proteins;Diffusion;Elements;Exhibits;Functional disorder;Genes;Goals;Hippocampus (Brain);Human;Image;Immunoblot Analysis;Immunoblotting;Immunohistochemistry;Individual;Infusion procedures;Injection of therapeutic agent;Injury;Lentivirus Vector;Location;Measurement;Mediating;Mediator of activation protein;Membrane;Membrane Proteins;Methods;Mitochondrial Proteins;Motor;Mus;Nerve Degeneration;Neurologic;Neurons;Pathogenesis;Peptide Hydrolases;Performance;Placebos;Prions;Promotor (Genetics);Proteolysis;Regulatory Element;Research;Role;Severities;Subfamily lentivirinae;Testing;Therapeutic;Tissues;Transgenic Mice;Transgenic Organisms;Trauma;Traumatic Brain Injury;Variant;Viral;behavior measurement;brain tissue;calpain inhibitor;calpastatin;cognitive function;cohort;controlled cortical impact;effective therapy;expectation;improved;inhibitor/antagonist;injured;morris water maze;motor deficit;novel;overexpression;receptor;response;treatment strategy

public_health_relevance:
Given the scope of traumatic brain injury it is imperative to understand the mechanisms of neuronal damage and death in order to develop effective treatment strategies. My research aims will not only seek to establish a functional neuroprotective role for calpastatin in brain trauma but also advance translational efforts for the treatment of brain injury.


application_id: 8060382
project_number: 2R44CA136017-02A1
project_title: SapC-DOPS nanovesicles for Treating Glioblastoma Multiforme
administering_ic: NCI
award_notice_date: 2010-09-28
opportunity_number: PA-10-050
application_type: 2
activity_code: R44
ic: CA
serial_number: 136017
suffix: A1
program_official: ANDALIBI, ALI
project_start_date: 2008-09-25
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZRG1 ETTN-C (11)]
contact_pi_person_id: 8717940
contact_pi: XU, KEVIN
other_pis: QI, XIAOYANG
congressional_district: 04
department: Unavailable
primary_duns: 782233501
primary_uei: HJPDQTK95NS8
duns_number: 782233501
uei: HJPDQTK95NS8
fips: US
organization_id: 10010035
organization_name: BEXION PHARMACEUTICALS, INC.
organization_city: COVINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 410112312
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):   
Our goal is to develop a new molecular entity with a novel mechanism of action for targeting and eliminating glioblastoma multiforme (GBM high grade glioma) a deadly and invasive brain tumor with no effective treatment. Of the 12000 patients expected to be diagnosed with GBM this year most will succumb within the first year. Clearly there is an urgent demand for an efficacious anti-glioma drug. To address this need we are developing a new class of therapeutic proteolipid nanovesicle that can target and destroy glioma tumors. Composed of the small lysosomal sphingolipid activator protein saposin C (SapC 80 aa) and the phospholipid dioleoylphosphatidylserine (DOPS); the stable 200 nm SapC-DOPS nanovesicles have unusually high affinity for phosphatidylserine-enriched membrane surfaces that occur widely in many types of tumor cells and tumor neovasculature. In a mechanism consistent with activation of sphingolipid protein function SapC- DOPS also appears to selectively induce tumor cells to undergo apoptosis. In Phase I of this proposal we demonstrated the feasibility of using SapC-DOPS nanovesicles to target and kill intracranial gliomas in mouse models. Injections of SapC-DOPS in mice with orthotopically implanted gliomas resulted in dose-dependent improvement in survival. Specific targeting of SapC-DOPS to the tumor mass was demonstrated using fluorescently-tagged nanovesicles in live animal imaging experiments. We also showed that saposin C protein in specific association with DOPS is essential for targeting. Anticancer activity of SapC-DOPS was confirmed in a second orthotopic glioma model derived from an aggressive and invasive glioma line. Pilot toxicity data indicated SapC-DOPS to be relatively nontoxic with no evidence of behavioral abnormalities or pathological lesions. Our objective in Phase II proposal is to identify and select optimized SapC-DOPS formulations and treatment methods suitable for advancing toward planned human testing. The specific aims of Phase II are: (1) optimize protein expression and purification and develop clinically suitable formulation; (2) conduct preclinical pharmacokinetics stability and brain and tissue distribution analysis in animal models to determine in vivo disposition of the nanovesicles; and (3) carry out toxicity studies in two animal models to assess safety towards filing of the IND. Upon the completion of these studies we expect to have compelling evidence to progress clinical development of SapC-DOPS nanovesicles as a potent new anti-cancer therapeutic (during SBIR Phase III). This research is innovative because SapC-DOPS nanovesicles offer a unique approach for slowing tumor growth and eliminating deep-seated brain tumors. Ultimately we expect to adapt our technology for targeting different types of tumors and for developing tumor-targeted diagnostics.  
  
PUBLIC HEALTH RELEVANCE:   
We are developing a new molecular entitity for treating glioblastoma multiforme a deadly form of brain tumor that kills over 90% of afflicted patients. Current standards of treatment consisting of surgery radiation and chemotherapy have not been effective in significantly reducing morbidity. Our strategy involves using new proteolipid nanovesicles that can penetrate the tumors and selectively destroy malignant cells without harming normal cells. Success in the proposed animal models will enable us to test the product in humans.

project_terms:
Address;Affinity;Amino Acid Sequence;Animal Model;Animals;Antibodies;Antineoplastic Agents;Apoptosis;Behavioral;Biodistribution;Biological Assay;Blood;Brain;Brain Neoplasms;Cardiotoxicity;Catabolism;Clinical;Clinical Research;Data;Development;Diagnosis;Diagnostic;Dose;Drug Formulations;Drug Kinetics;Drug or chemical Tissue Distribution;Endotoxins;Epitopes;Escherichia coli;Excretory function;Fermentation;Freeze Drying;Future;Glioblastoma;Glioma;Glucosylceramides;Goals;High Pressure Liquid Chromatography;Human;Image;Immune response;Implant;Inflammation;Injection of therapeutic agent;Killings;Lead;Lesion;Life;Macaca fascicularis;Maximum Tolerated Dose;Measures;Membrane;Metabolism;Methods;Modeling;Molecular;Monitor;Monkeys;Morbidity - disease rate;Mus;Normal Cell;Nude Mice;Pathology;Patients;Peptide Sequence Determination;Pharmaceutical Preparations;Phase;Phosphatidylserines;Phospholipids;Plan B;Preparation;Primates;Procedures;Process;Production;Property;Proteins;Proteolipids;Protocols documentation;Radiolabeled;Radiosurgery;Rattus;Research;Rodent;Safety;Small Business Innovation Research Grant;Sphingolipid Activator Proteins;Sphingolipids;Surface;System;Technology;Testing;Therapeutic;Tissues;Toxic effect;Toxicokinetics;Xenograft Model;anti-cancer therapeutic;anticancer activity;base;beta-Glucosidase Stimulating Protein;brain tissue;cancer cell;chemotherapy;citrate carrier;clinical efficacy;effective therapy;expectation;glioma cell line;immunogenic;immunogenicity;immunotoxicity;improved;in vivo;innovation;lysosomal proteins;meetings;mouse model;neoplastic cell;neovasculature;nonhuman primate;novel;pre-clinical;preclinical study;protein expression;protein function;radiotracer;research study;response;scale up;standard care;success;tumor;tumor growth

public_health_relevance:
We are developing a new molecular entitity for treating glioblastoma multiforme a deadly form of brain tumorthat kills over 90% of afflicted patients. Current standards of treatment consisting of surgery radiation andchemotherapy have not been effective in significantly reducing morbidity. Our strategy involves using newproteolipid nanovesicles that can penetrate the tumors and selectively destroy malignant cells without harmingnormal cells. Success in the proposed animal models will enable us to test the product in humans.


application_id: 8060060
project_number: 1R44HD065388-01A1
project_title: FastFES Neural Prothesis for Stroke Ambulation and Rehabilitation
administering_ic: NICHD
award_notice_date: 2011-03-15
opportunity_number: PA-10-050
application_type: 1
activity_code: R44
ic: HD
serial_number: 065388
suffix: A1
program_official: SHINOWARA, NANCY
project_start_date: 2011-04-01
project_end_date: 2012-06-30
study_section: Special Emphasis Panel[ZRG1 MOSS-F (15)]
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: 2011-04-01
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.  
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.

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 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:
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: 8059773
project_number: 1F32DK089717-01A1
project_title: Insulin effects in the vagal complex
administering_ic: NIDDK
award_notice_date: 2010-09-24
opportunity_number: PA-10-110
application_type: 1
activity_code: F32
ic: DK
serial_number: 089717
suffix: A1
program_official: CASTLE, ARTHUR
project_start_date: 2010-12-01
project_end_date: 2013-11-30
study_section: Special Emphasis Panel[ZDK1 GRB-W (O1)]
contact_pi_person_id: 10299496
contact_pi: KASERMAN, CAMILLE BLAKE
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The dorsal vagal complex (DVC) is essential to integrating visceral sensory afferents and various other inputs in order to produce appropriate parasympathetic motor outputs via the vagus nerve which is vital for energy homeostasis. Certain pathologies such as diabetes can cause disruption of this circuit. Diabetes mellitus is a metabolic disorder that results in dysfunctional glucose regulation by insulin deficiency (type-1) or resistance (type-2). Hyperglycemia a condition of diabetes significantly alters central vagal function and diabetics often experience gastric dysfunction gastroparesis and other visceral symptomatology. Insulin crosses the blood brain barrier and is transported into the brainstem over twice as rapidly as into whole brain and neuronal insulin receptors are expressed in the DVC. Neuronal insulin and insulin receptors are required for normal control of glucose homeostasis and the regulation of peripheral energy homeostasis and glucose metabolism. Despite the importance of the DVC and the evidence that insulin action in the brain is critical for homeostasis very little is known about insulin's action in the brain specifically the DVC. This proposal will test the effects of insulin on cellular communication within the DVC. The general hypothesis is that insulin is inhibiting neurons in the dorsal motor nucleus (DMV). I predict that this occurs directly and indirectly by acting on glutamatergic neurons of in the nucleus of the solitary tract (NTS) that project to the DMV. Electrophysiological studies will be conducted in brainstem slice preparations from adult mice. Gastric-related neurons of DMV and NTS will be identified by their anatomical connection with the proximal stomach. With whole-cell patch clamp recordings the effects of insulin will be examined on: 1) input to DMV neurons and 2) glutamatergic neurons of the NTS identified with RT-PCR that project to the DMV by "uncaging" glutamate in these neurons and examining paired-pulse responses in the DMV to electric stimulation of the NTS. These results will be coordinated with pharmacological and molecular biological analyses to generate models of insulin action in the vagal complex in mice.  
  
PUBLIC HEALTH RELEVANCE: This proposal will test the effects of insulin on the dorsal vagal complex which controls gastric function. Because this region is located in the brainstem which is adjacent to an incomplete portion of the blood brain barrier hormones found in the bloodstream such as insulin can readily access this part of the brain. Diabetic patients often experience gastric dysfunction; thus the actions of insulin in this brain region are important to our understanding of the physiology of this disease. The results of this study will provide a clearer understanding of how insulin regulates autonomic function which could lead to new insights in designing treatments for diabetes.

project_terms:
Adult;Affect;Area;Binding (Molecular Function);Biological;Blood - brain barrier anatomy;Blood Circulation;Brain;Brain Part;Brain Stem;Brain region;Cell Nucleus;Cells;Communication;Complex;Data;Diabetes Mellitus;Disease;Dorsal;Eating;Electric Stimulation;Event;Frequencies (time pattern);Functional disorder;Gastric Emptying;Gastrointestinal tract structure;Gastroparesis;Glutamates;Homeostasis;Hormones;Hyperglycemia;Hypothalamic structure;In Vitro;Insulin;Insulin Receptor;Label;Lead;Mediating;Metabolic Diseases;Methods;Modeling;Molecular;Motor output;Mus;Neurons;Nucleus solitarius;Output;Pathology;Peripheral;Phosphotransferases;Physiologic pulse;Physiology;Potassium Channel;Preparation;Regulation;Resistance;Reverse Transcriptase Polymerase Chain Reaction;Satiation;Sensory;Signal Transduction;Slice;Stomach;Testing;Vagus nerve structure;Visceral;blood glucose regulation;cell body (neuron);diabetic;diabetic patient;dorsal motor nucleus;experience;glucose metabolism;hepatic gluconeogenesis;insight;male;patch clamp;postsynaptic;presynaptic;public health relevance;receptor;research study;response;therapy design

public_health_relevance:
Project Narrative This proposal will test the effects of insulin on the dorsal vagal complex which controls gastric function.Because this region is located in the brainstem which is adjacent to an incomplete portion of the blood brainbarrier hormones found in the bloodstream such as insulin can readily access this part of the brain. Diabeticpatients often experience gastric dysfunction; thus the actions of insulin in this brain region are important to ourunderstanding of the physiology of this disease. The results of this study will provide a clearer understanding ofhow insulin regulates autonomic function which could lead to new insights in designing treatments fordiabetes.


application_id: 8059474
project_number: 1R43DK088503-01A1
project_title: A TELEHEALTH INNOVATION TO SUPPORT WEIGHT LOSS SURGERY
administering_ic: NIDDK
award_notice_date: 2010-09-29
opportunity_number: PA-10-050
application_type: 1
activity_code: R43
ic: DK
serial_number: 088503
suffix: A1
program_official: DENSMORE, CHRISTINE L
project_start_date: 2010-09-30
project_end_date: 2012-09-29
study_section: Special Emphasis Panel[ZRG1 HDM-K (10)]
contact_pi_person_id: 7691024
contact_pi: BRUE, VESTA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 830125485
duns_number: 830125485
fips: US
organization_id: 10023819
organization_name: CARE TEAM SOLUTIONS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071936
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-09-30
project_abstract:
DESCRIPTION (provided by applicant): For such life-changing impact that bariatric surgery represents for obesity this popular procedure is noted for its poor post- operative follow-up rates and outcomes tracking. Laparoscopic Gastric Bypass (LGB) has emerged as one of the most popular surgical procedures in the U.S. and an effective treatment for morbid obesity (MO). Close to a quarter-million surgeries are performed annually in the U.S. Post-surgical patients can see dramatic weight loss due to mal-absorption of food through bypassing sections of the small intestine limits food intake. However mal-absorption also results in loss of nutrients which appears to persist or worsen over time often resulting in dangerous nutritional deficiencies. Assuring that these nutrients are added to the diet in the form of appropriate supplements is critical. Yet no systematic and scalable program exists currently for weight loss surgery clinics to provide ongoing nutritional education and management. Further physical activity is fundamental to maintaining smart weight loss and body composition. However specific exercise prescriptions and professional support for activity plans are rarely offered by surgery clinics. Bariatric surgery is not a "magic bullet" and should be regarded as an adjunctive tool that helps the patient initiate and sustain new dietary and physical activity behaviors that will support weight loss. Unfortunately a huge gap exists in tools to aid patients in initiating and sustaining these behaviors. There have emerged few individualized scalable programs for patients to avoid behavioral pitfalls that accompany rapid weight loss following such revolutionary surgery. Because the current postoperative pattern is all-too-often self-managed with less-than-optimal provider support a guided self-care program is much-needed to assure smart weight management supplemented by remotely-delivered professional support. In order to facilitate systematic follow-up and to improve adherence to post-operative protocols we propose an evidence-based structured tele-health guided program for self-managing behaviors that will sustain healthy weight loss. This multi-disciplinary package provides a patient-centered scalable fitness promotion and monitoring system to improve: 1) adherence to nutritional supplements 2) sustained physical activity at goal levels and 3) frequent weighing. Because these activities are electronically monitored the program furnishes accurate patient behavior profiles to allow professionals to better tailor the patient's plan. In addition gaps will be filled for surgeons as certification of weight loss clinics is trending toward greater outcomes reporting requirements - a difficult production when clinics maintain little post-surgical follow-up data.  
  
