# projects

application_id: 8277565
project_number: 3R25RR023304-05S1
project_title: "TRY-IT" Translating Research to Youth through Information Technology
administering_ic: NCRR
award_notice_date: 2011-07-08
opportunity_number: PAR-06-080
application_type: 3
activity_code: R25
ic: RR
serial_number: 023304
suffix: S1
program_official: BECK, LAWRENCE A
project_start_date: 2006-09-15
project_end_date: 2014-06-30
study_section: ZRR1-SEPA-9(01)
contact_pi_person_id: 1873108
contact_pi: LEUKEFELD, CARL G
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This Science Education (SEPA) project called "TRY-IT" (Translating Research to Youth through Information Technology) is submitted by the University of Kentucky with the Explorium Science Museum to increase minority and underrepresented student knowledge and participation in biomedical science careers as well as interest in clinical research trials. The project addresses the limited opportunities for disadvantaged middle school and minority youth to learn about careers in biomedical research and clinical trials because the number of underrepresented minority students who enter biomedical sciences and go on to pursue graduate education is very small. This project focuses on helping students apply technology to better understand biomedical science. This novel approach uses interactive 3-D visualization as a "hook" or an "engagement point" so middle school students can progress to learn more about biomedical science technology and human health. This is a combined Phase I development and a Phase II dissemination application. During Phase I middle school students their teachers school counselors and parents will participate in a two-year year round science-enrichment program to increase the likelihood that participating students will consider careers in biomedical sciences. Project teams will work with the Explorium Science Museum to create traveling exhibits involving interactive 3-D models. During Phase II the curriculum and the exhibits that are developed by the student/teacher/researcher project teams will be disseminated to all middle school students in Kentucky and made available online. The specific project aims are to: (1) Increase the interest and knowledge of minority and underrepresented middle school students ages 11 to 15 in biomedical science clinical trials and scientific uses of technology; (2) Expand the biomedical science technology skills and biomedical science career knowledge of middle school teachers and counselors serving minority and underrepresented students; (3) Evaluate changes in student interest knowledge skills and changes in career paths in biomedical science; and (4) Design and distribute the "TRY-IT" curriculum which includes a technology-rich exhibit for K-12 students.

project_terms:
3-Dimensional;Academy;Address;Age;Awareness;Behavioral Sciences;Biomedical Research;Biomedical Technology;Clinical Research;Clinical Trials;Commit;Communities;County;Development;Disadvantaged;Drug abuse;Educational Curriculum;Educational aspects;Educational workshop;Exhibits;Family;Future;Gambling;Gender;Goals;Graduate Education;Health;Human;Human Biology;Imagery;Information Technology;Institutes;Institution;Instruction;Kentucky;Knowledge;Learning;Life Style;Mentors;Minority;Modeling;Museums;National Center for Research Resources;Parents;Participant;Pharmaceutical Preparations;Phase;Play;Population Scientist Supplement (R25);Professional counselor;Research;Research Personnel;Rural;School Teachers;Schools;Science;Science Enrichment;Scientist;Students;Technology;Testing;Translating;Travel;Underrepresented Minority;United States National Institutes of Health;Universities;Woman;Work;Youth;alcohol research;boys;career;design;experience;girls;interest;literacy;middle school;novel;novel strategies;programs;research study;rural area;science education;skills;success;teacher


application_id: 8274900
project_number: 5R01HL103750-02
project_title: Respiratory motor control and blood pressure regulation after spinal cord injury
administering_ic: NHLBI
award_notice_date: 2012-07-17
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 103750
program_official: LAPOSKY, AARON D
project_start_date: 2011-06-07
project_end_date: 2015-05-31
study_section: Clinical and Integrative Cardiovascular Sciences Study Section[CICS]
contact_pi_person_id: 9348839
contact_pi: OVECHKIN, ALEXANDER VLADIMIROVICH
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   Many individuals with chronic spinal cord injury (SCI) face the challenge of managing their unstable blood pressure which frequently results in persistent hypotension due to decreased cardiac output and autonomic nervous system dysfunction. In addition blood pooling in the lower body during upright posture leads to a further decrease in blood pressure known as orthostatic hypotension. These conditions severely impact the overall health of SCI individuals delay their participation in rehabilitative treatment limit the effectiveness of such treatment and significantly interfere with activities of daily living. In our clinic that utilizes activity-based therapy programs we have observed that one of the most common impediments to full participation in these programs was orthostatic hypotension. Further orthostatic intolerance increases the cost and decreases the efficacy of rehabilitative treatment. Another common impediment to rehabilitation after SCI is respiratory insufficiency due to paresis and paralysis of respiratory muscles. Physiologically these respiratory and cardiovascular dysfunctions are closely related. Data from our laboratory show that resting blood pressure correlates positively with pulmonary function outcomes and the location and severity of spinal cord lesion. These relationships could be due to better venous return to the heart as a result of higher negative intrapleural pressure and/or higher sympathetic tone due to better baroreflex response in individuals with better inspiratory and expiratory motor control. Our preliminary data showed that respiratory motor function after SCI can be improved by respiratory muscle training (RMT) a rehabilitative technique based on the breathing with resistance exercise. We observed that resting blood pressure and orthostatic tolerance were also improved after RMT in individuals with SCI. Therefore for the current proposal we hypothesize that RMT will improve blood pressure regulation in individuals with chronic SCI. We will examine the response of physiological regulatory mechanisms to RMT. Based on statistical power analysis forty five individuals who have chronic SCI will be recruited for this study over a four-year period. All subjects will have been diagnosed as having respiratory function deficits and orthostatic hypotension. We will evaluate pulmonary and cardiovascular function using spirometry respiratory muscle strength sympathetic skin response tests and surface electromyography of respiratory muscles. In addition we will use continuous beat-to-beat recording of systemic arterial blood pressure heart rate cardiac output and the measurements of blood catecholamines level during orthostatic stress test. Autonomic regulation outcomes will be calculated from beat-to-beat blood pressure and heart rate frequency composition analysis. We will also evaluate Spinal Cord Injury Independence (SCIM-III) and quality of life (CHART) measures. These outcomes will be obtained before a total of 20 RMT sessions lasting 45 minutes each / 5 days per week immediately after RMT and during 6-month follow-up period in 35 research participants forming the experimental group. Another 10 individuals serving as a control group will undergo the same procedures except the RMT intervention during the same time course. This technique as a therapeutic intervention in order to improve the blood pressure regulation and investigate its mechanisms in individuals with SCI has never been tested before. The results of this study will have direct effect on the SCI population by improving our understanding of the mechanisms of pulmonary function and blood pressure regulation and offering a pathophysiologically based rehabilitation strategy.

project_terms:
Activities of Daily Living;Affect;Area;Autonomic nervous system;Baroreflex;Blood;Blood Pressure;Breathing;Cardiac Output;Cardiovascular Physiology;Cardiovascular system;Catecholamines;Cause of Death;Chronic;Clinic;Control Groups;Data;Diagnosis;Diastolic blood pressure;Educational Intervention;Effectiveness;Electromyography;Exercise;Face;Frequencies (time pattern);Functional disorder;Goals;Health;Heart;Heart Rate;Hypotension;Individual;Injury;Laboratories;Location;Lung;Measurement;Measures;Motor;Muscle;Muscle Weakness;Neurologic;Orthostatic Hypotension;Outcome;Outcome Measure;Paralysed;Paresis;Participant;Performance;Persons;Physiological;Play;Population;Posture;Procedures;Pulmonary Function Test/Forced Expiratory Volume 1;Quality of life;Recovery;Recruitment Activity;Regulation;Rehabilitation therapy;Research;Resistance;Respiration;Respiratory Insufficiency;Respiratory Muscles;Respiratory Paralysis;Respiratory physiology;Response Latencies;Rest;Role;Secondary to;Severities;Skin;Spinal Cord Lesions;Spinal cord injury;Spirometry;Stress;Stress Tests;Surface;Techniques;Testing;Therapeutic Intervention;Time;Training;Training Technics;Venous;Vital capacity;base;blood pressure regulation;cardiopulmonary system;clinically relevant;cost;density;experience;follow-up;functional outcomes;improved;improved functioning;motor control;muscle strength;novel;novel therapeutic intervention;pressure;programs;pulmonary function;rehabilitation strategy;respiratory;response

public_health_relevance:
Spinal cord injury (SCI) is commonly associated with paralysis resulting in pulmonary and cardiovascular dysfunctions which are listed among the leading causes of death in SCI population. The overall goal of this project is use a respiratory to muscle training to enhance respiratory motor function improve blood pressure regulation and to investigate the mechanisms of such improvement in persons with chronic SCI. The results of this study will have direct effect on the SCI population by providing the opportunity to significantly improve the overall health in individuals with SCI using novel rehabilitative approaches.


application_id: 8274829
project_number: 5R01DK080874-04
project_title: Regulation of the ABCG5 ABCG8 Sterol Transporter
administering_ic: NIDDK
award_notice_date: 2012-06-06
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: 2014-05-31
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:
6. Project SummaryThe 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 diseaseelevated plasma cholesterol levels and a predilection for cholesterol synthesis rather than absorption. High-fatdiets 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 cholesterolsynthesis decreased biliary cholesterol and resistance to cholethiasis. These observations suggest that inobesity the presence or absence of a functional leptin axis profoundly impacts cholesterol metabolism withrespect to absorption synthesis and hepatobiliary transport.The central hypothesis of this proposal is that hepatic leptin signaling maintains G5G8 and prevents reductionsin hepatobiliary cholesterol transport by ER stress in diabesity. The Aims are to 1) determine the role ofhepatic leptin receptors on G5G8 abundance activity and cholesterol metabolism in vivo 2) determine the roleof ER stress on G5G8 abundance in vivo and 3) determine the molecular mechanisms for regulation of G5G8abundance by leptin ER stress and the ISR. Leptin receptors will be selectively deleted from liver and brain toassess the role of this signaling pathway on G5G8 and cholesterol metabolism in obesity. The effects of leptinER 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 leptinaxis 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 ofobesity on risk factors for cardiovascular disease.