PUBLIC HEALTH RELEVANCE:  Obesity represents the largest public health crisis in the US. Gastric Bypass Surgery has emerged as a highly effective treatment for morbid obesity and cure for obesity-related diseases such as diabetes that once were considered incurable. Inadequate postoperative self-care however creates serious complications. Two primary behavioral pitfalls are nutritional mismanagement and insufficient physical activity. Consistent with NIH's mission to promote innovative approaches to combat obesity we propose a scalable tele-health program to improve adherence promote smart behavior and assure healthy weight loss management.

project_terms:
Accountability;Address;Adherence (attribute);American;Americas;Bariatrics;Behavior;Behavioral;Body Composition;Body Weight;Body Weight decreased;Bypass;Case Management;Certification;Chronic;Climacteric;Clinic;Cognitive;Communities;Comorbidity;Counseling;Data;Development;Devices;Diabetes Mellitus;Diet;Dietary Supplements;Dietitian;Disease;Eating;Educational aspects;Electronics;Exercise;Feedback;Food;Gastric Bypass;Goals;Guidelines;Home environment;Individual;Intake;Intervention;Magic;Maintenance;Malabsorption Syndromes;Malnutrition;Marketing;Measures;Medical;Mission;Monitor;Morbid Obesity;Names;Nurses;Nutrient;Nutritional;Obesity;Obesity associated disease;Online Systems;Operative Surgical Procedures;Outcome;Participant;Patients;Pattern;Phase;Physical activity;Population;Postoperative Period;Procedures;Production;Professional counselor;Protocols documentation;Provider;Psychological reinforcement;Randomized;Recommendation;Records;Regimen;Reporting;Self Care;Self Management;Small Intestines;Solutions;Specialist;Structure;Support System;Surgeon;Surgical complication;System;Technology;Telephone;Time;Weight;Wireless Technology;Work;abstracting;bariatric surgery;base;behavior change;combat;commercialization;consumer product;cost;effective therapy;evidence base;fitness;follow-up;improved;innovation;interest;meetings;multidisciplinary;novel;patient oriented;pill (pharmacologic);population based;programs;public health medicine (field);satisfaction;telehealth;theories;tool;treatment as usual;trend;usability

public_health_relevance:
PROJECT NARRATIVEObesity represents the largest public health crisis in the US. Gastric Bypass Surgery has emerged as a highly effectivetreatment for morbid obesity and cure for obesity-related diseases such as diabetes that once were considered incurable.Inadequate postoperative self-care however creates serious complications. Two primary behavioral pitfalls are nutritionalmismanagement and insufficient physical activity. Consistent with NIH's mission to promote innovative approaches tocombat obesity we propose a scalable telehealth program to improve adherence promote smart behavior and assurehealthy weight loss management.


application_id: 8059236
project_number: 1R43NR012629-01
project_title: Beyond Pillboxes: Medminding for Universal Drug Delivery
administering_ic: NINR
award_notice_date: 2011-08-19
opportunity_number: PA-10-050
application_type: 1
activity_code: R43
ic: NR
serial_number: 012629
program_official: COTTON, PAUL
project_start_date: 2011-09-01
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZRG1 RPHB-C (10)]
contact_pi_person_id: 7795913
contact_pi: HAHN, JEROME
other_pis: BRUE, VESTA
congressional_district: 06
department: Unavailable
primary_duns: 829912182
duns_number: 829912182
fips: US
organization_id: 10024016
organization_name: TELEHEALTH HOLDINGS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071936
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-09-01
budget_end_date: 2012-08-31
project_abstract:
DESCRIPTION (provided by applicant):  Medication errors are now the leading cause of accidental death. Smart electronic devices are emerging to aid medication adherence with organizing reminding monitoring and communicating medication use. Most are focused on bulk pills and are structured to dispense pills remind at pill-time monitor when pills are taken or communicate pill histories to caregivers. As pharmaceutical packaging and delivery forms have evolved in recent years bulk pills are losing dominance among medication forms. For example in Europe they represent only 10-15% of oral medication sales with 85-90% packed in single- unit doses in blister packs or multi-pill dosing packets. Moreover injections are gaining market share and are expected to outsell oral meds as biotech introduces many biologics that are injected. They now account for one fifth of new drugs launched on the world market and soon that share is expected to rise to one-half that are biotechnology-derived. These biologics can be unstable require refrigeration and sometimes are time-critical in their dosing schedules. None of these trend-setting drugs fit into traditional medminding models. Five major medication user groups are underserved with the present models. Yet their patterns of nonadherence are equally as concerning and the risks to their safety are just as alarming. It is these five major drug forms that this project addresses:  " Blister packed pills.  " Injectables in both prefilled and syringe/vial forms  " Refrigerated medications  " Time-critical medications with immediate reports to caregivers.  " Liquid and topical medication dispensers and over-sized pills. We propose a novel multi-purpose dispenser that performs critical functions to improve medication adherence. The product will fill a large gap in the market now for medication users of the five targeted forms whose care teams need instant awareness of their risk and for whom there are no other assistive devices that serve these needs. This project will leverage our team's decade of experience and existing portfolio of products and intellectual property in developing and commercializing a pioneering electronic medminder.  
  
PUBLIC HEALTH RELEVANCE:  A critical public health concern is mismanagement of medications which all-too-often exacerbates diseases and multiplies comorbidities. It is part of NIH's mission to promote innovation in combating diseases. We propose a novel multi-purpose dispenser that serves to improve medication adherence for emerging medication forms packaging and delivery systems for which there is no technological aid currently.

project_terms:
Accounting;Address;Adherence (attribute);Advanced Development;Awareness;Biotechnology;Bulla;Caregivers;Caring;Cessation of life;Chronically Ill;Cigarette;Communication;Comorbidity;Computer software;Cream;Data;Development;Device Designs;Devices;Disease;Dose;Drug Delivery Systems;Drug Packaging;Effectiveness;Elderly;Electronics;Engineering;Europe;Expenditure;Eyedrops;Focus Groups;Funding;Funding Category;Future;Gel;Generations;Health;Housing;Information Systems;Injectable;Injection of therapeutic agent;Intellectual Property;Investments;Leadership;Liquid substance;Marketing;Medication Errors;Medicine;Minor;Mission;Modeling;Molds;Monitor;Names;Operating System;Oral;Parents;Participant;Patients;Pattern;Performance;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Population;Recording of previous events;Refrigeration;Reporting;Research Infrastructure;Research Personnel;Risk;Route;Safety;Sales;Schedule;Self-Help Devices;Signal Transduction;Solutions;Source;Structure;Syringes;System;Technology;Testing;Time;United States National Institutes of Health;Vial device;base;cohort;combat;cost;design;drug market;efficacy testing;experience;improved;innovation;medication compliance;novel;pill (pharmacologic);prototype;public health medicine (field);smoking cessation;telehealth;tool;trend;usability;wasting

public_health_relevance:
A critical public health concern is mismanagement of medications which all-too-often exacerbates diseases and multiplies comorbidities. It is part of NIH's mission to promote innovation in combating diseases. We propose a novel multi-purpose dispenser that serves to improve medication adherence for emerging medication forms packaging and delivery systems for which there is no technological aid currently.


application_id: 8059127
project_number: 1F31NS070329-01A1
project_title: Interactions between Urological and Locomotor Systems during Treadmill Training i
administering_ic: NINDS
award_notice_date: 2011-01-04
opportunity_number: PA-10-108
application_type: 1
activity_code: F31
ic: NS
serial_number: 070329
suffix: A1
program_official: KLEITMAN, NAOMI
project_start_date: 2011-01-04
project_end_date: 2014-01-03
study_section: Special Emphasis Panel[ZRG1 F01-L (20)]
contact_pi_person_id: 10107392
contact_pi: WARD, PATRICIA JILL
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Spinal cord injury (SCI) results in detrimental effects on the upper and lower urinary tract. Currently there is no effective therapy for urological dysfunction. Having control over voiding function is of primary importance to this patient population as this affects independence overall health and self-image. Current attempts at treatments with various drugs and surgeries have unwanted side effects and limited success. One of our goals is to provide a natural therapeutic alternative. Body weight supported treadmill training is advancing our knowledge on how the spinal cord can learn and adapt and the results of its positive effects for SCI patients continues to grow. We have clinical observations from patients that step training can have beneficial outcomes on bladder maintenance and that there is an inhibitory interaction between the limbs and the bladder. Therefore we propose to study these observations in a clinically relevant animal model to identify mechanisms involved. Eighty-six male rats will receive a 225 kdyn force contusion injury at the T8 spinal level using the IH impact or device. Twenty-six rats will be implanted with a bladder catheter and EMG wires in the soleus and tibialis anterior muscles to determine the influence of noxious and innocuous bladder afferent input on locomotor (vesico-somatic) performance in intact SCI and inflammatory conditions. The role of C-fiber inputs will also be determined via capsaicin pre-treatment. Inflammation and distention from bladder may be altering sensory inputs for the lumbosacral cord in turn altering the ability for locomotor output and spinal learning. Beginning 14 days post-injury twenty rats will undergo daily step training on a treadmill with manual assistance for 8 weeks. Two other groups forelimb trained (n=20) and non-trained (n=20) will be tested simultaneously. Functional urological data will be obtained with 1) conscious cystometry- catheter infused saline and 2) natural voiding patterns gathered using a metabolic monitoring system. Terminal molecular studies eleven weeks post- SCI will assess the exercise's regulation of bladder mRNA content of various neurotrophic factors which have been identified as important modulators in both the exercise and bladder dysfunction literature. Thus this study will be the first to investigate the influence of exercise therapy on the spinally mediated reflexive relationship between viscera and somatic structures involving detrusor external urethral sphincter and limb musculature. Although partially masked in normal subjects these reflexes are highly apparent after an upper motor neuron disease or SCI. Each part of this study is specifically designed to be applicable to the SCI patient and activity based therapies such as locomotor training.    
  
PUBLIC HEALTH RELEVANCE: Both quadriplegics and paraplegics rank bladder function as one of the most important factors affecting their quality of life and 96.5% of 681 survey respondents believe that exercise is an important part of functional recovery yet at least 63.6% do not have access to a trained therapist to oversee their regiments. With over 1 million people in the U.S. alone affected by SCI and the annual cost in federal funds estimated at $9.7 billion the knowledge gained from our study on locomotor training effects on bladder function will not only be immediately applicable to patients providing immense improvements in quality of life but also reduce life-long burdens on patient family and care centers.

project_terms:
Adverse effects;Affect;Afferent Neurons;Animal Model;Animals;Behavioral;Bladder;Bladder Control;Bladder Dysfunction;Body Size;Body Weight;C Fiber;Capsaicin;Caring;Catheterization;Catheters;Chemicals;Clinical;Conscious;Contusions;Cystitis;Data;Development;Devices;Electromyography;Equilibrium;Exclusion Criteria;Exercise;Exhibits;Family;Forelimb;Functional disorder;Funding;Goals;Growth Factor;Health;Hindlimb;Implant;Infective cystitis;Inflammation;Inflammatory;Injury;Investigation;Knowledge;Lead;Learning;Life;Limb structure;Literature;Lower urinary tract;Maintenance;Manuals;Masks;Measures;Mediating;Messenger RNA;Metabolic;Methods;Molecular;Monitor;Morphology;Muscle;Operative Surgical Procedures;Organ;Outcome;Output;Paraplegia;Patient observation;Patients;Pattern;Performance;Pharmaceutical Preparations;Physical therapy exercises;Play;Polyuria;Quadriplegia;Quality of life;Rattus;Recovery;Recovery of Function;Reflex action;Regulation;Reporting;Respondent;Role;Saline;Self Perception;Sensory;Skeletal muscle structure;Source;Sphincter;Spinal;Spinal Cord;Spinal cord injury;Spinal cord injury patients;Step training;Stimulus;Structure;Surveys;System;Testing;Therapeutic;Tibialis anterior muscle structure;Training;Upper Motor Neuron Disease;Urethral sphincter;Urodynamics;Viscera;Visceral;Walking;Water;arm;base;cell body (neuron);clinically relevant;cost;desensitization;design;effective therapy;irritation;male;neurotrophic factor;patient population;prevent;response;success;urinary;urologic

public_health_relevance:
Both quadriplegics and paraplegics rank bladder function as one of the most important factors affecting their quality of life and 96.5% of 681 survey respondents believe that exercise is an important part of functional recovery yet at least 63.6% do not have access to a trained therapist to oversee their regiments. With over 1 million people in the U.S. alone affected by SCI and the annual cost in federal funds estimated at $9.7 billion the knowledge gained from our study on locomotor training effects on bladder function will not only be immediately applicable to patients providing immense improvements in quality of life but also reduce life-long burdens on patient family and care centers.