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;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: 8274802
project_number: 5R01DK080327-05
project_title: Effects of Fish Oil on Inflammation and Metabolic Syndrome
administering_ic: NIDDK
award_notice_date: 2012-04-17
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 080327
program_official: LESCHEK, ELLEN W
project_start_date: 2008-05-01
project_end_date: 2014-04-30
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:
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 PPAR&#947; agonists also have anti-inflammatory properties. In addition to their beneficial effects on serum lipids and heart disease fish oils (&#969;-3 fatty acids) activate PPAR&#947; and demonstrate antiinflammatory 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 &#969;-3 fatty acids for 12 weeks. We will determine whether there is evidence of macrophage apoptosis in adipose tissue and we will determine whether &#969;-3 fatty acids increases the level or secretion of adiponectin. Hypothesis 2. Anti-inflammatory effects of fish oils are mediated by activation of PPAR&#947; 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 PPAR&#947; inhibitor and we will measure PPAR&#947; responses such as the secretion of HMW adiponectin and macrophage apoptosis. In addition we will determine whether &#969;-3 fatty acids induce changes in recruitment of inflammatory receptors such as toll-like receptor 4 (TLR4) and TNF&#945; 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_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;TNFRSF1A 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: 8274683
project_number: 5R01NS045103-08
project_title: Regulation of Neuronal Survival by the Rit GTPase
administering_ic: NINDS
award_notice_date: 2012-05-15
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 045103
program_official: MAMOUNAS, LAURA
project_start_date: 2003-07-01
project_end_date: 2015-05-31
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 7875195
contact_pi: ANDRES, DOUGLAS ALLEN
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): Signaling pathways that contribute to cell death/survival influence diseases including cancer and many neurodegenerative conditions. Elaborating signal transduction mechanisms that regulate these processes are thus important for understanding basic biology and for therapeutic intervention. Neurotrophins potently stimulate neuronal survival in part by activating the small GTP-binding protein Ras which functions by translating neurotrophin-initiated signals into multiple signaling pathways including PI-3 kinase/Akt and MEK/ERK to promote survival. In the initial funding period it was proposed that a novel and evolutionarily conserved group of Ras-related GTPases including two mammalian proteins (Rit and Rin) and a single Drosophila ortholog (Ric) play critical roles in regulating apoptotic signaling. From this work it is now clear that both Rit and Ric promote neuronal survival in a manner distinct from that of Ras. The original hypothesis is now expanded to address how these anti-apoptotic signaling cascades are regulated. The central hypothesis of this proposal is that the Rit GTPase functions as a molecular switch in neurons responding to both apoptotic stresses and neurotrophin-initiated signals to activate a distinct pro-survival signaling cascade that relies upon p38 MAP kinase signaling. Three specific aims are proposed: Aim 1 will characterize the ability of activated Rit to promote neuronal survival. In particular we will assess the ability of Rit signaling to protect neurons from trophic factor-withdrawal mediated apoptosis. Using primary neurons from two transgenic mouse models either expressing activated Rit specifically in neurons or a homozygous Rit knockout mouse (developed during the previous period) it is now possible to analyze these critical issues. In addition microarray analysis will be used to catalog the neuronal transcriptional program regulated by Rit signaling. Aim 2 will determine the regulatory mechanism that couples NGF-stimulated TrkA to Rit activation and the nature of Rit-dependent regulation of the p38 MAP kinase cascade. Aim 3 will explore the critical signaling pathways utilized for Rit anti-apoptotic signaling. In particular Rit-mediated activation of both the p38- MSK1/2 kinase cascade and CREB transcriptional pathways appear to play central roles and will be tested using a combination of both cell model systems and primary neurons. Importantly data developed since the previous review suggests that a second novel Rit-p38-HSP27-MK2 pathway may stimulate AKT signaling to afford neuronal protection. In summary these studies will establish a role for Rit in neuronal survival. Regulation of this novel Ras-related G-protein may have a pronounced impact on neuronal physiology and would make Rit and its effectors potential targets for the development of new therapeutic strategies. PUBLIC HEALTH RELEVANCE: The death of neurons causes or contributes to various neurodegenerative disorders including stroke epilepsy Parkinson's disease Huntington's disease and Alzheimer's disease. Importantly we have discovered a protein that promotes neuronal survival protecting neurons from potentially lethal stimuli. Understanding the mechanism that foster neuronal survival is of fundamental importance to the development of treatment strategies for these disorders. Thus the goal of this research is to speed progress toward therapeutic exploitation of this protein in neurodegenerative disease.

project_terms:
1-Phosphatidylinositol 3-Kinase;Address;Alzheimer's Disease;Apoptosis;Apoptotic;Biochemical;Biological;Biological Models;Biology;CREB1 gene;Cataloging;Catalogs;Cell Death;Cell Survival;Cell model;Cells;Cellular Stress;Cessation of life;Complex;Couples;Coupling;DNA Microarray Chip;Data;Development;Disease;Dominant-Negative Mutation;Drosophila genus;Epilepsy;Family;Family member;Fostering;Funding;GTP-Binding Proteins;Gene Expression;Genes;Genetic Transcription;Goals;Guanosine Triphosphate Phosphohydrolases;HSPB1 gene;Health;Hippocampus (Brain);Human;Huntington Disease;Injury;Knock-out;Knockout Mice;Ligands;MAP Kinase Modules;MAPK14 gene;MAPK8 gene;MEKs;Malignant Neoplasms;Mediating;Microarray Analysis;Molecular;Nature;Nerve Degeneration;Nervous system structure;Neurodegenerative Disorders;Neuronal Differentiation;Neurons;Orthologous Gene;Parkinson Disease;Pathway interactions;Pheochromocytoma;Phosphotransferases;Physiological;Physiology;Play;Process;Proteins;Proto-Oncogene Proteins c-akt;RPS6KA5 gene;Reactive Oxygen Species;Recovery;Recruitment Activity;Regulation;Research;Role;Signal Pathway;Signal Transduction;Site;Son of Sevenless Proteins;Speed (motion);Stimulus;Stress;Structure of superior cervical ganglion;Testing;Therapeutic;Therapeutic Intervention;Transducers;Transgenic Mice;Transgenic Organisms;Translating;Withdrawal;Work;biological adaptation to stress;cell growth regulation;extracellular;in vivo;inhibitor/antagonist;insight;mitogen-activated protein kinase p38;mouse model;neuronal survival;neurotrophic factor;novel;novel therapeutics;programs;ras-Related G-Proteins;repaired;response;stroke;treatment strategy

public_health_relevance:
The death of neurons causes or contributes to various neurodegenerative disorders including stroke epilepsyParkinson's disease Huntington's disease and Alzheimer's disease. Importantly we have discovered aprotein that promotes neuronal survival protecting neurons from potentially lethal stimuli. Understanding themechanism that foster neuronal survival is of fundamental importance to the development of treatmentstrategies for these disorders. Thus the goal of this research is to speed progress toward therapeuticexploitation of this protein in neurodegenerative disease.