application_id: 8059092
project_number: 2R44RR025737-02
project_title: A non-surgical embryo transfer (NSET) device for producing gene-modified mice
administering_ic: NCRR
award_notice_date: 2011-03-14
opportunity_number: PA-10-050
application_type: 2
activity_code: R44
ic: RR
serial_number: 025737
program_official: O'NEILL, RAYMOND R
project_start_date: 2009-09-03
project_end_date: 2013-02-28
study_section: Special Emphasis Panel[ZRG1 IMST-J (15)]
contact_pi_person_id: 9710810
contact_pi: FATH-GOODIN, ANGELIKA
other_pis: SPEAR, BRETT
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The use of research animals in research has been essential to development of vaccines and study of most human diseases. Modern rodent research is increasingly powerful with the ability to manipulate the genomes of mice and rats such that they closely mimic complex human diseases such as Alzheimer's and artherosclerosis. Generating transgenic mice and rats requires that embryos that are manipulated by researchers be transferred into recipient female mice where they can complete their development. Up to this point these transfers have required surgical procedures in which the embryo is implanted into the uterus. Recently a device has been developed that enables these embryo transfers to be performed without surgery which eliminates the post-operative recovery period thereby reducing pain of the animals. This proposal investigates and expands upon the utility of this embryo transfer device by establishing the optimal ages and mouse strains for embryo transfer (Aim 1) determining whether embryonic stem cells can be effectively and efficiently transferred with this device (Aim 2) determining whether the device is useful for artificial inseminations (Aim 3) directly visualizing the device in the uterus which may enable design improvements (Aim 4) and quantifying measures of stress relative to surgical procedures to support widespread adoption of this procedure in the research community (Aim 5). The primary project objective is to produce data that will prove the efficacy of this embryo transfer device and thereby enable researchers to replace surgical procedures with a non-surgical method that is equally effective. Proving that this non-surgical transfer method is effective under a range of conditions will expand its use over this range of applications and thereby maximize its impact in enabling researchers to refine and reduce the number of surgical procedures performed in mice.  
  
PUBLIC HEALTH RELEVANCE: Animal use in research is essential for biomedical research and with the developing abilities to genetically engineer mice for research; these animals are becoming even more important as they can be modified to mimic most human diseases. Genetic engineering of mice requires as one of many other things the ability to transfer embryos into mice where they complete their development. This project supports further development of a device that enables these embryo transfers to be performed without surgery and therefore greatly reduces the pain category that these research animals experience and thereby supports progress in biomedicine.

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

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


application_id: 8059084
project_number: 1F32DC011427-01
project_title: The role of cAMP signaling in OSN axon convergence in the olfactory bulb
administering_ic: NIDCD
award_notice_date: 2010-07-26
opportunity_number: PA-10-110
application_type: 1
activity_code: F32
ic: DC
serial_number: 011427
program_official: CYR, JANET
project_start_date: 2010-09-01
project_end_date: 2013-08-31
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 10351735
contact_pi: HERON, PAULA MICHELLE
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): This postdoctoral F32 Kirschstein NRSA proposes a comprehensive research and training plan in the study of neurogenesis and axon guidance in the olfactory system with relevance to neural regeneration therapies. Failure of the damaged nervous system to repair itself has debilitating consequences for millions of people worldwide. Regeneration therapies are focused on restoring damaged circuitry by regrowth and guidance of the axons of spared neurons or replacement of dead neurons. The olfactory system provides a useful model to study cell replacement and axon targeting in a mature nervous system. Although the mechanisms by which olfactory sensory neuron (OSN) axons are targeted to the olfactory bulb remain largely unknown the anterior-posterior patterning of glomerular convergence in the bulb correlates with neuronal levels of cAMP and altered expression of activity-dependent guidance cues. However direct evidence of the involvement of cAMP in axon targeting and the genetic mechanisms involved are lacking. The specific aims of this proposal will test the hypothesis that cAMP plays a definitive role in glomerular convergence of axons in the bulb. If this idea is correct then transgenic mice exhibiting sustained increases in cAMP in immature OSNs should show altered glomerular convergence and position. Aim 1 will use transgenic mice that express a constitutively active G-protein-coupled receptor GPR12 in immature OSNs. GPR12 couples to Gas adenylyl cyclase and cAMP production. To follow specific populations of OSN axons GPR12 transgenic mice will be crossed with OR-tauLacZ mice such as the M71-tauLacZ strain. This will allow visualization of the coalescence of OSN axons. Aim 2 will investigate changes in cAMP-mediated downstream signaling events that lead to alterations in gene expression. Identification of cAMP driven signal transduction in immature OSNs will help to elucidate mechanisms that control the position of OSN axon convergence in the olfactory bulb. Aim 3 will test whether cAMP over expression will rescue the lack of target innervation in mice lacking the emx2 gene. The results from these studies will provide novel insight into the role of cAMP signaling in OSN axon growth and convergence in the olfactory bulb.  
  
PUBLIC HEALTH RELEVANCE: Cell replacement as a regenerative approach to repair the injured nervous system remains promising. My research aims will contribute to understanding the processes that allow normal cellular replacement and appropriate target innervation in the olfactory system. This understanding of endogenous neural replacement can only help advance the design of effective regenerative therapies for brain and spinal cord injuries.

project_terms:
Adenylate Cyclase;Affect;Afferent Neurons;Anterior;Axon;Behavior;CREB1 gene;Cells;Couples;Cues;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Data;Event;Exhibits;Failure (biologic function);G-Protein-Coupled Receptors;Gases;Gene Expression;Genes;Genetic;Genetic Transcription;Growth;Imagery;Lead;Link;Location;Measures;Mediating;Modeling;Mus;National Research Service Awards;Natural regeneration;Nerve Regeneration;Nervous System Trauma;Nervous system structure;Neurons;Neurophysiology - biologic function;Neuropilin-1;Olfactory Epithelium;Olfactory Nerve;Pattern;Penetration;Physiological Processes;Play;Population;Positioning Attribute;Process;Production;Proto-Oncogene Proteins c-akt;Research;Research Training;Role;Signal Pathway;Signal Transduction;System;Testing;Therapeutic;Transduction Gene;Transgenic Mice;axon growth;axon guidance;design;emx2 protein;injured;insight;knockout animal;nerve supply;neural circuit;neurogenesis;novel;offspring;olfactory bulb;overexpression;public health relevance;reconstruction;regenerative;regenerative therapy;relating to nervous system;repaired;spinal cord and brain injury;success

public_health_relevance:
PROJECT NARRATIVECell replacement as a regenerative approach to repair the injured nervous systemremains promising. My research aims will contribute to understanding the processes thatallow normal cellular replacement and appropriate target innervation in the olfactorysystem. This understanding of endogenous neural replacement can only help advancethe design of effective regenerative therapies for brain and spinal cord injuries.


application_id: 8059069
project_number: 3R01CA104333-05S1
project_title: DNA Mismatch Repair Deficiency and Leukemia Relapse
administering_ic: NCI
award_notice_date: 2010-04-16
application_type: 3
activity_code: R01
ic: CA
serial_number: 104333
suffix: S1
program_official: OGUNBIYI, PETER
project_start_date: 2005-04-01
project_end_date: 2012-02-28
study_section: Cancer Genetics Study Section[CG]
contact_pi_person_id: 7956619
contact_pi: GU, LIYA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the molecular mechanisms underlying leukemia relapse. There are more than 21000 deaths to relapsed leukemia each year in the United States but the molecular basis of this deadly disease is still unknown. Since leukemia relapse is always associated with chemotherapy and since cells exposed to therapeutic agents usually acquire a mismatch repair (MMR) deficient phenotype we hypothesize that leukemia relapse in many cases is caused by a small fraction of leukemic cells that have adopted an MMR deficient phenotype during the course of chemotherapy. Our preliminary studies have showed that defects in MMR are indeed associated with cell lines derived from relapsed leukemia and patients with relapsed leukemia. To further test our hypothesis this application proposes both genetic and biochemical approaches to analyze the relationship between relapsed leukemia and MMR proficiency. First real-time PCR will be used to analyze the status of microsatellite sequences in adult acute leukemia patient samples at presentation remission and relapse to dynamically and quantitatively determine how leukemic cells transform from a microsatellite stable form to a microsatellite instable form during the development of relapse. Second leukemic cells from relapsed patients will be analyzed for genetic alterations and epigenetic modifications in key MMR genes such as hMSH2 and hMLH1 using combination technologies of PCR-based single strand conformation polymorphism DNA sequencing and methylation-specific PCR. Third individual alterations identified in leukemia patients will be introduced into MMR genes to express recombinant mutant proteins. To determine the actual impact of these alterations on MMR function individual recombinant mutant proteins will be examined for their ability to restore MMR to the corresponding MMR mutant extracts using an in vitro functional MMR assay. This study will provide significant insight into the mechanism underlying leukemia relapse as well as vital information for designing therapeutic regimens for the disease.

project_terms:
Acute leukemia;Adopted;Adult;Biochemical;Biological Assay;Cell Line;Cells;Cessation of life;Characteristics;Complement;DNA;DNA Sequence;Data;Defect;Detection;Detection of Minimal Residual Disease;Development;Diagnostic;Disease;Disease remission;Epigenetic Process;Evolution;Genes;Genetic;Goals;In Vitro;In complete remission;Individual;Leukemia Myelocytic Acute;Leukemic Cell;MLH1 gene;Methylation;Microsatellite Instability;Microsatellite Repeats;Mismatch Repair;Modification;Molecular;Mutation;Nuclear Extract;Pathogenesis;Patients;Phenotype;Proteins;Publishing;Recombinants;Regimen;Relapse;Research;Research Personnel;Residual state;Sampling;Single-Stranded Conformational Polymorphism;Site-Directed Mutagenesis;Staging;Technology;Testing;Therapeutic;Therapeutic Agents;Time;United States;Work;base;chemotherapy;design;expectation;expression vector;insight;leukemia;mutant;prevent;programs;tool


application_id: 8059053
project_number: 3R01GM050388-16S2
project_title: Role of Lipid Phosphatases in Cholesterol and Triglyceride Synthesis
administering_ic: NIGMS
award_notice_date: 2010-04-23
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: GM
serial_number: 050388
suffix: S2
program_official: GERRATANA, BARBARA
project_start_date: 2010-05-15
project_end_date: 2011-04-30
study_section: Biochemistry and Biophysics of Membranes Study Section[BBM]
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Cardiovascular and cerebrovascular diseases are the leading causes of death worldwide. Obesity elevations in circulating levels of cholesterol and triglycerides and alterations in the composition of circulating lipoproteins are major risk factors for cardiovascular and cerebrovascular disease. Obesity is a disorder of energy balance. When energy input exceeds energy output most of the excess calories consumed are converted to triglycerides and stored in adipose tissue. Similarly increases in circulating cholesterol leading to cholesterol deposition in the vasculature occur when the balance between de novo synthesis of cholesterol and provision of cholesterol from dietary sources exceeds normal cholesterol requirements and capacity to eliminate this essential sterol. Clinical management of obesity and its complications including hypercholesterolemia presently focuses on modifications of diet physical activity and behavior. Because these strategies are of limited effectiveness the prevalence of obesity continues to increase. Pharmacological inhibition of cholesterol synthesis is the primary and presently most effective strategy for the clinical management of hypercholesterolemia. Although to date efforts to develop pharmacological strategies for treatment of obesity focusing on appetite suppression and interference with lipid absorption have met with moderate success recent advances using mouse models suggest that inhibition of triglyceride synthesis may be a viable and effective treatment strategy. Identification of components of the pathways responsible for synthesis of triglycerides and cholesterol and development of a complete understanding of how these processes are regulated is therefore critical for the development of new or improved agents for treatment of obesity and hypercholesterolemia. Because of their pivotal position in cellular metabolism the pathways responsible for the de novo synthesis of cholesterol and triglycerides have been intensively studied but significant gaps in our knowledge remain. Two classes of lipid phosphate esters polyisoprenoid diphosphates and phosphatidic acid are critical intermediates in the synthesis of cholesterol and triglyceride but enzymes that dephosphorylate these intermediates have only recently been identified. The overall goal of this research is to address these gaps in our knowledge by investigating the regulation and function of two newly identified lipid phosphatases that play central roles in the synthesis of isoprenoids sterols and triglycerides. Our research uses techniques of biochemistry cell and molecular biology to study the regulation and function of these enzymes in vitro and in biomedically relevant model cell systems. In the first aim we will use these approaches to test the hypothesis that an integral membrane enzyme termed polyisoprenoid diphosphate phosphatase is a regulator of cholesterol synthesis and protein isoprenylation. In the second aim of the proposal we will test the hypothesis that activity of a phosphatidic acid phosphatase enzyme that catalyses a critical step in triglyceride synthesis is regulated by a novel membrane targeting motif. PUBLIC HEALTH RELEVANCE: Obesity and elevated cholesterol levels are major risk factors for Cardiovascular and Cerebrovascular disease which are the leading causes of death in this country. Obesity is a disorder of energy balance. When energy input exceeds energy output most of the excess calories consumed are converted to triglycerides and stored as body fat. Similarly increases in circulating cholesterol occur when the balance between cholesterol synthesis and provision of cholesterol from dietary sources exceeds normal cholesterol requirements and cholesterol excretion. In this research project we will test specific hypotheses about the regulation and function of newly identified enzymes that play central roles in the synthesis and metabolism of fat and cholesterol. Completion of our work will provide new insights into how synthesis of these lipids is regulated how this process may be altered in disease and the feasibility of targeting these processes to provide novel therapies for obesity and cardiovascular disease.