application_id: 8273992
project_number: 1R01ES021502-01
project_title: FRESH: Dual Home Screening for Lung Cancer Prevention
administering_ic: NIEHS
award_notice_date: 2012-08-25
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: ES
serial_number: 021502
program_official: BOYLES, ABEE
project_start_date: 2012-09-01
project_end_date: 2017-05-31
study_section: Psychosocial Risk and Disease Prevention Study Section[PRDP]
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN J
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    
The purposes of this randomized controlled trial are to test the effectiveness of Freedom from Radon Exposure and Smoking in the Home (FRESH) a dual home screening and tailored environmental feedback intervention designed to reduce environmental risks for lung cancer and to identify factors associated with monetary incentives for radon mitigation. The combination of firsthand smoke secondhand smoke (SHS) and radon exposure increases the risk of lung cancer nearly tenfold. The long-term goals are to foster environmental justice by reducing home exposure to radon and SHS and to promote equity in radon mitigation by policy change to provide tax credits. A randomized controlled trial enrolling 550 primary care patients will test four hypotheses controlling for contextual factors of age gender home smoking and socioeconomic status (SES): 1) Those who receive FRESH will be more likely to take action to test and mitigate for radon and institute and enforce a smoke-free home policy compared to the control group; 2) Those receiving FRESH will have lower radon and home SHS levels at 15 months post-intervention compared to the control group; 3) Those who receive FRESH will have greater increases in perceived risk of lung cancer and synergistic risk perception (SHS x radon) health-related self-concept readiness to change and self-efficacy to prevent lung cancer and a greater decrease in lung cancer worry compared to controls at 15 months post-intervention; and 4) Those with at least one smoker in the home will be less likely to take action to reduce exposure to radon and SHS. The Treatment group (n = 275) will receive free test kits in the primary care clinic to measure their homes for radon and SHS at baseline receive their test results and the tailored environmental feedback intervention and take part in baseline and three follow up online surveys and home testing 15 months post-intervention. Those with high radon will receive a voucher for 30% of the cost up to $600 for radon mitigation. The Control group (n = 275) will receive information on how to request test kits for radon and SHS and a brochure on radon and SHS and take part in all study surveys. Participants in both groups will be asked to test their homes for radon and SHS 15 months post-intervention. Project   
   
The proposal is directly relevant to public health in that it has the potential to prevent lung cancer by reducing exposure to radon and secondhand smoke in the home.

project_terms:
Address;Adopted;Adoption;Age;Area;Behavior;Clinic;Clinical;Control Groups;Counseling;Effectiveness;Enrollment;Environmental Risk Factor;Environmental Tobacco Smoke;Event;Exposure to;Feedback;Fostering;Freedom;Gender;Goals;Government;Health;Home environment;Housing;Incentives;Institutes;Intervention;Malignant neoplasm of lung;Measures;Modeling;Non-smoker;Pamphlets;Participant;Patients;Policies;Preventive;Primary Health Care;Process;Psychosocial Factor;Radon;Randomized Controlled Trials;Readiness;Research;Risk;Risk Factors;Safety;Screening for Lung Cancer;Screening procedure;Secondary Prevention;Self Concept;Self Efficacy;Services;Simulate;Smoke;Smoker;Smoking;Socioeconomic Status;Staging;Surveys;Taxes;Test Result;Testing;Tobacco Use Cessation;Tobacco smoke;base;behavior change;cancer diagnosis;contextual factors;cost;environmental justice;follow-up;heuristics;high risk;innovation;intervention effect;lung cancer prevention;neglect;post intervention;prevent;prospective;public health medicine (field);remediation;risk perception;therapy design;voucher


application_id: 8271271
project_number: 5R01DE019243-05
project_title: Mathematical Model of Parotid Acinar Differentiation
administering_ic: NIDCR
award_notice_date: 2012-05-10
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: 2014-05-31
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:
Abstract.The long term goal of the proposed project is to define the development of signaling networks that inducedifferentiation of cells into mature salivary serous acinar cells to allow gene therapy approaches toregenerating or replacing salivary tissue in patients. Millions of patients suffer loss of salivary gland functiondue to Sjogren's syndrome or radiation therapy. Understanding the differentiation of salivary cells is anecessary step to enable the restoration of diseased or destroyed parotid salivary tissue. Previous work hasdescribed terminal differentiation of acinar cells histologically and by characterizing the expression of markersof differentiation but has not used genomics-level approaches or mathematical models to define regulatorypathways. The primary goal of the current application is to develop formal mathematical and statistical modelsthat will identify networks which cause terminal differentiation of parotid acinar cells. The dynamicalmathematical models will serve to generate hypotheses which will be tested and the model will be repeatedlyrefined by the incorporation of new data. This proposal is responsive to the RFA "A Systems Approach toSalivary Gland Biology." Our overall hypothesis for these studies is that a mathematical model can identifykey regulatory pathways that control parotid acinar cell differentiation. Specific Aim #1 will use Laser CaptureMicrodissection (LCM) to obtain RNA from embryonic and newborn rat parotid acinar cells for microarrayanalysis of the patterns of gene expression across the period of differentiation. A coupled Ordinary DifferentialEquation (ODE) model will be created to describe the hypothetical interactions that direct the process ofdifferentiation. The hypotheses will be tested and the ODE model refined by a combination of RT-PCR IHCand western blots. Since microRNAs are important regulators of development Specific Aim #2 will define theexpression of microRNAs in acinar cells and the pattern of changes during differentiation. There are currentlyno publications describing microRNAs in the parotid. The results will be used to revise the mathematical modelof differentiation. Specific Aim #3 will create a statistical algorithm to validate and revise the ODE model bydefining the sources of bias and variation as well as by assessing the model's predictive power overall and inits various sub-modules. This will allow confidence intervals to be associated with different pathways within theODE model. Specific Aim #4 will use the ODE model to make hypotheses about specific pathways regulatinggene expression in the parotid acinar cells. These hypotheses will be tested by transfection and transductionexperiments and the results shall be used to refine and validate the mathematical model. This systems biologyapproach 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 ofcells into secretory salivary acinar cells. This addresses the needs of millions of Americans who suffer fromsalivary gland dysfunction due to Sjgren's Syndrome radiation therapy or xerostomia due to essentialmedications. This research is a necessary foundation for developing new technologies such as gene transfertherapy 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 Expression Profile;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;System;Systems Biology;Testing;Time;Tissues;Transfection;Validation;Variant;Western Blotting;Work;Xerostomia;abstracting;cell type;expectation;gene therapy;laser capture microdissection;mathematical model;new technology;parotid cell;predictive modeling;prototype;research study;restoration;salivary acinar cell;salivary cell;transcription factor


application_id: 8270641
project_number: 5R01AR055974-04
project_title: Respiratory Muscle Weakness in Chronic Inflammation
administering_ic: NIAMS
award_notice_date: 2012-03-19
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AR
serial_number: 055974
program_official: NUCKOLLS, GLEN H
project_start_date: 2009-04-01
project_end_date: 2014-02-28
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1869134
contact_pi: REID, MICHAEL B
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The long-term goal of this project is to identify therapies that will preserve diaphragm function in chronic inflammatory conditions including heart failure and chronic obstructive pulmonary disease. Our current focus is loss of specific force in diaphragm which promotes exercise intolerance breathlessness and respiratory failure. A promising therapeutic target is tumor necrosis factor (TNF). TNF serum levels are elevated in chronic disease correlate with muscle weakness and are a predictor of morbidity and mortality. TNF depresses contractile function of diaphragm and stimulates oxidant production by diaphragm muscle fibers. The oxidants appear to cause weakness since interventions that limit oxidant activity prevent loss of force. Our central hypothesis is that respiratory muscle function can be preserved in chronic inflammatory disease by inhibiting TNF receptor-mediated effects on diaphragm muscle fibers. This project will define signaling events and redox mechanisms by which TNF depresses force and will evaluate pharmacologic and genetic interventions to preserve diaphragm function. We also will evaluate pathophysiologic relevance defining the role of TNF in a mouse model of disease and testing the capacity of clinical therapeutic agents to preserve diaphragm function. The project addresses three specific aims: Aim 1. To evaluate sphingolipid signaling as an early post-receptor mechanism by which TNF/TNFR1 stimulates oxidant activity and weakness. Cell culture studies will assess sphingomyelinase activation and ceramide-sensitive signaling events downstream of the TNF receptor subtype 1. Aim 2. To assess the source composition and post-translational target of oxidants that mediate TNF-stimulated weakness. Diaphragm fiber bundles and isolated mitochondria will be used to define ROS and NO contributions via redox assays and pharmacologic and genetic tools. Aim 3. To test TNF signaling as a contributor to respiratory muscle weakness in heart failure and a potential target for therapy. An animal model of heart failure will be used to define the diaphragm response to chronic inflammation to test TNF as a systemic mediator and to evaluate potential therapies that are approved for use in humans. PUBLIC HEALTH RELEVANCE: Chronic inflammatory diseases including heart failure and emphysema weaken the muscles used for breathing. This promotes the debilitating sensation of breathlessness decreases exercise tolerance and can lead to respiratory failure. The goal of this project is to identify new therapies that preserve respiratory muscle function in order to lessen illness and prolong life.