project_terms:
12-diacylglycerol;Address;Adipose tissue;Amplifiers;Anabolism;Basic Science;Behavior;Binding (Molecular Function);Biochemical;Biochemistry;Biological;Biological Assay;Body fat;Calories;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell Nucleus;Cell model;Cells;Cerebrovascular Disorders;Cholesterol;Cholesterol Synthesis Inhibition;Clinical Management;Country;Data;Deposition;Desire for food;Detergents;Development;Diet;Diet Modification;Dietary Cholesterol;Diglycerides;Diphosphates;Disease;Drug Delivery Systems;Effectiveness;Endoplasmic Reticulum;Enzymatic Biochemistry;Enzymes;Equilibrium;Excretory function;Exhibits;Farnesol;Funding;Gene Family;Genes;Genetic;Glycerophospholipids;Goals;In Vitro;Intervention;Intracellular Membranes;Isoprenoid Phosphates;Knowledge;Lecithin;Lipids;Lipoproteins;Malignant Neoplasms;Mediating;Membrane;Membrane Lipids;Membrane Proteins;Metabolic;Metabolic Diseases;Metabolism;Molecular;Molecular and Cellular Biology;Mono-S;Morbidity - disease rate;Mortality Vital Statistics;Nuclear Envelope;Obesity;Output;Pathway interactions;Peripheral;Pharmaceutical Preparations;Phosphatidate Phosphatase;Phosphatidic Acid;Phospholipids;Phosphoric Monoester Hydrolases;Physical activity;Play;Positioning Attribute;Prevalence;Process;Protein Isoforms;Protein Isoprenylation;Proteins;Regulation;Research;Research Project Grants;Role;Signal Transduction;Source;Specific qualifier value;Sphingolipids;Sterols;System;Techniques;Testing;Triglycerides;Viral Vector;Work;Yeasts;absorption;base;cardiovascular risk factor;effective therapy;energy balance;enzyme activity;enzyme pathway;geranylgeraniol;human disease;hypercholesterolemia;improved;inorganic phosphate;insight;isoprenoid;lipid metabolism;lipine;meetings;member;membrane model;mevalonate;mouse model;novel;obesity management;obesity treatment;phosphate ester;preference;programs;prospective;public health relevance;success;therapeutic target;treatment strategy


application_id: 8058718
project_number: 5P01NS058484-05
project_title: Calpain as a Therapeutic Target for TBI (P01)
administering_ic: NINDS
award_notice_date: 2011-04-25
application_type: 5
activity_code: P01
ic: NS
serial_number: 058484
program_official: HICKS, RAMONA R
project_start_date: 2007-05-01
project_end_date: 2013-04-30
study_section: ZNS1-SRB-R(24)
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W.
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
budget_start_date: 2011-05-01
project_abstract:
The overall goal of this PPG is to evaluate the hypothesis that calpain inhibition represents a viable therapeutic target for intervention following traumatic brain injury (TBI). TBI represents a leading cause of death and disability in adults and children and improved treatment options are urgently needed. Calpains
are excessively activated following TBI and are strongly implicated in the secondary neuronal degeneration.
The resultant hypothesis is that calpain inhibition will protect against the pathological and functional consequences of TBI. Although straightforward this hypothesis has proven to be surprisingly difficult to evaluate. A handful of studies in animal models of TBI have demonstrated improved neurological recovery and attenuated axonal injury with calpain inhibitor treatment. However evidence that these benefits are
directly related to calpain inhibition has been elusive. Moreover there are numerous unanswered questions regarding the mechanisms by which calpains contribute to cell death and dysfunction. This PPG brings together investigators with strong expertise in calpain biochemistry and in animal models of TBI to evaluate
three distinct mechanisms of calpain inhibition following TBI. Project 1 explores the role of the endogenous specific and potent calpain inhibitor calpastatin in modulating calpain function and improving outcome following TBI. Project 2 is translational and will investigate the ability of new small molecule calpain inhibitors
to attenuate the pathological and functional consequences of TBI. Project 3 will examine the roles of individual calpain isoforms in neurodegeneration and TBI focusing on the hypothesis that u-calpain is a pathologic isoform and is localized to mitochondria. In addition to the three projects there will be three cores:
A Administrative and Biostatistical Core; B Animal Core; and C Proteomics and Biomarker Core. Together these projects and cores will provide a clear indication as to whether calpain inhibition represents a viable
therapeutic target for TBI and whether the small molecule calpain inhibitors are suitable for subsequent preclinical and clinical investigation.


application_id: 8058717
project_number: 5P01NS058484-04
project_title: Proteomics and biomarker
administering_ic: NINDS
application_type: 5
activity_code: P01
ic: NS
serial_number: 058484
study_section: ZNS1
subproject_number: 9002
contact_pi_person_id: 3079616
contact_pi: GUTTMANN, RODNEY P
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: 2010-05-01
budget_end_date: 2011-04-30
funding_mechanism: Non-SBIR/STTR
project_abstract:
This Program Project focuses on the hypothesis that calpain inhibition represents a rationale and feasibletarget for therapeutic intervention following TBI. Traumatic brain injury (TBI) results in more than 50000deaths each year with over 5 million Americans suffering the effects of some type of TBI. In addition theneed for improved therapeutics it is important to understand the mechanisms underlying the pathologicalsequelae to TBI. One area that has been implicated as an important contributor to cellular injury followingTBI is the calcium- and redox-dependent calpain/calpastatin proteolytic system. The central hypothesis ofthis core is that calpain cleavage of specific proteins is linked to cell and neuronal and dysfunction followingTBI. The related hypothesis is that attenuation of this proteolysis will result in reduced degeneration andimproved functional outcome. Given the strong evidence for the role of calpains in neurodegeneration thelong-term goal is to identify the targets of calpain that contribute to neurodegeneration following TBI. Thegoals of this Core are to: 1) provide uniform assessment of calpain substrates following TBI including celltypespecific substrates thereby better characterizing the time-course and localization of calpain activity; 2)identify and verify biomarkers of neurodegeneration to monitor injury progression as well as efficacy oftherapeutics and; 3) determine the extent to which oxidative stress inhibits calpain activity over the timecourse of TBI an area that remains unexplored. In collaboration with the three projects these core studieswill utilize 2D-gel electrophoresis mass-spectrometry Western blot analysis and calpain activity assays withbrain tissue CSF and serum to achieve these goals. In summary this core will provide the needed tools andassistance for uniform analysis of calpain substrate degradation within the projects provide additionalsupport for the discovery of calpain substrates and related biomarkers and provide direct measurements ofcalpain activity to determine the influence of oxidative stress on calpain activity following TBI.

project_terms:
4 hydroxynonenal;Address;Alzheimer's Disease;American;Amyotrophic Lateral Sclerosis;Animal Model;Area;Astrocytes;Behavioral;Biological Assay;Biological Models;Brain Injuries;Calcium;Calpain;Cell Culture Techniques;Cell Death;Cells;Cerebral Ischemia;Cerebrospinal Fluid;Cessation of life;Cleaved cell;Collaborations;Data;Digestion;Disease;Effectiveness;Electrophoresis Gel Two-Dimensional;Enzymes;Functional disorder;Future;Goals;Huntington Disease;In Vitro;Individual;Injury;Ionophores;Knockout Mice;Link;Lipid Peroxidation;Mass Spectrum Analysis;Measurement;Measures;Mediating;Methods;Microglia;Mitochondria;Modeling;Monitor;Nature;Nerve Degeneration;Neuroglia;Neuronal Dysfunction;Neurons;Oligodendroglia;Outcome;Oxidation-Reduction;Oxidative Stress;Parkinson Disease;Pathway interactions;Peptide Hydrolases;Population;Primary Cell Cultures;Prions;Protein Isoforms;Proteins;Proteolysis;Proteomics;Publishing;Role;Serum;Spectrin;Spinal cord injury;System;Therapeutic;Therapeutic Intervention;Time;Traumatic Brain Injury;Treatment Efficacy;Western Blotting;Work;attenuation;base;biomarker;brain tissue;calpastatin;cell injury;cell type;disability;efficacy testing;functional outcomes;improved;in vivo;inhibitor/antagonist;insight;m-calpain;neurofilament;novel;oxidation;prevent;programs;small molecule;therapeutic effectiveness;tool;working group


application_id: 8058716
project_number: 5P01NS058484-04
project_title: Animal
administering_ic: NINDS
application_type: 5
activity_code: P01
ic: NS
serial_number: 058484
study_section: ZNS1
subproject_number: 9001
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-05-01
budget_end_date: 2011-04-30
funding_mechanism: Non-SBIR/STTR
project_abstract:
Although multiple lines of experimental evidence implicate calpains in the process of secondaryneurodegeneration following traumatic brain injury (TBI) little is understood about the downstream actions ofcalpains in the injured brain and how these pathways might differ in focal and diffuse TBI. In addition toelucidating novel targets and cellular pathways for calpains in the injured brain the Program will evaluateseveral novel strategies to inhibit posttraumatic calpain activation including enhancing activity of calpastatinknocking out the calpain I isoform and administering small molecule inhibitors. The overall goal of theAnimal Core (Core B) is to facilitate the Program's investigations of calpain-mediated neuropathology andevaluations of calpain inhibitory therapeutic strategies in mouse models of focal and diffuse TBI. To thisendthe Core will perform three specific functions in support of Program objectives: 1) produce consistentpredictable focal or diffuse traumatic brain injuries in mice to be further evaluated in Projects 1 2 and 3 andin Core C 2) provide reliable unbiased assessments of posttraumatic cognitive and motor function in brain-injured and control mice for evaluation of strategies to reduce posttraumatic calpain activation pursued inProjects 1 2 and 3 and 3) maintain and expand as necessary colonies of human calpastatinoverexpressing mice calpastatin deficient mice calpain I knockout mice and cyclophilin D deficient mice foruse in Projects 1 and 3 and Core C. Through these three major functions the Animal Core will increase theefficiency of the Program by reducing redundancy in training personnel and resources and will enhance theability of Projects and Cores to directly compare data by minimizing variability. In addition the Core willprovide behavioral assessments under blinded conditions and will provide centralized management oftransgenic and knockout mouse resources vital to the Program's scientific interests. The activities of theCore are essential to the successful completion of the scientific goals of the Program.

project_terms:
Adult;Animals;Behavior assessment;Behavioral;Blinded;Brain;Brain Injuries;Breeding;Calpain;Calpain I;Cell Culture Techniques;Cognitive;Craniocerebral Trauma;Data;Diffuse;Drops;Evaluation;Female;Generations;Genotype;Goals;Human;Human Resources;Individual;Injury;Investigation;Knock-out;Knockout Mice;Life;Literature;Maintenance;Mediating;Modeling;Monitor;Motor;Mus;Nerve Degeneration;Neurologic Dysfunctions;Operative Surgical Procedures;Pathway interactions;Performance;Procedures;Process;Program Efficiency;Protein Isoforms;Reagent;Research Personnel;Resources;Schedule;Survivors;Testing;Therapeutic;Time;Tissue Harvesting;Training;Transgenic Mice;Transgenic Organisms;Traumatic Brain Injury;Weight;brain pathway;calpastatin;cellular targeting;cognitive function;cohort;controlled cortical impact;cyclophilin D;functional outcomes;grasp;in vivo;inhibitor/antagonist;injured;insight;interest;memory retention;morris water maze;mouse model;neuropathology;novel;novel strategies;operation;overexpression;preclinical evaluation;pregnant;programs;research study;sharing data;small molecule;treatment strategy


application_id: 8058715
project_number: 5P01NS058484-04
project_title: Is u-calpain a pathologic isoform?
administering_ic: NINDS
application_type: 5
activity_code: P01
ic: NS
serial_number: 058484
study_section: ZNS1
subproject_number: 0003
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-05-01
budget_end_date: 2011-04-30
funding_mechanism: Non-SBIR/STTR
project_abstract:
Calpains are family of calcium-activated neutral proteases involved with signal transduction and cell motilitybut whose overactivation is strongly implicated in neurodegeneration following traumatic brain injury andother CMS insults and disorders. Although studies over the past 30 years have provided a wealth ofknowledge regarding calpains important questions remain: Which calpain isoforms are responsible for theneurodegeneration? How is calpain activated postinjury? What are the critical substrates? Are m- and u-calpain located in the same subcellular compartment? We recently found that mitochondria contain u-calpain(calpain 1 plus calpain small subunit 1). Based on the existing data and our preliminary results our workingmodel is that mitochondrial u-calpain is situated within the intermembrane space is activated followingopening of the mitochondrial permeability transition pore (mPTP) and that mitochondrial substrates of u-calpain include apoptosis inducing factor (AIF) which when cleaved by calpain is released into the cytosoland translocates to the nucleus to contribute to caspase-independent cell death. In addition we propose thatactivated u-calpain is released from the mitochondria into the cytosol where its substrates are similar tothose of m-calpain. In summary mitochondrial u-calpain is hypothesized to become activated followingmPTP opening and function as a death-related protease. We therefore hypothesize that neurons deficient incalpain 1will exhibit resistance to excitotoxic death and that neurodegeneration and functional impairmentfollowing traumatic brain injury will be markedly attenuated in mice deficient in u-calpain. Interactions withother projects include evaluating the ability of calpastatin (Project 1) and small molecule calpain inhibitors(Project 2) to inhibit mitochondrial u-calpain. This project will use the same injury models methods ofassessing functional impairment and methods for evaluating calpain activity as other projects enablingdirect comparison of results. In addition we will collaborate with the Proteomics and Biomarker Core C toidentify novel substrates of mitochondrial u-calpain. Together the experiments outlined in this project willenhance our understanding of the function of the u-calpain isoform mechanisms involved in its activationand its role in neuron death following traumatic brain injury and other CNS insults.