project_terms:
Address;Animal Model;Animals;Antioxidants;Arachidonic Acids;Area;Binding (Molecular Function);Biological Assay;Breathing;Calcium;Cardiovascular Diseases;Cell Culture Techniques;Ceramides;Chronic;Chronic Disease;Chronic Obstructive Airway Disease;Clinical;Complement;Data;Depressed mood;Diaphragm (Anatomy);Disease;Dyspnea;Esthesia;Event;Exercise;Exercise Tolerance;Extracellular Signal Regulated Kinases;Fiber;Functional disorder;Genetic;Goals;Health;Heart failure;Hour;Human;Inflammation;Inflammatory;Intervention;Lead;Life;Ligand Binding;Link;MAPK3 gene;Mediating;Mediator of activation protein;Microfilaments;Mitochondria;Morbidity - disease rate;Mortality Vital Statistics;Muscle;Muscle Fibers;Muscle Weakness;Muscle function;Neurons;Nitric Oxide Synthase;Oxidants;Oxidation-Reduction;Pathway interactions;Patients;Peroxonitrite;Phospholipase;Phospholipase A2;Phosphotransferases;Physiologic intraventricular pressure;Post-Translational Protein Processing;Production;Protein Isoforms;Protein Kinase;Proteins;Publishing;Pulmonary Emphysema;Reactive Oxygen Species;Research;Respiratory Failure;Respiratory Muscles;Role;Serum;Signal Transduction;Source;Sphingolipids;Sphingomyelinase;Symptoms;Testing;Therapeutic Agents;Tumor Necrosis Factor Receptor;Tumor Necrosis Factor-alpha;Work;drug development;gene therapy;mouse model;muscle strength;novel;premature;pressure;prevent;receptor;research study;response;therapeutic target;tool

public_health_relevance:
NARRATIVEChronic inflammatory diseases including heart failure and emphysema weakenthe muscles used for breathing. This promotes the debilitating sensation ofbreathlessness decreases exercise tolerance and can lead to respiratory failure.The goal of this project is to identify new therapies that preserve respiratorymuscle function in order to lessen illness and prolong life.


application_id: 8270372
project_number: 5R01DE019826-03
project_title: Tobacco-induced alterations to P. gingivalis-host interactions
administering_ic: NIDCR
award_notice_date: 2012-04-16
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.

project_terms:
Anabolism;Antibodies;Antigens;Area;Back;Bacteria;Bacterial Proteins;Cells;Cellular Structures;Characteristics;Chronic;Chronic Obstructive Airway Disease;Clinical;Communicable Diseases;Conditioned Culture Media;Coronary Arteriosclerosis;Cytokine Suppression;Data;Dental;Diabetes Mellitus;Disease;Economic Burden;Exhibits;Exposure to;Foundations;Future;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Genes;Genome;Genomics;Goals;Gram-Negative Anaerobic Bacteria;Health Care Costs;Human;IS Elements;Immune;Immune response;Immune system;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Investigation;Lipid A;Lung diseases;Membrane;Membrane Proteins;Microarray Analysis;Microbial Biofilms;Modeling;Molecular;Non-smoker;Operon;Organism;Pathogenesis;Patients;Periodontitis;Persons;Phenotype;Physiological;Play;Pneumonia;Polysaccharides;Population;Porphyromonas gingivalis;Predisposition;Proteins;Refractory;Relative (related person);Reporter Genes;Risk;Rodent Model;Role;Severities;Smoke;Smoker;Smoking;Specificity;Stress;Structure;Surface;Systemic disease;TNF gene;Testing;Tissues;Tobacco;Tobacco smoke;Tooth structure;Transcript;Transposase;United States;Vascular Diseases;Virulence;capsule (pharmacologic);cigarette smoke;cigarette smoke-induced;fimbria;in vivo;insight;microbial;monocyte;neutrophil;novel;pathogen;public health relevance;response;stroke;tobacco exposure;trait

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: 8269733
project_number: 5R01NS064247-03
project_title: Modulation of CNS Proinflammatory Cytokine Production
administering_ic: NINDS
award_notice_date: 2012-06-14
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 064247
program_official: CORRIVEAU, RODERICK A
project_start_date: 2010-07-01
project_end_date: 2014-06-30
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The serine/threonine protein kinase p381 MAPK is an established therapeutic target for a number of peripheral inflammatory diseases where increased proinflammatory cytokine production contributes to pathology. In contrast much less is known about the in vivo role of p381 MAPK in CNS dysfunction and its potential as a therapeutic target. Specifically little information is available on the quantitative contribution of microglial p381 MAPK signaling in vivo to up-regulation of proinflammatory molecules that lead to disease- relevant neuropathology the importance of p381 MAPK in the beneficial reparative and remodeling responses of activated microglia or the role of neuronal p381 MAPK in CNS dysfunction responses. We hypothesize that p381 (and not the closely related p382 MAPK isoform) is a key in vivo contributor to microglial inflammatory activation cascades that culminate in detrimental proinflammatory cytokine overproduction and subsequent neuronal/synaptic damage and that suppression of p38 MAPK signaling in the microglia and/or neuron can lead to selective beneficial outcomes. The field has been limited in its ability to pursue these questions because of the lack of CNS-penetrant selective small molecule p381 MAPK inhibitors. Our development of a novel orally bioavailable brain-penetrant selective small molecule p381 MAPK inhibitor (compound 069A) that attenuates hippocampal proinflammatory cytokine overproduction and leads to improved neurologic outcomes in a mouse CNS injury model now provides the opportunity to address these critical questions about p38 MAPK and CNS dysfunction in vivo as well as in vitro or in situ. We will use this unique chemical biology tool and novel knock-out (KO) and drug-resistant knock-in (KI) mice to pursue several important mechanistic investigations. First we will test the importance of p381 MAPK and p382 MAPK in vivo through the use of microglial p381 conditional KO and p382 global KO mouse models subjected to stressor stimuli. The temporal onset and profile of microglial activation and synaptic dysfunction responses will be determined. Second we will complement these in vivo studies by using cell culture models in order to explore in more detail the relative contributions of p38 MAPK isoforms in microglia and neurons. We will utilize microglial-neuronal co-cultures combined with pharmacological and genetic knock-down approaches to determine the importance of microglial and neuronal p38 MAPK isoforms to stressor-induced responses. Successful completion of this project will provide mechanistic insight into the role of the key regulatory protein p381 MAPK in microglial activation and neuronal damage caused by stressors that induce CNS pathophysiology and the contribution of microglial vs. neuronal p381 MAPK to the CNS dysfunction responses. In addition the studies will elucidate the potential role of the highly related p38 MAPK isoform p382 in the microglial and neuronal responses. Longer term the knowledge generated by the proposed studies will provide a firmer foundation for future development of new classes of disease-modifying therapeutics and fuller interpretation of disease progression investigations.    PUBLIC HEALTH RELEVANCE: Successful completion of this project will provide mechanistic insight into how the key regulatory protein p381 MAPK is involved in brain pro-inflammatory responses and CNS dysfunction caused by disease- relevant stressors. In addition the results will delineate the relative importance of microglial versus neuronal p381 MAPK and p382 MAPK to the disease-relevant pathological responses. Longer term the insights and knowledge generated by the proposed studies will provide a firmer foundation for future development of new classes of disease-modifying therapeutics and fuller interpretation of disease progression investigations.

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

public_health_relevance:
PROJECT NARRATIVE Successful completion of this project will provide mechanistic insight into how the key regulatoryprotein p38 MAPK is involved in brain pro-inflammatory responses and CNS dysfunction caused by disease-relevant stressors. In addition the results will delineate the relative importance of microglial versus neuronalp38 MAPK and p38 MAPK to the disease-relevant pathological responses. Longer term the insights andknowledge generated by the proposed studies will provide a firmer foundation for future development of newclasses of disease-modifying therapeutics and fuller interpretation of disease progression investigations.


application_id: 8269571
project_number: 5R01DE017921-03
project_title: Role of JAK2 in Innate Immunity
administering_ic: NIDCR
award_notice_date: 2012-04-12
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DE
serial_number: 017921
program_official: BURGOON, PENNY W
project_start_date: 2010-06-23
project_end_date: 2014-05-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: 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): Porphyromonas gingivalis is considered to be one of the major etiologic agents of periodontal diseases. Studies assessing the host inflammatory response to P. gingivalis have demonstrated that the innate immune receptors TLR2 and TLR4 are the major TLRs involved in the recognition of both the LPS and various pathogen associated molecular patterns isolated from P. gingivalis. However as demonstrated from both in vitro and in vivo studies TLR2 has been documented to be the predominant TLR involved in regulating the innate immune response to the whole bacterium of P. gingivalis. Studies have shown that the absence of TLR2 results in abrogated or suppressed host inflammation enhanced bacterial clearance and attenuated bone loss. Thus the TLR2-mediated inflammatory response induced by P. gingivalis appears to be critical for its ability to exacerbate the disease process. Due to the primary importance of TLR2 in mediating the inflammatory response to whole-cell P. gingivalis we focused on the intracellular signaling pathways activated by TLR2 and have subsequently identified that the Janus Kinase 2 (JAK2) plays an essential role in controlling the innate inflammatory response. Our specific hypothesis is that JAK2 is a central kinase controlling TLR2- mediated inflammation by P. gingivalis-stimulated innate immune cells and thus plays an essential role in the disease process. This hypothesis is based on: 1) stimulation of innate immune cells [human gingival epithelial cells (EC) dendritic cells (DC) and macrophages] with P. gingivalis resulted in the TLR2-dependent activation of JAK2 and inhibition of JAK2 attenuated the inflammatory response; (2) stimulation of innate immune cells with P. gingivalis resulted in the association of activated JAK2 with the cytosolic domain of TLR2; (3) immunoprecipitation of TLR2 from P. gingivalis-stimulated cells demonstrated the association of JAK members JAK2 JAK3 and TYK2 with TLR2; (4) inhibition of JAK2 resulted in the loss of P. gingivalis-mediated tyrosine phosphorylation of TLR2 and loss of JAK2 JAK3 and TYK2 recruitment to TLR2; (5) inhibition of JAK2 resulted in the abrogated activation of the NF-:B p65 signaling pathway; (6) JAK2 was activated in mice challenged with P. gingivalis; and (7) in vivo inhibition of JAK2 abrogated the host inflammatory response in mice challenged with P. gingivalis. These preliminary findings are the first to characterize a functional cell- signaling pathway for JAK2 in regulating TLR2-mediated innate immune responses including how JAKs are activated and recruited to TLR2 and have identified that the ability of TLR2 to activate/recruit JAKs to TLR2 is a fundamental process involved in the inflammatory response to P. gingivalis. The Specific Aims will define the functional role the JAK2 pathway plays in regulating the host inflammatory response to P. gingivalis and assess the importance of targeting JAK2 in vivo by determining how JAK2 inhibition affects the ability of P. gingivalis to induce host inflammation and bone loss in a mouse model.    PUBLIC HEALTH RELEVANCE:  Periodontitis is a chronic inflammatory disease. The host's immune response has been shown to play a fundamental role in the disease process by controlling the inflammatory response. Thus defining and characterizing the how the host controls the inflammatory response is critical for identifying potential therapeutic interventions.

project_terms:
1-Phosphatidylinositol 3-Kinase;Abscess;Acetylcysteine;Affect;Agonist;Alveolar Bone Loss;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Attenuated;Bacteria;Cell Nucleus;Cell surface;Cells;Chronic;Connective Tissue;Data;Dendritic Cells;Disease;Epithelial Cells;Event;Family;Family member;Gene Expression;Generations;Gingiva;Gram-Negative Anaerobic Bacteria;Host Defense;Human;Immune;Immune response;Immune system;Immunologic Receptors;Immunoprecipitation;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Invaded;JAK3 gene;Janus kinase 2;Life;Mediating;Modeling;Molecular;Mus;Natural Immunity;Nature;Pathogenesis;Pathway interactions;Pattern;Periodontal Diseases;Periodontitis;Phosphorylation;Phosphotransferases;Play;Porphyromonas gingivalis;Process;Production;Reactive Oxygen Species;Receptor Activation;Recruitment Activity;Role;Severity of illness;Signal Pathway;Signal Transduction;Signaling Molecule;TLR2 gene;TLR4 gene;TYK2;Therapeutic;Therapeutic Intervention;Toll-like receptors;Tooth structure;Tyrosine Phosphorylation;base;bone loss;cytokine;in vivo;macrophage;member;microbial;microorganism interaction;mouse model;p65;pathogen;prevent;public health relevance;receptor

public_health_relevance:
Project NarrativePeriodontitis is a chronic inflammatory disease. The host's immune response has beenshown to play a fundamental role in the disease process by controlling the inflammatoryresponse. Thus defining and characterizing the how the host controls the inflammatoryresponse is critical for identifying potential therapeutic interventions.


application_id: 8269567
project_number: 5R01DE012505-15
project_title: Molecular Aspects of Oral Plaque Formation
administering_ic: NIDCR
award_notice_date: 2012-02-20
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DE
serial_number: 012505
program_official: LUNSFORD, DWAYNE
project_start_date: 1998-09-01
project_end_date: 2013-05-01
study_section: Special Emphasis Panel[ZRG1-MOSS-E(02)M]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
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): Dental plaque develops as a complex multispecies biofilm on the tooth surface and is a direct precursor of periodontal diseases one of the most common bacterial infections of humans. The general principles of plaque biofilm development and transition from a commensal to a pathogenic entity are established. Pioneer colonizers such as oral streptococci first attach and accumulated on the tooth surface. Through a variety of adhesive signaling and physiologic interactions these early colonizers then foster the colonization of later arrivals including potential pathogens such as P. gingivalis. Our ongoing studies address the stage of biofilm development involving initial attachment of planktonic cells of P. gingivalis to a substratum of S. gordonii transition of P. gingivalis to a biofilm lifestyle and development of an architecturally distinct heterotypic biofilm. Adhesion of P. gingivalis to S. gordonii is mediated by the long and short fimbriae of P. gingivalis that interact with streptococcal GAPDH and Ssp surface proteins. Within SspB the amino acids in an adhesive domain spanning residues 1167-1193 designated BAR dictate binding activity and specificity. The interaction of SspB with the short fimbrial subunit protein Mfa induces a distinct transcriptional profile within P. gingivalis that provides the impetus for subsequent accumulation of a mixed species biofilm. One such regulated gene ptpA encodes a tyrosine phosphatase that participates in a control mechanism to optimize the size of the heterotypic biofilm community. Longer term adaptation to the community lifestyle causes P. gingivalis to downregulate expression of Mfa. The objectives of this application are to characterize the SspB-Mfa interacting interface; to define the role of the P. gingivalis tyrosine phosphatase PtpA in regulatory networks that control heterotypic biofilm development with S. gordonii; and to characterize the transcriptional regulation of mfa expression. We shall utilize global approaches such as transcriptomics and proteomics in combination with targeted approaches such as site specific mutagenesis protein-protein and protein-DNA binding assays to define and dissect the functions of individual biofilm effector molecules and to reveal the hierarchical network structure that controls heterotypic biofilm development. Public Health Significance: Of relevance to public health is the potential to translate this knowledge into the development of toothpastes or mouthrinses that contain inhibitors of the process of P. gingivalis build-up on the teeth. These would reduce the ability of P. gingivalis to persist in the mouth and consequently prevent or reduce the severity of gum disease caused by this organism.

project_terms:
Address;Adherence (attribute);Adhesions;Adhesives;Amino Acids;Anaerobic Bacteria;Bacteria;Bacterial Adhesins;Bacterial Infections;Binding (Molecular Function);Biological Assay;Cell Communication;Cells;Characteristics;Communication;Communities;Community Developments;Complex;DNA-Binding Proteins;Dental Plaque;Detection;Development;Disease;Down-Regulation;Electrostatics;Event;Family;Fostering;Genes;Goals;Human;Individual;Knowledge;Life Style;Mediating;Membrane Proteins;Microbial Biofilms;Minor;Molecular;Oral cavity;Organism;Peptides;Periodontal Diseases;Physiological;Porphyromonas gingivalis;Process;Property;Protein Subunits;Protein Tyrosine Phosphatase;Proteins;Proteomics;Role;Severities;Shapes;Signal Pathway;Signal Transduction;Signaling Molecule;Site-Directed Mutagenesis;Social Behavior;Specificity;Staging;Stimulus;Streptococcus gordonii;Structure;Surface;System;Therapeutic;Therapeutic Intervention;Tooth structure;Toothpaste;Transcriptional Regulation;Translating;base;fimbria;inhibitor/antagonist;microbial community;oral plaque;oral streptococci;pathogen;prevent;public health medicine (field);receptor;tooth surface;transcriptomics