project_terms:
Animals;Atractyloside;Attenuated;Behavior;Calpain;Cell Death;Cell Nucleus;Cells;Cessation of life;Cleaved cell;Cognitive;Cyclosporine;Cytosol;Data;Diffuse;Digitonin;Disease;Drops;Exhibits;Family;Functional disorder;Glycine;Injury;Knock-out;Knockout Mice;Knowledge;Methods;Mitochondria;Modeling;Motor;Mus;N-Methylaspartate;Nerve Degeneration;Neurons;Nuclear Translocation;Pathologic;Peptide Hydrolases;Protein Isoforms;Proteolysis;Proteomics;Research Personnel;Resistance;Role;Signal Transduction;System;Tissues;Traumatic Brain Injury;Weight;Work;apoptosis inducing factor;base;biomarker;calpain inhibitor;calpastatin;caspase;cell motility;controlled cortical impact;cyclophilin D;functional disability;m-calpain;mitochondrial membrane;mitochondrial permeability transition pore;neuroprotection;novel;overexpression;research study;small molecule


application_id: 8058714
project_number: 5P01NS058484-04
project_title: Newer small molecule calpain inhibitors for TBI
administering_ic: NINDS
application_type: 5
activity_code: P01
ic: NS
serial_number: 058484
study_section: ZNS1
subproject_number: 0002
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-05-01
budget_end_date: 2011-04-30
funding_mechanism: Non-SBIR/STTR
project_abstract:
Considerable experimental evidence now supports a critically important pathophysiological role for thecalcium-activated protein-degradative enzyme calpain in the secondary injury process that follows traumaticbrain injury (TBI). This has suggested that that early treatment with a calpain-inhibiting drug should be ableto reduce post-TBI secondary injury to brain tissue and thus facilitate neurological recovery and survival.Accordingly several small molecule calpain inhibitors have been discovered. A few of these have beentested in rodent TBI models and have shown some promise in terms of either a decrease in calpain-mediated proteolytic damage in the injured brain tissue or an improvement in neurological recovery.However none of the available calpain inhibitors have been systematically studies in TBI models so thattranslation of their effects into clinical development would be possible. Thus the overall goal of this projectis to carefully examine the ability of 5 carefully selected calpain inhibitors including three newer compoundsto be able to effectively inhibit post-traumatic cytoskeletal proteoytic degradation mitochondrial dysfunctionand neurodegeneration and to improve neurological recovery. The 5 compounds will first be screened fortheir ability to inhibit calpain activation in normal mice in a dose-related fashion (Aim 1). The most effectivecompounds will be advanced into testing for their cytoskeletal (Aim 2) mitochondrial (Aim 3) andneuroprotective effects (Aim 4) in a diffuse and a focal TBI model. One of the 5 compounds selected is adual inhibitor of calpain proteolytic degradation and free radical-induced lipid peroxidation. The lattersecondary injury process is known to enhance calpain activation by causing impairment of neuronal calciumhomeostatic mechanisms. As a result the increase in intracellular calcium exacerbates calpain activation.Therefore a dual inhibitor or calpain and lipid peroxidation would be expected to be more effective than aeither type of compound alone. In addition to looking at the dose-related benefits of early administration of acalpain inhibitor or a dual calpain inhibitor/lipid peroxidation inhibitor in two different TBI models thetherapeutic efficacy window and the optimum duration of treatment will be explored. The resulting data willaddress the overall hypothesis that calpain inhibition is a practical neuroprotective therapeutic approach anddefine how best to design anti-calpain therapy so that future clinical trials in TBI patients are enabled.

project_terms:
AK 295;Acute;Address;Animals;Antioxidants;Attenuated;Behavioral;Brain;Brain Injuries;Calcium;Calpain;Calpain I;Cathepsins;Cell Culture Techniques;Cell Death;Cells;Cessation of life;Clinical;Clinical Trials;Collaborations;Conceptions;Cysteine Protease;Cytoskeletal Proteins;Data;Development;Diffuse;Dose;Early treatment;Enzymes;Evaluation;Excision;Failure (biologic function);Free Radicals;Functional disorder;Future;Goals;Hand;Hour;Human Resources;Impairment;Infarction;Injury;Intravenous;Knock-out;Laboratories;Laboratory Research;Lead;Lipid Peroxidation;Lipids;Measures;Mediating;Mitochondria;Modeling;Mus;Nerve Degeneration;Neurons;Outcome;Oxygen;Papain;Patients;Peptides;Pharmaceutical Preparations;Pharmacodynamics;Phosphatidylethanolamine Binding Protein;Plasma;Play;Preparation;Principal Investigator;Process;Promotor (Genetics);Property;Proteins;Proteolysis;Proteomics;Recovery;Regimen;Relative (related person);Reporting;Research;Research Personnel;Rodent;Role;Running;Sampling;Screening procedure;Series;Solubility;Spectrin;Testing;Therapeutic;Time;Tissues;Transgenic Organisms;Translations;Traumatic Brain Injury;Treatment Efficacy;Work;apoptosis inducing factor;base;biomarker;brain tissue;calpain inhibitor;calpastatin;caspase;comparative;design;improved;in vivo;inhibitor/antagonist;injured;innovation;intraperitoneal;knockout animal;lipid peroxidation inhibitor;mitochondrial dysfunction;mouse model;neurological recovery;neuroprotection;novel;overexpression;oxidative damage;prevent;programs;protective effect;protective efficacy;research study;response;small molecule;therapeutic target;treatment duration;water solubility


application_id: 8058713
project_number: 5P01NS058484-04
project_title: Role of calpastatin in modulating function following TBI
administering_ic: NINDS
application_type: 5
activity_code: P01
ic: NS
serial_number: 058484
study_section: ZNS1
subproject_number: 0001
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-05-01
budget_end_date: 2011-04-30
funding_mechanism: Non-SBIR/STTR
project_abstract:
Traumatic brain injury (TBI) results in the prolonged activation of calpains which contributes to cytoskeletaldamage neuronal death and behavioral dysfunction. However surprisingly few in vivo cellular substrates ofcalpains have been identified in the traumatically injured brain and consequently little is understood aboutthe pathways through which calpains mediate posttraumatic morbidity. Calpastatin the endogenous inhibitorof calpains is the only known protein that exclusively inhibits calpains. As such calpastatin represents anideal molecular tool with which to isolate the actions of calpains within the injured brain. Efforts to translateexciting preclinical data demonstrating functional improvement in brain-injured rodents treated withexogenous calpain inhibitors have been slowed by challenges with solubility specificity and bioavailability ofsmall molecule inhibitors. Enhancing endogenous calpastatin activity may represent a novel and potenttherapeutic approach. The overall goals of Project 1 then are to evaluate the role of calpastatin inregulating posttraumatic calpain-mediated proteolysis and to assess the neuroprotective and behavioralefficacy of increasing calpastatin activity in the setting of TBI. Using genetically altered mice that eitheroverexpress human calpastatin or are calpastatin deficient Project 1 will: 1) evaluate the role of calpastatinin modulating behavioral outcome following focal or diffuse brain injury 2) quantify the effects of alteredcalpastatin expression on neuronal survival and axonal injury after focal or diffuse brain injury 3) determinethe in vivo role of calpastatin in limiting trauma-induced proteolysis of neuronal cytoskeletal proteins and 4)evaluate the role of posttraumatic calpain activation in modifying membrane proteins involved in calciuminflux and in modulating mitochondria-related cell death events. Our central hypothesis is that calpastatinoverexpression will prevent calpain-mediated cleavage of neuronal substrates critical for cell survivalthereby attenuating posttraumatic neuronal death and dysfunction. The proposed experiments will providethe first evidence for a functional role for calpastatin in posttraumatic pathology and elucidate differentialroles for the calpain/calpastatin system in focal and diffuse TBI. In addition this Project will provide thegroundwork for novel therapeutic approaches based on manipulation of the calpastatin system aimed atattenuating brain damage and dysfunction due to TBI as well as other CMS injury and disease states.

project_terms:
Acute;Address;Attenuated;Behavioral;Biological Availability;Brain;Brain Injuries;Calcium;Calpain;Cell Count;Cell Death;Cell Death Signaling Process;Cell Survival;Cells;Cerebrospinal Fluid;Cessation of life;Cognitive;Cytoskeletal Proteins;Data;Diffuse;Diffuse Brain Injury;Disease;Disinhibition;Dose;Drops;Evaluation;Event;Functional disorder;Genetic;Glutamate Receptor;Goals;Hippocampus (Brain);Human;Immunoblotting;Immunohistochemistry;Impairment;In Vitro;Injury;Knock-out;Knockout Mice;Maintenance;Mediating;Membrane Proteins;Mitochondria;Modeling;Molecular;Morbidity - disease rate;Motor;Mus;Nerve Degeneration;Neurons;Nuclear;Operative Surgical Procedures;Outcome;Outcome Measure;Pathology;Pathway interactions;Play;Principal Investigator;Property;Proteins;Proteolysis;Proteomics;Recovery;Relative (related person);Research Personnel;Rodent;Role;Serum;Signal Pathway;Signaling Protein;Silver Staining;Solubility;Specificity;Spectrin;Staining method;Stains;Standardization;System;Techniques;Testing;Therapeutic;Time;Tissue Sample;Tissues;Transgenes;Translating;Translations;Trauma;Traumatic Brain Injury;Weight;apoptosis inducing factor;base;brain tissue;calpain inhibitor;calpastatin;clinically relevant;controlled cortical impact;dentate gyrus;endonuclease G;functional disability;functional improvement;improved;in vivo;inhibitor/antagonist;injured;innovation;insight;memory retention;neurofilament;neuron loss;neuronal survival;neuroprotection;novel;novel therapeutic intervention;overexpression;pre-clinical;prevent;programs;research study;response;small molecule;tau Proteins;therapeutic target;tool


application_id: 8058450
project_number: 2R42DK074331-03A2
project_title: Induction of Donor Tolerance in Renal Transplants
administering_ic: NIDDK
award_notice_date: 2011-09-15
opportunity_number: PA-10-051
application_type: 2
activity_code: R42
ic: DK
serial_number: 074331
suffix: A2
program_official: GOSSETT, DANIEL ROBERT
project_start_date: 2005-06-03
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZRG1 DKUS-G (11)]
contact_pi_person_id: 1878929
contact_pi: ILDSTAD, SUZANNE T
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 140644969
duns_number: 140644969
fips: US
organization_id: 10001459
organization_name: REGENEREX, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-09-15
project_abstract:
DESCRIPTION: Renal transplantation is the preferred therapeutic approach for end organ failure. However the chronic use of immunosuppressive agents is critical to prevent rejection. The drugs are costly ($15000-25000/year) and have significant toxicities including opportunistic infection an increased rate of malignancy nephrotoxicity and other end organ damage. The induction of donor-specific tolerance would address these limitations. Bone marrow chimerism induces tolerance to transplanted organs. However the toxicity and complications associated with conventional hematopoietic stem cell transplants (HSCT) primarily graft-versus-host disease (GVHD) and the need for a matched donor has limited the therapeutic application of HSCT to tolerance induction. We have identified and patented a novel tolerogenic bone marrow cell population of CD8+/TCR- facilitating cells (FC) that enhances engraftment of stem cells in mismatched recipients without causing GVHD. The discovery of FC opens the door to employing HSCT as a viable cell-based approach for tolerance induction. The product FCRx addresses the major challenges preventing the widespread use of HSCT for tolerance induction. FCRx is a bioengineered bone marrow product that includes hematopoietic stem cells (HSC) and FC but avoids GVHD in mismatched recipients. In phase I of this proposal we achieved our proposed milestones demonstrating that we could reliably produce and transport FCRx and safely infuse it into nonmyeloablatively conditioned renal transplant recipients. We demonstrated that the proprietary FCRx procedure can routinely produce a graft with defined 12-TCR+ T cell composition and enriched for HSC and engraftment-enhancing FC. The ultimate goal is the induction of immune tolerance and the elimination of or reduction in the need for expensive and harmful immunosuppressive drugs. We have developed a nonmyeloablative conditioning regimen with 200 cGy TBI/fludarabine/cyclophosphamide/MMF/prograf to avoid the toxicity of conditioning. Since completing Phase I we have addressed a major concern expressed by the reviewers regarding our ability to enroll subjects and have now successfully transplanted 6 living donor kidney patients all of whom demonstrated donor chimerism at one month post-transplant. The approaches for collection shipping and FCRx preparation have also been approved by the FDA. Three patients show laboratory evidence of donor-specific tolerance and immunosuppression is being weaned. The remaining subjects are early in follow-up. The reproducibility and quality assurance of the FCRx process will lead to its successful commercial launch. In phase II we will increase the pace of transplants and demonstrate that FCRx consistently achieves engraftment of HLA mismatched HSC in nonmyeloablatively conditioned kidney transplant recipients induces donor-specific tolerance without causing significant GVHD and reduces or eliminates the need for long-term immunosuppression. A recent meeting with FDA classified our product as Phase II another milestone that will enhance commercialization.  
  