application_id: 8268929
project_number: 5R37DE011111-19
project_title: P.gingivalis Interactions with Gingival Epithelial Cells
administering_ic: NIDCR
award_notice_date: 2011-12-12
opportunity_number: PA-07-070
application_type: 5
activity_code: R37
ic: DE
serial_number: 011111
program_official: LUNSFORD, DWAYNE
project_start_date: 1995-04-01
project_end_date: 2013-12-31
study_section: Special Emphasis Panel[ZRG1-MOSS-B(02)M]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
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 PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Periodontal diseases are one of the most common bacterial infections of humans and impose a significant burden on the health care system. One of the predominant pathogens in periodontal disease is the gram- negative anaerobe P. gingivalis. However P. gingivalis can also inhabit the oral cavity in the absence of overt disease and can participate in a balanced interaction with host cells. Epithelial cells that line the gingival crevice function both as a physical barrier and as sensors of microbial colonization. The outcome of the interaction between P. gingivalis and gingival epithelial cells therefore makes a significant contribution to the degree of equilibrium between host and microbe and to overall gingival health status. P. gingivalis can manipulate epithelial cell signal transduction pathways in order to direct entry into the host cell and to reprogram host innate immunity. One of the effector molecules of P. gingivalis is the HAD family serine phosphatase SerB. The goal of this proposal is to define the mechanism of action of SerB as it relates to uptake of the organism by gingival epithelial cells and modulation of innate immunity. Firstly the ability of SerB to dephosphorylate and activate cofilin will be examined. Cofilin regulates actin dynamics through mediating the disassembly of actin filaments and our hypothesis is that activation of cofilin by SerB is required for P. gingivalis entry. This will be tested through up and down regulation of cofilin activity by siRNA and transfections with activation-altered cofilin. Secondly we shall determine the signaling pathways modulated by SerB that converge on suppression of the chemokine IL-8. The participation of MEK and NF-?B will be investigated by blotting mobility shift assays and dominant positive and negative mutations. Finally we shall characterize the interconnectivity between SerB-induced cytoskeletal signaling and IL-8 suppression by manipulation of actin filament structure and MEK activation status. These studies will provide a detailed molecular analysis of the targeting of host signal transduction by a specific effector phosphatase of P. gingivalis. Ultimately the knowledge gained could be developed into strategies that could be utilized to intervene in the P. gingivalis-epithelial cell interaction to ensure that the outcome is non-harmful to the host. PUBLIC HEALTH RELEVANCE: P. gingivalis is a cause of periodontal diseases that afflict millions of Americans. In this study we will examine the interactions between P. gingivalis and the human cells that are colonized by the organism. The information to be gathered could be used to identify targets for novel therapeutic agents designed to interfere with the colonization and survival strategies of P. gingivalis.

project_terms:
Actins;Address;American;Anaerobic Bacteria;Architecture;Bacteria;Bacterial Infections;Cell Communication;Cell Line;Cells;Choline phosphatase;Disease;Down-Regulation;Effector Cell;Electrophoretic Mobility Shift Assay;Ensure;Environment;Enzymes;Epithelial;Epithelial Cells;Equilibrium;Family;Genes;Genetic Transcription;Gingiva;Goals;Health;Health Status;Healthcare Systems;Human;IL8 gene;Immune;Immune response;Immunologic Surveillance;Intercept;Knowledge;MAP Kinase Signaling Pathways;MEKs;Mediating;Microbe;Microfilaments;Molecular;Molecular Analysis;Mucous Membrane;Mutation;Natural Immunity;Oral cavity;Organism;Outcome;Periodontal Diseases;Periodontium;Phosphoric Monoester Hydrolases;Physiological;Porphyromonas gingivalis;Process;Production;Protein Dephosphorylation;Role;Serine;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Small Interfering RNA;Structure;Surface;System;Testing;Therapeutic Agents;Tissues;Transfection;Up-Regulation (Physiology);actin depolymerizing factor;adverse outcome;chemokine;cofilin;design;haloacid dehalogenase;insight;microbial colonization;microorganism;novel;pathogen;prevent;sensor;uptake

public_health_relevance:
P. gingivalis is a cause of periodontal diseases that afflict millions of Americans. In this study we will examinethe interactions between P. gingivalis and the human cells that are colonized by the organism. The informationto be gathered could be used to identify targets for novel therapeutic agents designed to interfere with thecolonization and survival strategies of P. gingivalis.


application_id: 8268680
project_number: 1R03DE022538-01
project_title: NOVEL STATISTICAL MODELS FOR DENTAL CARIES
administering_ic: NIDCR
award_notice_date: 2012-06-08
opportunity_number: PAR-09-182
application_type: 1
activity_code: R03
ic: DE
serial_number: 022538
program_official: HARRIS, EMILY L
project_start_date: 2012-07-01
project_end_date: 2014-06-30
study_section: Special Emphasis Panel[ZDE1 MH (03)]
contact_pi_person_id: 9020729
contact_pi: DATTA, SOMNATH
other_pis: Not Applicable
congressional_district: 03
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this application is to undertake a detailed statistical examination of caries data obtained from the Iowa Fluoride Study. In this process novel statistical models will be developed for univariate and bivariate count data both longitudinally as well as cross-sectionally and marginally both at person level and tooth level.
In the United States dental caries this is a major chronic childhood disease. Nevertheless our understanding of various risk factors is limited. The Iowa Fluoride Study is an ongoing study on a cohort of Iowa children that began in 1991 led by Dr. Steven Levy who is a co-I on this application. It is anticipated that through innovative and efficient statistical modeling it will e possible to mine the resulting data more fully and discover novel relationships between caries incidences/severity and various potential risk factors. We also plan to reinvestigate the issue of optimal fluoride use through joint modeling of bivariate count data of caries and fluorosis. Prior analysis using univariate approaches indicated that a recommendation of optimal dosage is problematic since the two marginal intervals for fluoride use towards caries and fluorosis prevention did not overlap on the face of subject to subject variability. Thus the following three
broad interconnected aims will be undertaken. We will develop count data models to study the dynamical changes of the various (risk) factors on caries incidence and severity including efficient computational methods for parameter estimation (Aim 1). We will develop various marginal models to understand the relationship between caries incidences and severity with various factors that are applicable across the population and evaluation periods (Aim 2). We will develop bivariate count data regression models to study the joint relationships of caries and fluorosis at comparable evaluations (Aim 3). We will compare our results to those obtained from existing approaches. Statistical software (R packages/codes) for the novel data analysis methods will be freely distributed through the Comprehensive R Archive Network.   
   
PUBLIC HEALTH RELEVANCE: The proposed research will lead to a detailed statistical examination of caries data obtained from the Iowa Fluoride Study. It will lead to novel findings regarding the role of potential risk factor for caries. In particular it will construct a predictie model for the bivariate relationships of development of caries and fluorosis that might lead to new recommendation for the optimal childhood fluoride intake. This research will not only be useful in greater understanding of dental caries but also will it add valuable contribution to biostatistics methodological research of statistical (regression) models for count data.

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

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


application_id: 8268441
project_number: 8P20GM103453-10
project_title: Molecular Determinants of Developmental Defects
administering_ic: NIGMS
award_notice_date: 2012-05-14
opportunity_number: RFA-RR-07-001
application_type: 8
activity_code: P20
ic: GM
serial_number: 103453
program_official: DOUTHARD, REGINE
project_start_date: 2002-09-30
project_end_date: 2014-05-31
contact_pi_person_id: 1861667
contact_pi: GREENE, ROBERT M
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
budget_start_date: 2012-06-01
project_abstract:
The present application represents a resubmission (01A1) of a COBRE application wherein we have addressed all concerns noted by reviewers (see "Introduction"). Revised individual project proposals are each preceded by an "Introduction" in which COBRE Investigators respond to Project Critiques provided by reviewers. The primary purpose of this renewal application continues to be fostering of health-related research and mentoring-enhanced competitiveness of junior unfunded investigators. In this renewal application we have included proposals from: 2 junior investigators who have not previously been a PI on a funded research project grant or program project grant; 2 early career investigators who were COBRE supported during our initial funding period and who were successful in obtaining independent funding from the NIH (R01 and K02); a senior investigator whose proposal will facilitate a mid-career research transition; and a pilot project from a clinical junior investigator seeking to redefine his academic career as a clinical research scientist. Two (2) new faculty lines representing sustained commitment from the university have been pledged as part of this competitive renewal application. Two junior faculty who complement the thematic scope of our COBRE will thus be recruited and will be COBRE-supported. Each of these investigators will be mentored by an established well-funded senior biomedical research scientist recognized for his/her scientific expertise in the area of the COBRE investigator's research proposal. 
 
The program continues to be led by Robert M. Greene Ph.D. an established biomedical research scientist well recognized for his extensive expertise central to the research theme of the proposalmolecular mechanisms underlying developmental defects. This renewal application if funded will 1) substantially enhance the research career development and research competitiveness of no less than five (5) junior investigators two early career investigators and one senior investigator and 2) promote the development and enhance the evolution of our Center such that it will be able to successfully compete for independent Center and/or program project funding. A detailed plan for each COBRE investigator's research career development has been formulated; expectations and objectives for achieving independent funding are clearly articulated; clear and tangible evidence of continuing and expanded institutional commitment is documented; excellent research resources and a supportive intellectual environment exists.