PUBLIC HEALTH RELEVANCE: Life-long immunosuppressive therapy is necessary following solid organ transplant. These drugs are expensive and have significant toxicities including opportunistic infection an increased rate of cancer and kidney failure. Hematopoietic stem cell transplantation (HSCT) induces tolerance to transplanted organs and tissue eliminating the need for life-long immunosuppressive therapy. If successful the process proposed for commercialization called FCRx will produce a bioengineered HSCT graft-enriched for facilitating cells and stem cells that will safely induce tolerance eliminating the need for immunosuppressive therapy along with its high monetary and health-related cost.

project_terms:
Address;Aplastic Anemia;Autoimmunity;Biological Assay;Biomedical Engineering;Biopsy;Blood;Bone Marrow;Bone Marrow Cells;Businesses;CD8B1 gene;Cell Transplants;Cells;Childhood;Chimerism;Chronic;Chronic Granulomatous Disease;Collection;Creatinine;Cyclophosphamide;Data;Diabetes Mellitus;Disease;Dose;Engineering;Engraftment;Enrollment;FDA approved;Face;Generations;Goals;Graft-vs-Host Disease;Grant;Hand;Health;Heart;Hematopoiesis;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Hemoglobinopathies;Immune;Immune Tolerance;Immune system;Immunologic Monitoring;Immunosuppressive Agents;Inherited;Islets of Langerhans;Kidney;Kidney Failure;Kidney Transplantation;Laboratories;Lead;Legal patent;Life;Liver;Living Donors;Lupus;Macular degeneration;Malignant Neoplasms;Metabolic Diseases;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mucopolysaccharidosis II;Multiple Sclerosis;Myocardial Infarction;Natural immunosuppression;Natural regeneration;Opportunistic Infections;Organ;Organ Transplantation;Organ failure;Patients;Pharmaceutical Preparations;Phase;Population;Preparation;Procedures;Process;Prograf;Property;Protocols documentation;Psoriasis;Regimen;Regulatory T-Lymphocyte;Renal function;Reproducibility;Rheumatoid Arthritis;Safety;Serum;Shipping;Ships;Sickle Cell Anemia;Solid;Stem cell transplant;Stem cells;T-Lymphocyte;Technology;Testing;Thalassemia;Therapeutic;Therapeutic immunosuppression;Tissues;Toxic effect;Transplant Recipients;Transplantation;Universities;Weaning;base;commercialization;conditioning;cost;experience;fludarabine;follow-up;in vitro Assay;in vivo;islet;kidney allograft;large bowel Crohn's disease;leukemia;leukodystrophy;meetings;mouse model;nephrotoxicity;novel;prevent;quality assurance;regenerative;repaired;stem

public_health_relevance:
Life-long immunosuppressive therapy is necessary following solid organ transplant. These drugs are expensive and have significant toxicities including opportunistic infection an increased rate of cancer and kidney failure. Hematopoietic stem cell transplantation (HSCT) induces tolerance to transplanted organs and tissue eliminating the need for life-long immunosuppressive therapy. If successful the process proposed for commercialization called FCRx will produce a bioengineered HSCT graft-enriched for facilitating cells and stem cells that will safely induce tolerance eliminating the need for immunosuppressive therapy along with its high monetary and health-related cost.


application_id: 8058113
project_number: 7R01CA107181-06
project_title: Age related ubiquitin defect on T-cell response to tumor
administering_ic: NCI
award_notice_date: 2010-08-03
application_type: 7
activity_code: R01
ic: CA
serial_number: 107181
program_official: MCCARTHY, SUSAN A
project_start_date: 2005-05-01
project_end_date: 2012-04-30
study_section: Cancer Immunopathology and Immunotherapy Study Section[CII]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
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
budget_start_date: 2010-08-03
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this revised proposal is to determine the biologic effects of a novel breast tumor antigen containing F-box and WD40 domains with an emphasis on its roles in age- and T cell-dependent susceptibility to tumor growth. We have identified a novel human breast tumor antigen (HBTA1) that strongly inhibits proliferation of T cells from aged but not young mice. Immunization of 2-mo-old BXD 12 mice with HBTA1 protects against the tumor challenge at 16-mo-of-age. Sucrose gradient purification of a mouse homologue HBTA1 (mHBTA1) followed by electromicroscope examination of the purified samples led to the realization that mHBTA1 is packed in the exosomes of the TS/A tumors. The TS/A exosomal mHBTA1 strongly inhibits the proliferation of T cells isolated from aged but not young BXD12 mice. The ability of T cells to proliferate in the presence of TS/A exosomes is correlated with the ubiquitination status of exosomal mHBTA1. Our aims are (1) To determine if ubiquitination of mHBTA1 is correlated with susceptibility to tumor growth and the tumor-specific cytotoxic T-cell response. Aged-mice will be immunized with ubiquitinated exosomal mHBTA1 to determine its effects on enhancement of protection against the tumor growth. In parallel we will determine if the production of endogenous ubiquitinated mHBTA1 in TS/A exosomes is correlated with the tumor susceptibility. (2) To use siRNA technology to determine if knockout of exosomal mHBTA1 of tumor cells is sufficient to reverse the inhibition of T cell proliferation mediated by TS/A exosomes or whether other exosomal proteins are required. (3) To determine if the age-dependent T cell factors we recently identified play a role in ubiquitination of exosomal mHBTA1 and thus inactivation of mHBTA1-mediated inhibition of T-cell activation; we will further determine the pathway by which TS/A exosomal mHBTA1 interacts with T-cell factors. (4) To determine if an age-related T-cell factor(s) regulates the ubiquitination of exosomal HBTA1 of human breast tumors and further to determine its possible association with the age-related incidence of breast cancers. The data generated should elucidate the cellular and molecular basis for the role of tumor exosomes and exosomal mHBTA1 in the development of age- and T cell-dependent breast cancer.

project_terms:
Age;Cell Aging;Cells;Cytotoxic T-Lymphocytes;Data;Defect;Development;Exhibits;F Box Domain;Figs - dietary;Generations;Goals;Growth;Homologous Gene;Human;Immune response;Immunization;Immunologic Surveillance;Implant;Incidence;Knock-out;Knockout Mice;Lead;Lymphocyte;Mammary Neoplasms;Mediating;Membrane;Modeling;Molecular;Mouse Protein;Mus;Pathway interactions;Play;Predisposition;Prevention;Production;Proliferating;Proteins;Recombinants;Resistance;Role;Sampling;Small Interfering RNA;Sucrose;T cell factor 4;T-Cell Activation;T-Cell Proliferation;T-Lymphocyte;TCF Transcription Factor;Technology;Testing;Tumor Antigens;Ubiquitin;Ubiquitination;Vesicle;WD Repeat;age related;aged;base;cancer cell;cell age;cytotoxicity;malignant breast neoplasm;neoplastic cell;novel;response;tumor;tumor growth


application_id: 8057061
project_number: 3R01GM077422-03S1
project_title: Targeting Nucleic Acids with an Integrated Vitural and Actual Screen
administering_ic: NIGMS
award_notice_date: 2010-04-19
application_type: 3
activity_code: R01
ic: GM
serial_number: 077422
suffix: S1
program_official: PREUSCH, PETER
project_start_date: 2007-02-01
project_end_date: 2012-03-31
study_section: Special Emphasis Panel[ZRG1-GGG-J(10)]
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Nucleic acids are under-represented molecular targets for small molecule therapeutic agents even though recent research shows that unusual nucleic acid structures play a profound role in gene expression and DNA replication. We propose an innovative interdiscplinary high-throughput screening approach for the discovery of new nucleic acid-targeted therapeutic agents. Our approach integrates an actual experimental screening assay with a virtual screening assay. The former is a unique competition dialysis assay that we invented for the discovery of small molecules that target specific nucleic acid sequences or structures. In the competiton dialysis assay an array of designed nucleic acid structures and sequences are dialyzed against a common test ligand solution. At equilibirum more ligand accumulates in the dialysis cell that contains the preferred structure or sequence. The assay is thermodynamically rigorous and allows for quantitative measurement of ligand binding free energies. In our integrated approach an in silico virtual screening assay will be implemented that will contain an array of receptors that is identical to the actual array of nucleic acids used in the competiton dialysis assay. The virtual assay can easily screen millions of compounds for their selective binding to particular nucleic acid structures of functional significance. "Hits" from the virtual screen will be passed to the actual competition dialysis assay for validation. With proposed improvements the competiton dialysis can rapidly screen hundreds of compounds. Our strategy will be to identify libraries of compounds that selectively recognize particular structures with the virtual screen then to rigorously verify these "hits" by high-throughput competition dialysis. Specific plans for the development of the competition dialysis assay include : i) implementation of the assay in a 96-well plate format (facilitating automation) ii) reduction of sample volumes iii) expansion of the biologically significant nucleic acid array and iv) reduction of throughput time. The virtual and actual screens will be fully integrated by an iterative feedback loop to refine the scoring algorithm using actual data obtained from the first generation dialysis assay in which the interaction of 126 compounds with 13 nucleic acids structures was studied. Our approach matches the Road Map Initiative goals by its interdisciplinary approach and by its emphasis on expanding the toolbox available for the discovery of new therapeutics.

project_terms:
Adopted;Algorithms;Antineoplastic Agents;Automation;Base Sequence;Binding (Molecular Function);Biological Assay;Biological Factors;Cancer Biology;Cells;Computer Simulation;Computer software;DNA;DNA Binding;DNA biosynthesis;Data;Data Set;Development;Development Plans;Dialysis procedure;Diamidine;Drug Delivery Systems;Equilibrium;Feedback;Fluorescence;Free Energy;G-Quartets;Gene Expression;Generations;Genetic Transcription;Goals;Hybrids;Intercalating Agents;Laboratories;Lead;Libraries;Ligand Binding;Ligands;Liquid substance;Malignant Neoplasms;Maps;Measurement;Measures;Methods;Molecular;Molecular Target;Nucleic Acid Binding;Nucleic Acids;Nucleic acid sequencing;Paste substance;Phase;Play;Porphyrins;Publishing;Research;Research Personnel;Role;Sampling;Screening procedure;Site;Solutions;Specificity;Structure;System;Telomerase;Testing;Therapeutic Agents;Thermodynamics;Time;Validation;Virtual Library;analytical method;cyanine dye;design;high throughput screening;innovation;intercalation;interdisciplinary approach;interest;novel;novel therapeutics;nucleic acid structure;phase 1 study;programs;receptor;repository;small molecule;tool;virtual


application_id: 8056628
project_number: 5R01AI076169-04
project_title: Antiviral lectins as microbicides
administering_ic: NIAID
award_notice_date: 2011-03-11
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 076169
program_official: TURPIN, JIM A
project_start_date: 2008-04-15
project_end_date: 2012-12-31
study_section: AIDS Discovery and Development of Therapeutics Study Section[ADDT]
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
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): For practical application microbicides must be available in massive amounts and must be produced cost- effectively. These requirements might eliminate recombinant proteins from consideration as costs of production in cell-based fermentation systems are prohibitively high. We developed a practical solution by expressing and purifying recombinant forms of the algal lectin Griffithsin (GRFT) the most potent HIV-1 entry inhibitor yet described from tobacco leaf tissues. GRFT has no known homologs in vertebrates and hence has the potential to be immunogenic and thus possibly to induce an inflammatory response incompatible with its use as a microbicide. This is a theoretical concern that applies to most if not all peptide-based microbicides and it is of vital importance to the field that this phenomenon be investigated more thoroughly. We will generate a mutant of GRFT that lacks lectin activity to allow us to answer the question whether lectin activity plays a role in induction of mucosal inflammatory responses. We will use a comprehensive mouse vaginal administration model developed by our consultant and collaborator Dr. Betsy Herold to evaluate the mucosal toxicity of hydroxyethylcellulose-formulated GRFT. Toxicology endpoints will include histology measurement of molecular markers of inflammation and phenotypes of leukocyte infiltrate in vaginal tissues. Since immunogenicity of protein microbicides is a concern we will also measure immune responses to the vaginal microbicide in animals in which we have intentionally raised an anti-GRFT immune response. We will use Dr. Herold's elegant mouse genital herpes simplex virus (HSV) infectivity assay that functions as a surrogate measurement of microbicide safety. Susceptibility to challenge with HSV-2 in animals treated with GRFT will inform us whether the complex of biological responses to treatment with GRFT can increase susceptibility to infection with HSV-2 and hence to possible enhanced susceptibility to HIV-1 infection in humans. We will also study the mechanism of resistance to GRFT in a mutant HIV-1 Clade C virus that we isolated in a selection experiment. Collectively the data that we generate in the course of this research will provide a comprehensive assessment of the utility of GRFT as a component of a vaginal microbicide to prevent HIV-1 transmission.   
  
PUBLIC HEALTH RELEVANCE: In the absence of an effective vaccine against HIV there is an urgent need for alternative strategies to prevent sexual transmission of HIV such as vaginally-applied microbicidal gels. We aim to answer the question whether proteins called lectins which bind the sugar structures found on the surface of the AIDS virus generate an inflammatory response when administered in the vagina of mice. These studies will provide important information that will help determine whether lectins have acceptable toxicity profiles to justify further development as microbicides.

project_terms:
Agriculture;Animals;Antibodies;Antiviral Agents;Attention;Binding (Molecular Function);Binding Sites;Biological;Biological Assay;Cells;Chlamydia trachomatis;Clinical;Collaborations;Complex;Data;Data Set;Development;Dose;Drug Kinetics;Epithelial;Epithelium;Evaluation;Exhibits;Fermentation;Gel;Genetic;Goals;HIV;HIV-1;Hemophilus;Histology;Histopathology;Homologous Gene;Human;Human Herpesvirus 2;Human Papillomavirus;Immune;Immune response;In Vitro;Infection;Inflammation;Inflammatory Response;Intravaginal Administration;Investigation;Lectin;Leukocyte Chemotaxis;Leukocytes;Mannose;Measurement;Measures;Modeling;Molecular;Mus;Mutate;Oryctolagus cuniculus;Peptides;Pharmaceutical Preparations;Pharmacology and Toxicology;Phenotype;Placebo Control;Plant Leaves;Play;Predisposition;Prevention;Production;Proteins;Recombinant Proteins;Recombinants;Recruitment Activity;Research;Resistance;Risk Factors;Role;Safety;Series;Sexual Transmission;Sexually Transmitted Diseases;Simplexvirus;Site-Directed Mutagenesis;Solutions;Structure;Sum;Surface;System;Testing;Tissues;Tobacco;Toxic effect;Toxicology;Vaccines;Vagina;Vertebrates;Virus;base;chemokine;cost;cytokine;genital herpes;hydroxyethylcellulose;immunogenic;immunogenicity;in vivo;inhibitor/antagonist;insight;irritation;lymphocyte proliferation;microbicide;molecular marker;mutant;pathogen;practical application;prevent;public health relevance;rectal microbicide;research study;resistance mechanism;response;sugar;transmission process;vaginal microbicide


application_id: 8056618
project_number: 5K01DK080951-03
project_title: Endoplasmic Reticulum-Induced Stress and Apoptosis in the Renal Tubule
administering_ic: NIDDK
award_notice_date: 2011-03-22
opportunity_number: PA-06-001
application_type: 5
activity_code: K01
ic: DK
serial_number: 080951
program_official: RANKIN, TRACY L
project_start_date: 2009-04-01
project_end_date: 2014-03-31
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 9091714
contact_pi: BARATI, MICHELLE T
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  
The candidate's overall career goal is to establish an independent research program devoted to investigating cellular mechanisms of proteinuric nephropathies with an emphasis on diabetic nephropathy (DN). Currently DN is the leading cause of end stage renal disease in the United States. Proteinuria is an independent risk factor critical to pathogenesis and progression of renal function loss. Regardless of disease origin renal tubule function is critical to the progression of renal damage and development of renal failure. The precise molecular mechanisms and targets of proteinuria and hyperglycemia causing tubule damage in DN remain unclear. This emphasizes the health-related importance for discovery of novel regulatory events as potential therapeutic targets. The endoplasmic reticulum (ER) stress response induced by accumulation of misfolded proteins in the ER is a mechanism elicited by cells to alleviate stress through induction of specific genes. Unresolved ER stress response leads to ER stress-induced apoptosis. Initial studies from our laboratory demonstrate induction of ER stress and ER stress-induced apoptosis in tubules of proteinuric diabetic mice. This suggests the hypothesis that ER stress is pathogenic in renal tubule damage in DN. This project will define the role of proteinuria and hyperglycemia alone and in combination to tubule ER stress and apoptosis in a transgenic mouse model of type I diabetes. Next cell signaling events mediating tubule ER stress and apoptosis induction in DN will be examined. To accomplish this the candidate will be trained in development of speed congenic transgenic mice. In addition the candidate will be trained in protein purification mass spectrometry and informatic techniques to define interactions in protein complexes mediating ER stress. Finally the candidate will receive training in advanced molecular biology techniques to define the specific role of proteins involved in stress response to tubule cell function. The combination of training obtained during this award coupled to the identification of molecular events mediating tubule damage in DN will enable the candidate with resources to continue and expand research pertaining to DN.  
PUBLIC HEALTH RELEVANCE: Currently DN is the leading cause of end stage renal disease in the United States. Proteinuria is an independent risk factor critical to pathogenesis and progression of renal function loss. The precise molecular mechanisms and targets of proteinuria and hyperglycemia causing tubule damage in DN remain unclear. This emphasizes the importance for discovery of novel regulatory events as potential therapeutic targets.

project_terms:
Address;Albumins;Apoptosis;Award;Calcium;Cell physiology;Cells;Coupled;Data;Defect;Development;Diabetes Mellitus;Diabetic Nephropathy;Diabetic mouse;Disease;End stage renal failure;Endoplasmic Reticulum;Event;Functional disorder;Generations;Genes;Glucose;Goals;Growth Factor;Health;Homeostasis;Hyperglycemia;Induction of Apoptosis;Informatics;Insulin-Dependent Diabetes Mellitus;Islet Cell;Kidney;Kidney Diseases;Kidney Failure;Laboratories;Lead;Lesion;Mass Spectrum Analysis;Mediating;Molecular;Molecular Biology Techniques;Molecular Chaperones;Mus;Neurodegenerative Disorders;Oxidative Stress;Pathogenesis;Permeability;Play;Process;Protein Export Pathway;Protein Synthesis Induction;Proteins;Proteinuria;Puromycin;Quality Control;Rattus;Reactive Oxygen Species;Renal function;Renal tubule structure;Research;Resources;Risk Factors;Role;Signal Transduction;Speed (motion);Stimulus;Stress;Techniques;Testing;Training;Transgenic Mice;Tubular formation;United States;biological adaptation to stress;career;congenic;cytokine;diabetic;endoplasmic reticulum stress;mouse model;neuron loss;novel;outcome forecast;programs;protein complex;protein misfolding;protein purification;public health relevance;therapeutic target


application_id: 8056232
project_number: 1R13ES019778-01
project_title: The 6th Conference on Molecular Mechanisms of Metal Toxicity and Carcinogenesis
administering_ic: NIEHS
award_notice_date: 2010-09-10
opportunity_number: PA-10-071
application_type: 1
activity_code: R13
ic: ES
serial_number: 019778
program_official: QUINN, ASHLINN KO
project_start_date: 2010-09-15
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZES1 LWJ-J (R3)]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Project Summary/Abstract. "The 6th Conference on Molecular Mechanisms of Metal Toxicity and Carcinogenesis" will be held November 14-17 2010 at Hilton Hotel downtown Lexington Kentucky. The meeting is sponsored by Markey Cancer Center and the Graduate Center for Toxicology University of Kentucky. The interdisciplinary scientific conference is an international workshop that brings together a community of scientists in the area of metal toxicity and carcinogenicity. The objectives of meeting are to coordinate exchange and disseminate information and to explore metal-induced toxicity and carcinogenicity. The focus will be mechanisms of metal-induced toxicity strategies for intervention and prevention strategies and possible translation from basic studies into clinical or public policy.  
  
PUBLIC HEALTH RELEVANCE: The "6th Conference on Molecular Mechanisms of Metal Toxicity and Carcinogenesis" will be held November 14-17 2010 at Hilton Hotel downtown Lexington Kentucky. The Conference is an international workshop that brings together a community of scientists in the area of metal toxicity and carcinogenicity. The goals of meeting ate to coordinate exchange and disseminate information and to explore metal-induced toxicity and carcinogenicity.

project_terms:
Address;Area;Cancer Center;Clinical;Collaborations;Communities;Development;Eating;Educational workshop;Funding;Goals;International;Intervention;Kentucky;Knowledge;Metals;Methodology;Methods;Minority;Molecular;Prevention strategy;Public Policy;Research;Science;Scientist;Toxic effect;Toxicology;Translations;Universities;Woman;abstracting;carcinogenesis;carcinogenicity;instrumentation;meetings;metal poisoning;novel;novel strategies;programs;public health relevance;symposium

public_health_relevance:
NARRATIVEThe "6th Conference on Molecular Mechanisms of Metal Toxicity and Carcinogenesis"will be held November 14-17 2010 at Hilton Hotel downtown Lexington Kentucky. TheConference is an international workshop that brings together a community of scientists inthe area of metal toxicity and carcinogenicity. The goals of meeting ate to coordinateexchange and disseminate information and to explore metal-induced toxicity andcarcinogenicity.


application_id: 8055946
project_number: 5P30ES014443-04
project_title: Community Outreach & Education Core
administering_ic: NIEHS
opportunity_number: RFA-ES-05-008
application_type: 5
activity_code: P30
ic: ES
serial_number: 014443
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 9003
contact_pi_person_id: 9898612
contact_pi: RAMOS, IRMA N
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Research Centers
project_abstract:
Goals and Theme of the Community Outreach Educational Core (COEC)The primary goal of the COEC will be to educate residents in the Louisville Metropolitan Area (nine counties inKentucky and four counties in Indiana) on the importance of interactions between genes environment cultureand disease. Our focus during the first four years will be the fast-growing Hispanic community of Shelbyville inShelby County Kentucky. This community consists of 4-8 thousand individuals many of which lack basicsocial and economic infrastructure support and consequently a group deficient in essential tools for promotionof a healthy community. As the Center matures and research programs are established in both the Hispanicand African American communities of Louisville the COEC will extend its educational programs to WestLouisville another disadvantaged community in close proximity to a large industrial chemical complex knownas Rubbertown. These efforts will be complementary to those of the Integrated Health Sciences Facility Core(IHSFC). As detailed in Section 7A the IHSFC will initially work with the more established and environmentallyfocused community-based organizations in West Louisville with plans to increasingly involve Hispanic-focusedorganizations as they acquire a higher level of knowledge about environmental health through the work of theCOEC. This approach will create a synergistic relationship that can significantly advance the Center's goalsand its impact.To achieve our primary goal we seek to empower the community of Shelbyville with sound medical andscientific information on the role of genes in health and disease and how environmental factors and lifestylepractices influence health outcomes. We will begin by working with existing community organizations toidentify community leaders who will be trained by COEC staff and in turn these leaders will train others in theircommunity using a well-established train-the-trainer model (Ramos I. 2003). This approach has been shownto gradually build an environmental health infrastructure that can positively impact the community and itsresidents.The ultimate goal of the COEC is to build a self-sustainable educational program that persists within the targetcommunity after the intervention is completed. Modern theorists have proposed that systems thinking can beused to tackle intractable social issues such as environmental health in depressed communities. Unlikeprevious social theories influenced by a reductionist approach to social problems (reminiscent of theapproaches used in the biomedical sciences) theories developed through systems thinking incorporate theawareness that the entry of new knowledge may lead to conflict between those who are or perceivethemselves to be at risk and those perceived as being responsible for creating or preventing that risk. Thesesocial tensions must be factored into our community outreach efforts with the expectation that application ofintegrative approaches will enhance the quality of its products of the COEC.

project_terms:
African American;Area;Awareness;Chemicals;Communities;Community Outreach;Complex;Conflict (Psychology);Core Facility;County;Depressed mood;Disadvantaged;Disease;Economics;Educational Curriculum;Educational aspects;Effectiveness;Environment;Environmental Health;Environmental Risk Factor;Evaluation;Genes;Goals;Health;Health Sciences;Health Status;Hispanics;Human Resources;Indiana;Individual;Institution;Intervention;Kentucky;Knowledge;Lead;Life Style;Medical;Modeling;Outcome;Plant Roots;Research;Research Infrastructure;Resources;Risk;Role;Science;Services;Social Problems;System;Thinking function;Trainers Training;Training;Work;base;community organizations;design;empowered;expectation;instrument;metropolitan;prevent;programs;social;sound;theories;tool


application_id: 8055945
project_number: 5P30ES014443-04
project_title: Facility Core B: Bioinformatics Biostatistics & Computational Biology
administering_ic: NIEHS
opportunity_number: RFA-ES-05-008
application_type: 5
activity_code: P30
ic: ES
serial_number: 014443
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 9002
contact_pi_person_id: 8436899
contact_pi: PARRISH, RUDOLPH SANDERS
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: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Research Centers
project_abstract:
BIOINFORMATICS BIOSTATISTICS AND COMPUTATIONAL BIOLOGY FACILITY COREA. SPECIFIC AIMSThe availability of genomic sequences from a growing number of human and model organisms has fueled anexplosion of data information and knowledge that has a clear and present impact on our ability to decipherkey genetic signals and responses in the exposure-disease continuum. This information revolution is reflectedin the public Molecular Biology Database Collection (http://nar.oupiournals.org/). which now numbers 858 [1].Consider Gene Expression Omnibus which is the principal NIH repository for high-content gene expressiondata (http://www.ncbi.nlm.nih.gov/geo/) [2]. GEO is growing by 100 samples daily to increase from 18235 inJune 2004 to 69017 samples in January 2006 (Knudsen personal observation).As the genomics repositories approach 'peda-bytes' of digital information environmental health scienceresearchers are faced with the challenge of mobilizing vast data into cogent models regarding the biology ofinformation processing in complex systems. Researchers must begin to synthesize knowledge of the unit partsof their study models into relationships and properties that are determined by function of the system as awhole. Advanced computing support databasing services data modeling and knowledge management toolsare essential for this synthesis to occur.The Bioinformatics Biostatistics and Computational Biology (BBCB) Facility Core (hereafter 'Core') willsupport Center investigators with training and services in research design data management statisticalanalysis and computational modeling relevant to environmental genomics and integrative biology. The Corewill function as an interdisciplinary hub to bring together scientific expertise in computer sciences genomicsclinical informatics bioinformatics programming statistics and mathematical modeling. Our overarching goalis to help Center investigators pursue the biology of information processing in living systems from individualpathways to increasingly complex regulatory networks. Toward this end the Core will interact with Centerpersonnel through face to face meetings a dedicated website and specialized tools and services. The SpecificAims are as follows.Aim 1: Provide Center members and Junior investigators with 'Assistance and Support' of research inthe areas of informatics biostatistics and systems modeling.Aim 2: Provide Center investigators students and fellows with 'Education and Training1 on applicationof relevant tools and methods to problems of environmental injury and disease.Aim 3: Promote 'Discovery and Collaboration' to translate research in genomics and integrativebiology into knowledge in environmental health sciences.

project_terms:
Animal Model;Area;Bioinformatics;Biological Models;Biology;Biometry;Clinical Informatics;Collaborations;Collection;Complex;Computational Biology;Computer Simulation;Core Facility;Data;Databases;Disease;Educational aspects;Environmental Health;Explosion;Face;Gene Expression;Genetic;Genomics;Goals;Human;Human Resources;Individual;Informatics;Information Resources Management;Injury;Knowledge;Methods;Modeling;Molecular Biology;Organism;Pathway interactions;Property;Research;Research Design;Research Personnel;Research Support;Sampling;Services;Signal Transduction;Students;Study models;System;Training;Translating;United States National Institutes of Health;computer science;data management;data modeling;digital;information processing;mathematical model;meetings;member;programs;repository;response;statistics;tool;web site


application_id: 8055944
project_number: 5P30ES014443-04
project_title: Facility Core A: Integrative Health Sciences
administering_ic: NIEHS
opportunity_number: RFA-ES-05-008
application_type: 5
activity_code: P30
ic: ES
serial_number: 014443
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 9001
contact_pi_person_id: 1871961
contact_pi: TOLLERUD, DAVID J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Research Centers
project_abstract:
The central goal of the Integrative Health Sciences Facility Core (IHSFC) is to provide Center investigators withservices and resources that will facilitate the translation of basic research findings into clinical or public healthapplications. The general goals of the Core are to: Provide services instrumentation and technologies that support the bench-to-bedsidetranslation of basic science findings into clinical and public health applications. Support research to improve early detection prevention and/or therapy for disorders related toenvironmental exposures. Foster partnerships between researchers and community-based organizations and healthagencies that will enhance the development and conduct of clinical and public health research. Educate Center investigators on the nature and requirements of clinical and public healthresearch including ethical legal and social implications  and provide technical support formeeting human subjects HIPAA and other human subjects research requirements. Facilitate clinical or public health-oriented pilot projects. Promote synergistic interactions with the Bioinformatics Biostatistics and ComputationalBiology (BBCB) Facility Core.

project_terms:
Basic Science;Bioinformatics;Biometry;Clinical;Communities;Computational Biology;Core Facility;Development;Disease;Early Diagnosis;Environmental Exposure;Environmental Health;Fostering;Goals;Health Insurance Portability and Accountability Act;Health Sciences;Housing;Human;Human Subject Research;Nature;Pilot Projects;Prevention;Public Health Applications Research;Research;Research Personnel;Research Project Grants;Research Support;Resources;Scientist;Services;Technology;Translations;base;bench to bedside;biomarker;ethical legal social implication;health organization;human subject;improved;instrumentation;meetings;member;public health medicine (field);public health research


application_id: 8055943
project_number: 5P30ES014443-04
project_title: Pilot Project Program
administering_ic: NIEHS
opportunity_number: RFA-ES-05-008
application_type: 5
activity_code: P30
ic: ES
serial_number: 014443
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 0003
contact_pi_person_id: 1878918
contact_pi: DARLING, DOUGLAS S
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: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Research Centers
project_abstract:
OverviewCEGIB will support a Pilot Project Program designed to encourage new and innovative research approacheswith emphasis given to creative new lines of research in environmental genomics and integrative biology. TheProgram will support short-term research projects to enable researchers to collect the data necessary to obtainfunding through governmental and private sector agencies. The primary goal for this program will be todevelop innovative ideas of importance to environmental health sciences. Emphasis will be given to support ofyoung investigators as a tool to launch their research programs and to increase collaborative opportunities withestablished environmental health investigators.\Dr. Douglas S. Darling Associate Professor in the Department of Periodontics Endodontics and DentalHygiene in the School of Dentistry will direct the Center Pilot Project. Dr. Darling is an experienced leader ininternal grant review processes having provided oversight for the Center for Genetics and MolecularMedicine's pilot project efforts for the past three years. He is respected for the high degree of integrity andconfidentiality with which he manages award determinations. He will provide 5% effort to the oversight of thePilot Project Program and service as a member of the Internal Advisory Board. Dr. Darling's researchinterests are in the regulation of gene transcription in eukaryotic cells. His laboratory investigates themolecular mechanism of action of the zfh family of transcription factors. They have isolated cDNA andgenomic clones of the Zinc Finger Homeodomain Enhancer-binding Protein (Zfhep) gene and current projectsare investigating the role of molecular interactions that underlie Zfhep and related genes in earlydevelopment.The Pilot Project Program procedures will function under the following guidelines: A Request for Proposals announcement will be distributed by the CEGIB Administrative Core toUofL investigators and laboratories via electronic and hardcopy flyer distribution and campusbulletin board postings at least 60 days prior to the date of submission. A sample Request forProposals is included with this application. Submitted proposals will be collected by the Administrative Core and forwarded to the PilotProject Committee. The Pilot Project Committee will be chaired by Dr. Douglas Darling and willconsist of four ad hoc members selected by the Center Director for their expertise andrepresentation of all Research Cores. Committee members will be screened for conflict ofinterest that might arise from one or more of the submitted proposals. The Pilot Project Committee will forward the submissions to experts in their appropriate field forexternal scientific merit review. The Committee will conduct an NIH-style review includingconsideration of the external reviews and scores. This information will be used to makerecommendations to the Center Director concerning funding. As directed by the CEGIB Director the Administrative Core staff will prepare a Letter of Awardand will establish accounting access to the awarded funds for the recipients. Projects will be funded for one year. The number and amounts awarded each year may varywith the number of meritorious proposals received and the availability of funds. At least 20%and up to the maximum allowed 25% of the direct cost budget for each year will be designatedfor the Pilot Project Program. Pilot Project recipients will be encouraged to use the CEGIBFacility Cores where they will be afforded the same incentives as CEGIB members.Each Pilot Project recipient will provide a written progress report on his or her projects and willgive an oral presentation to CEGIB members at the annual meeting of the External AdvisoryBoard. Records of the Pilot Project Program will be maintained by the CEGIB Administrative Coreincluding minutes of the Pilot Project Committee meetings reviewer comments accountingrecords written progress reports and copies of all submitted proposals and their outcomes.

project_terms:
Accounting;Award;Binding (Molecular Function);Biology;Budgets;Committee Members;Complementary DNA;Confidentiality;Conflict of Interest;Core Facility;Data;Dental Hygiene;Development;Direct Costs;Electronics;Endodontics;Environmental Health;Eukaryotic Cell;Family;Funding;Genes;Genetic;Genetic Transcription;Genomics;Goals;Grant Review Process;Guidelines;Incentives;Laboratories;Letters;Molecular Mechanisms of Action;Molecular Medicine;Oral;Outcome;Periodontic specialty;Pilot Projects;Private Sector;Procedures;Progress Reports;Published Comment;Recommendation;Records;Regulation;Request for Proposals;Research;Research Personnel;Research Project Grants;Role;Sampling;School Dentistry;Services;Writing;Zinc Fingers;design;enhancer binding protein;experience;flyer;homeodomain;innovation;interest;meetings;member;professor;programs;tool;transcription factor


application_id: 8055942
project_number: 5P30ES014443-04
project_title: Career Development of Environmental Health Investigators
administering_ic: NIEHS
opportunity_number: RFA-ES-05-008
application_type: 5
activity_code: P30
ic: ES
serial_number: 014443
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 0002
contact_pi_person_id: 1886009
contact_pi: PROUGH, RUSSELL ALLEN
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: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Research Centers
project_abstract:
CAREER DEVELOPMENTSpecific AimsThe Center's Career Development Program will provide training and mentoring for junior basic and clinicalscientists with interests in environmental health sciences with the aim of assisting them in the development ofproductive independent research careers with an emphasis in the environmental health sciences and bringingthem to full Center membership.

project_terms:
Clinical;Development;Environmental Health;Mentors;Research;Research Personnel;Scientist;Training;career;career development;interest;programs


application_id: 8055941
project_number: 5P30ES014443-04
project_title: Strategic Vision & Impact on Environmental Health
administering_ic: NIEHS
opportunity_number: RFA-ES-05-008
application_type: 5
activity_code: P30
ic: ES
serial_number: 014443
project_start_date: 2010-04-01
project_end_date: 2011-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 0001
contact_pi_person_id: 6221833
contact_pi: RAMOS, KENNETH S.
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: 2010-04-01
project_abstract:
Strategic Vision and Impact on Environmental HealthA. OverviewEnvironmental genomics focuses on the study of the gene-gene and gene-environment interactions thatmediate many of the complex diseases affecting human populations in today's world. This field combines theknowledge derived from modern human and molecular genetics with studies of mRNA protein and metaboliteprofiling to understand how genes and genetic variations interact with environmental factors to cause disease.Integrative biology is a closely related field focused on the application of systems theory to the study ofbiological behavior and pathways critical to the preservation of health or the onset and progression of disease.Advances in the fields of environmental genomics and integrative biology during the past five years have beenfueled by the need to translate molecular knowledge into concepts that impact our day-to-day lives and thatimprove the practice of environmental medicine and public health. To this end University of Louisville (UofL)researchers have implemented academic and research programs in the areas of genetics and molecularmedicine leading to the development of a strong infrastructure in DMA sequencing technologies siRNArepositories transcriptional profiling mass-spectrometry (MS)-based protein analysis and proteomics NMRandMS-based metabolomics and more recently bioinformatics.The establishment of a federally-funded Center for Environmental Genomics and Integrative Biology (CEGIB)at UofL will help environmental health researchers with the management and interpretation of data emergingfrom 'omic technologies and facilitate translation of these findings to public health and clinical practice. Fullrealization of the benefits offered by molecular understanding of gene protein and metabolite expressionprofiles the molecular circuitry that integrates the biological response to environmental injury and theidentification of novel biomarkers of disease will require strong infrastructure support in the areas ofbioinformatics biostatistics computational biology and bench-to-bedside or bench-to-community integration.In this application we seek funding to create a National Institute of Environmental Health Sciences (NIEHS)Core Center at UofL that focuses on the application of genomics and integrative biology to problems inenvironmental health. The UofL Center will promote scientific achievements that advance our molecularunderstanding of human diseases and the role of environmental factors in the pathogenesis of disorders ofcellular growth and differentiation. The thematic areas of scientific focus at UofL are environmentalcardiology environmental carcinogenesis and developmental origins of health and disease. TheseNIEHS-funded areas of scientific activity are ripe for continued expansion and will be greatly facilitated by thecentralized infrastructure promoted by CEGIB. NIEHS investments at UofL will be leveraged by outstandinginstitutional commitments to continue support of core functions in transcriptional profiling proteomics andmetabolomics and to establish clinical and epidemiological research centers. Concerted efforts over the nextfour years will be directed at the integration of disparate datasets to identify gene protein and metabolitenetworks the development of mathematical models to simulate and predict biological behavior and theestablishment of productive partnerships between basic and clinical researchers that advance researchfindings in environmental genomics from the bench to the bedside. These efforts will help UofL environmentalhealth science investigators remain competitive and at the cutting edge of biomedical research.Biological complexity is perhaps nothing more than a reflection of the complexities inherent to the naturalworld. If environmental health researchers are to sustain their impact in advancing the biomedical researchagenda in this country an integrated way of thinking that "marries" molecular biology to the higher levels ofbiological organization needs to be nurtured and cultivated among the environmental health researchcommunity. In this context it is important to recognize that systems level thinking in environmental genomicsis not restricted to biomedical questions but that it crosses over to the domains of clinical medicine and publichealth. Indeed realization of the potential of 'omic technologies will require creation of structures that supportthe research enterprise and advance translation of molecular findings to practice. The team of UofLresearchers assembled in this application can contribute in meaningful ways to this goal.

project_terms:
Achievement;Affect;Area;Behavior;Biochemical Pathway;Bioinformatics;Biological;Biological Preservation;Biology;Biomedical Research;Biometry;Cancer Grant Supplements (P30);Cardiology;Cardiovascular Diseases;Clinical;Clinical Medicine;Communities;Community Integration;Complex;Computational Biology;Country;Critical Pathways;Data;Data Set;Development;Disease;Disease Progression;Environment;Environmental Health;Environmental Medicine;Environmental Risk Factor;Epidemiology;Funding;Gene Proteins;Genes;Genetic;Genetic Crossing Over;Genomics;Goals;Health;Health Sciences;Human;Injury;Investigation;Investments;Knowledge;Life;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Messenger RNA;Molecular;Molecular Biology;Molecular Genetics;Molecular Medicine;Molecular Profiling;National Institute of Environmental Health Sciences;Pathogenesis;Population;Protein Analysis;Proteomics;Recruitment Activity;Research;Research Activity;Research Infrastructure;Research Personnel;Research Support;Role;Simulate;Small Interfering RNA;Structure;System;Systems Theory;Talents;Technology;Thinking function;Translating;Translations;Universities;Variation (Genetics);Vision;base;bench to bedside;biomarker;cell growth;clinical practice;environmental carcinogenesis;gene environment interaction;human disease;improved;innovation;mathematical model;metabolomics;novel;programs;protein metabolite;public health medicine (field);repository;response


application_id: 8055918
project_number: 5T32HL072743-08
project_title: Interdisciplinary Cardiovascular Training Program
project_terms: Cardiovascular system;Training Programs
administering_ic: NHLBI
award_notice_date: 2011-03-31
opportunity_number: PA-08-226
application_type: 5
activity_code: T32
ic: HL
serial_number: 072743
program_official: CARLSON, DREW E
project_start_date: 2004-04-01
project_end_date: 2014-04-30
study_section: NHLBI Institutional Training Mechanism Study Section[NITM]
contact_pi_person_id: 1887495
contact_pi: RANDALL, DAVID C
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This training program offers pre-doctoral trainees a breadth of exposure and a depth of expertise to acquire the essential aptitudes and tools to thrive in an aggressive cardiovascular research environment. Our specific goals are to:(a) provide rigorous state-of-the-art education in basic sciences of the cardiovascular system; (b) provide training in ethical conduct of research; (c) facilitate translational science by providing our trainees with the requisite tools and experience to compete in this arena; and (d) create future "citizens of science" by fostering an environment that promotes advocacy of research with highest ethical standards. We propose to train 5 pre-doctoral fellows and 4 Summer Minority Scholars. Our training faculty composed of 30 scientists are all extramurally funded with laboratories well suited to train young scientists and with excellent training records. The highly collaborative training faculty will implement a structured program covering the areas of cardiac hypertrophy and heart failure arrhythmogenesis central nervous control of cardiovascular function and vascular biology with a focus on mechanisms of atherosclerosis abdominal aortic aneurysms and thrombosis. This breadth of cardiovascular research opportunities for fellows is supported and enhanced by strong links to the Cardiovascular Research Center and the Gill Heart Institute. A multidisciplinary training faculty represent the combined resources of 11 academic departments in 3 Colleges and 3 Centers providing both faculty and students a rich environment within which to work and interact and opportunities for translational research. The curriculum exposes students to essential knowledge ranging from molecules to the integrated physiology of the whole organism with numerous opportunities for in-depth study of focused areas of cardiovascular function. An important feature of our program is the development of new vehicles to train fellows in techniques of translational research. Moreover our successful minority recruitment program will continue to promote diversity within our training program. Finally the University of Kentucky strategic plan targets the cardiovascular sciences for focused development optimizing the environment for the training of superbly-equipped young scientists.