project_terms:
Address;Area;Biology;Biomedical Research;Centers of Research Excellence;Clinical;Clinical Research;Complement;Congenital Abnormality;Critiques;Defect;Development;Discipline;Doctor of Philosophy;Embryonic Development;Environment;Etiology;Evolution;Faculty;Fostering;Funding;Health;Individual;Mentors;Molecular;Pilot Projects;Program Research Project Grants;Recruitment Activity;Research;Research Personnel;Research Project Grants;Research Proposals;Resources;School Dentistry;Scientist;United States National Institutes of Health;Universities;career;career development;craniofacial;disability;expectation;falls;flexibility;multidisciplinary;programs;research and development;success


application_id: 8268090
project_number: 9R24OD010435-12
project_title: Research Resources for Model Amphibians
administering_ic: OD
award_notice_date: 2012-07-23
opportunity_number: PAR-10-289
application_type: 9
activity_code: R24
ic: OD
serial_number: 010435
program_official: O'NEILL, RAYMOND R
project_start_date: 2001-10-01
project_end_date: 2016-06-30
study_section: Special Emphasis Panel[ZRR1 CM-2 (01)]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Salamanders are important vertebrate model organisms in biomedical research. The Salamander Genome Project (SGP) is developing applying and making available genomic and bioinformatics resources for salamanders and in particular the Mexican axoloti (Ambystoma mexicanum). This renewal application proposes two objectives to further enhance axoloti genome resources. First a 3x Bacterial Artificial Chromosome (BAC) library will be created and screened to identify clones that contain axoloti genes of interest. This list of clones will be made available via the SGP website (Sal-Site) and 25 BACs will be prioritized by the community for isolation and sequencing. A second objective will innovate an approach to sequence the large axoloti genome. Whole axoloti chromosomes that correspond to the third largest chromosome (Chr3) in the karyotype will be isolated by laser capture microscopy. DNA fragment libraries will be generated from the captured chromosomes and these will be sequenced to yield a Chr3 draft assembly whose contiguity and conceptual context will be increased by integrating paired-end sequences from fosmids protein-coding sequences deriving from expressed sequence tags and markers defining linkage group 3 of the Ambystoma meiotic map. Accomplishment of these objectives will yield resources to enable functional studies of genes and epigenetic mechanisms. Also the project will innovate a 'one-chromosome-at- a time' approach to sequence the large axoloti genome. As a final objective of the application a historically significant collection of axolotis in the Ambystoma Genetic Stock Center (AGSC) will be maintained and distributed to NIH-funded researchers. Since 1969 the AGSC axoloti collection has been supported by funds received from the National Science Foundation. An increasing number of NIH researchers are requesting axoloti living stocks for regeneration research and at the same time there is need to develop a stable long term funding model to maintain this irreplaceable resource. A dual NIH-NSF funding model is proposed where costs associated with the maintenance and distribution of axoloti stocks will be split equally between the NSF and NIH.   
   
PUBLIC HEALTH RELEVANCE (provided by applicant): Fundamental genome and living stock resources are needed for salamanders so that biomedical researchers can translate biological information to humans. In particular salamanders are primary vertebrate models for organ regeneration tissue repair and post-embryonic development.

project_terms:
Ambystoma;Ambystoma mexicanum;Amphibia;Animal Model;Bacterial Artificial Chromosomes;Bioinformatics;Biological;Biomedical Research;Chromosome Mapping;Chromosomes;Chromosomes Human Pair 3;Code;Collection;Communities;Community Surveys;Complex;Custom;DNA;DNA Sequence;Databases;Development;Embryonic Development;Ensure;Epigenetic Process;Expressed Sequence Tags;Foundations;Functional RNA;Funding;Funding Mechanisms;Future;Gene Expression;Genes;Genetic;Genetic Polymorphism;Genome;Genome Mappings;Genomics;Grant;Human;Karyotype;Lasers;Libraries;Life;Location;Maintenance;Maps;Meiosis;Methods;Mexican;Microscopy;Modeling;Natural regeneration;Phenotype;Process;Proteins;Quantitative Trait Loci;Research;Research Personnel;Resources;Salamander;Science;Shotgun Sequencing;Site;Technology;Time;Transcript;Translating;United States National Institutes of Health;Update;comparative;cost;gene function;genetic linkage;genome sequencing;innovation;interest;laser capture microdissection;mutant;organ regeneration;sex;tissue repair;web site


application_id: 8267690
project_number: 5R01HL090749-05
project_title: Myocardial Stiffness in Diastolic Heart Failure
administering_ic: NHLBI
award_notice_date: 2012-06-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 090749
program_official: SCHWARTZ, LISA
project_start_date: 2008-09-01
project_end_date: 2015-05-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 8356696
contact_pi: CAMPBELL, KENNETH S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Diastolic heart failure is a major cause of illness and death. The condition is nearly always associated with increased ventricular stiffness and is more common in elderly and/or obese populations. There are no effective clinical treatments. The central hypothesis underlying this research is that diastolic myocardial stiffness is the sum of an 'active' stiffness component (due to myosin heads that continue to cycle during diastole) and a 'passive' stiffness component (attributed to titin collagen elastin and intermediate filaments). The proposed research determines the relative contributions from these components in preparations ranging from single myocytes to whole hearts and uses these results to create a predictive computational model of diastolic stiffness. Specific Aim 1 will identify the molecular components responsible for the increased stiffness of myocardium from aged rats. The working hypothesis is that the increased stiffness reflects slowed acto-myosin kinetics. Experiments will measure the mechanical properties of myocardium from 6 18 22 and 26-month-old Fischer 344 rats by subjecting chemically permeabilized single myocytes and multicellular preparations to repeated stretches at different levels of calcium activation. Additional experiments will measure ventricular stiffness in the different aged animals by rapidly inflating balloons placed inside the left ventricles of Langendorff-perfused hearts. Titin and myosin isoform content will be measured by gel electrophoresis. Collagen and elastin content and collagen cross-linking will be determined using histological and biochemical techniques. Specific Aim 2 will use identical methods to identify the molecular components responsible for the increased myocardial stiffness evident in a rat model of diet-induced obesity. The working hypothesis for this aim is that the elevated myocardial stiffness observed in obese Sprague-Dawley rats reflects increased collagen content and/or collagen cross-linking. Specific Aim 3 uses the experimental results from Aims 1 and 2 to create a predictive computational model of diastolic stiffness. The model framework will consist of elastic and visco-elastic elements (representing titin collagen elastin and intermediate filaments) arranged in parallel with a spatially-explicit simulation of acto-myosin interactions. Model parameters will be determined by multi-dimensional optimization. The final model will be used to test predictions about the cross-bridge component of myocardial stiffness and should prove useful for assessing the likely effects of potential new treatments for diastolic heart failure. NARRATIVE This research is relevant to public health because it seeks to identify why hearts become excessively stiff in a common cardiovascular disease called Diastolic Heart Failure. The experimental results should help scientists to develop better treatments for the disease in overweight and elderly patients.

project_terms:
Actins;Affect;Aging;American;Animal Model;Animals;Biochemical;Calcium;Cardiac;Cardiovascular Diseases;Categories;Catheters;Cessation of life;Characteristics;Clinical;Clinical Treatment;Collagen;Computer Simulation;Control Animal;Control Groups;Data;Diagnosis;Diastole;Diastolic heart failure;Diet;Disease;EFRAC;Elastin;Elderly;Elements;Etiology;Extracellular Matrix;Failure (biologic function);Fat-Restricted Diet;Fatty acid glycerol esters;Figs - dietary;Filament;Functional disorder;Future;Gene Expression;Head;Health Care Costs;Heart;Heart failure;Histological Techniques;Inbred F344 Rats;Individual;Intermediate Filaments;Kinetics;Left ventricular structure;Measurement;Measures;Mechanics;Methods;Modeling;Molecular;Molecular Profiling;Muscle Cells;Myocardial;Myocardium;Myosin ATPase;Myosin Heavy Chains;Obesity;Overweight;Patients;Physiological;Preparation;Principal Investigator;Property;Protein Isoforms;Proteins;Rat-1;Rattus;Relative (related person);Research;Research Project Grants;Resistance;Sampling;Scientist;Simulate;Sprague-Dawley Rats;Stretching;Sum;Symptoms;Takeda brand of pioglitazone hydrochloride;Techniques;Testing;Therapeutic;Tissues;Ventricular;Ventricular Function;Weight;Work;age related;aged;connectin;crosslink;feeding;gel electrophoresis;in vivo;mathematical model;older patient;particle;pressure;public health medicine (field);research study;sensor;simulation


application_id: 8267408
project_number: 1T32NS077889-01
project_title: Neurobiology of CNS Injury and Repair
project_terms: Neurobiology;central nervous system injury;injury and repair
administering_ic: NINDS
award_notice_date: 2012-02-29
opportunity_number: PA-11-184
application_type: 1
activity_code: T32
ic: NS
serial_number: 077889
program_official: KORN, STEPHEN J
project_start_date: 2012-07-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZNS1 SRB-P (63)]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: GEDDES, JAMES W.
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT This is a new T32 application requesting funding for a Neurobiology of CNS Injury and Repair Training Program for 4 predoctoral fellows/year. The training of the predoctoral fellows will be carried out by training faculty in the University of Kentucky Spinal Cord & Brain Injury Research Center (SCoBIRC). The overall goal of the proposed program is to provide broad-based training in modern research concepts regarding the acute subacute and chronic pathophysiology of SCI and TBI and the identification of potential disease-modifying molecular targets that can drive the discovery of pharmacological and gene therapeutic strategies by which the devastating effects of these injuries can be ameliorated. These strategies will include both "neuroprotective" and "neurorestorative" approaches. Although it is anticipated that most of the trainees will pursue careers in laboratory-based therapeutic discovery research they will also receive training in clinical aspects of the targeted neurological disorders and the practical issues involved in the design and conduct of neurological clinical trials. To accomplish this the predoctoral fellows wil also spend one day/week for a semester shadowing neurological neurosurgical and/or neurorehabilitation clinical faculty and attending weekly grand rounds to gain an understanding of the clinical nature of TBI and SCI that their research is focused upon. This will enhance their future ability as independent investigators to not only make therapeutic discoveries in experimental injury models but also provide them with knowledge concerning how to design their basic research in a manner that will more readily enable the translation of promising therapeutic approaches into clinical studies and therapeutic trials.       
   
PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE This project will involve the development of a new training program to prepare 4 predoctoral fellows/year for neurological research careers directed at the discovery and translation of novel neuroprotective and neurorestorative therapies for the treatment of traumatic spinal cord and brain injuries. The training will be directed by basic science and clinical faculty of the University of Kentucky Spina Cord & Brain Injury Research Center.

public_health_relevance:
PROJECT NARRATIVE This project will involve the development of a new training program to prepare 4 predoctoral fellows/year for neurological research careers directed at the discovery and translation of novel neuroprotective and neurorestorative therapies for the treatment of traumatic spinal cord and brain injuries. The training will be directed by basic science and clinical faculty of the University of Kentucky Spina Cord & Brain Injury Research Center.


application_id: 8267109
project_number: 5R01MH086784-04
project_title: Building a Selective Inhibitory Control Tone in Autism: An rTMS Study
administering_ic: NIMH
award_notice_date: 2012-06-11
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: 2014-05-31
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:
Project summary  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;Area;Asperger Syndrome;Autistic Disorder;Autopsy;Axon;Behavioral;Brain;Brain region;Cells;Clinical;Cognitive;Cognitive deficits;Development;Discrimination (Psychology);Electroencephalography;Environment;Frequencies (time pattern);Functional disorder;Grant;Interneurons;Intervention;Investigation;Laboratories;Language;Lateral;Link;Long-Term Depression (Physiology);Magnetism;Measures;Modeling;Neuronal Plasticity;Neuropil;Outcome Measure;Pathology;Patients;Pattern;Persons;Pervasive Child Development Disorders;Population;Prefrontal Cortex;Psychiatric therapeutic procedure;Recruitment Activity;Reporting;Rett Syndrome;Sensory Process;Social Interaction;Source;Stereotyped Behavior;Surface;Symptoms;Techniques;Testing;Therapeutic Intervention;Thinking function;Tissues;Transcranial magnetic stimulation;Treatment outcome;functional outcomes;interest;magnetic field;neuropathology;neurophysiology;repetitive transcranial magnetic stimulation;response;sex;social communication;socioeconomics;theories;tool

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


application_id: 8267082
project_number: 5R01MH083621-05
project_title: A Brief Clinic-Based HIV Prevention Program for African American Teen Males
administering_ic: NIMH
award_notice_date: 2012-05-14
opportunity_number: PAR-07-379
application_type: 5
activity_code: R01
ic: MH
serial_number: 083621
program_official: KAMATH, SUSANNAH M A
project_start_date: 2008-09-30
project_end_date: 2014-05-31
study_section: Special Emphasis Panel[ZRG1-RPHB-K(50)R]
contact_pi_person_id: 8234905
contact_pi: CROSBY, RICHARD A
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The Centers for Disease Control and Prevention has declared that AIDS is a "state of emergency" in the US relative to African Americans. Teen males attending STD clinics are one important yet often neglected population of African Americans at risk of HIV acquisition. Despite extremely high rates of STD acquisition (and subsequent infection) among this population effective clinic-based interventions specifically designed to reduce their sexual risk behavior for STD/HIV have not been developed/disseminated. A recent intervention trial (conducted by Dr. Crosby) demonstrated the efficacy of a brief clinic-based intervention designed to prevent subsequent STI acquisition among African American males 18 to 29 years of age. The proposed study will test the efficacy this intervention (in modified form) to reduce STI incidence among African American teen (15 to 20 years old). The primary hypothesis is that teens randomized to receive the intervention will have a lower incidence rate of laboratory-confirmed STIs at 2 and 6-month follow-up assessments (as well as 12-month follow-up conducted by a medical records review) compared to those receiving an attention-equivalent control condition. Teens (N = 840) will be recruited from a publicly-funded STD clinic located in an urban area of the South. After completing an A-CASI assessment teens will be rated on their ability to apply condoms to a penile model and then asked to donate a urine specimen for STI testing. Specimens will be tested for C. trachomatis N. gonorrhoeae and T. Vaginalis using nucleic acid amplification assays. Randomization will then be achieved by a concealment of allocation technique. Teens will be randomized to immediately receive: 1) a brief (60 minute) theory-based one-on-one interactive intervention delivered by a lay health advisor or 2) an attention equivalent control condition. The assessment battery will be repeated 2 months subsequent to enrollment and again 6 months after enrollment. A medical records review will be conducted 12 months after enrollment to compare clinic reported incidence rates between the randomized groups of teens. If incidence of STIs in this population of teens can be decreased as substantially as was found in the previous study of 18 to 29 year-old African American males (percent relative difference = 36.7) the public health significance for African American teen males will substantially contribute to rectify the racial disparity in HIV/STD experienced by African American teen males. By extension we suggest that their partners (typically African American teen females) will also benefit. Because our program is designed for ease of implementation the number of dissemination and translation issues will be greatly minimized thereby greatly facilitating the process of translating research into practice. PUBLIC HEALTH RELEVANCE: The proposed efficacy trial tests an innovative method of bridging the gap between research and practice. By providing a brief clinic-based HIV/STD prevention program to African American teen males attending an STD clinic the study will be the first to demonstrate that teen's sexual risk behavior can be reduced without excessive time and resources. The focus on African American teen males is also quite timely given the recent declaration by CDC that AIDS is a "state of emergency" for African Americans.

project_terms:
20 year old;Acquired Immunodeficiency Syndrome;African American;Age-Years;Attention;Biological Assay;Brothers;Caring;Centers for Disease Control and Prevention (U.S.);Chlamydia;Clinic;Emergency Situation;Enrollment;Female;Frequencies (time pattern);Funding;Future;Glare;Goals;Gonorrhea;HIV;Health;Health Educators;Hispanics;Incidence;Infection;Instruction;Intervention;Intervention Trial;Kentucky;Laboratories;Life;Low income;Medical Records;Methods;Modeling;Neisseria gonorrhoeae;Newly Diagnosed;Nucleic Acids;Perception;Population;Prevention program;Process;Randomized;Randomized Controlled Trials;Recruitment Activity;Relative (related person);Reporting;Research;Research Design;Resources;Risk;Science;Services;Sex Behavior;Sexual Partners;Specimen;Techniques;Teenagers;Testing;Time;Translating;Translational Research;Translations;Treatment Efficacy;Trichomonas Infections;Trichomonas vaginalis;Uncertainty;United States;Urine;Vagina;Woman;Work;arm;avoid sex;base;condoms;design;disorder prevention;effective intervention;efficacy testing;efficacy trial;experience;flexibility;follow-up;high risk men;improved;innovation;intervention effect;intervention program;male;man;medical specialties;men;neglect;post intervention;prevent;programs;public health medicine (field);research to practice;response;safer sex;sex;sex risk;theories;therapy design;urban area;young man


application_id: 8267011
project_number: 5T32HL091812-05
project_title: Clinical Scholars in Cardiovascular Science
project_terms: Cardiovascular system;Clinical;Science
administering_ic: NHLBI
award_notice_date: 2012-02-22
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: 2014-05-31
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: 8266877
project_number: 5R01CA153132-03
project_title: Oncopigs as a better model for human cancer
administering_ic: NCI
award_notice_date: 2012-05-09
opportunity_number: RFA-GM-10-009
application_type: 5
activity_code: R01
ic: CA
serial_number: 153132
program_official: MIETZ, JUDY
project_start_date: 2010-08-05
project_end_date: 2014-05-31
study_section: ZCA1-SRLB-R(M1)R
contact_pi_person_id: 8801334
contact_pi: CLARK, GEOFFREY J.
other_pis: RUND, LAURETTA ;SCHOOK, LAWRENCE B.
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This project is driven by the hypothesis that current in vivo models for evaluating cancer therapies are too non-predictive of the human condition for efficient use. This may become a major impediment to the translation of new potential drugs into effective therapies for patients. The project proposes to determine if transgenic pigs may serve as a novel and more human-like model for cancer. Although pigs have been used extensively in biomedical research to date there is no reported transgenic swine model for cancer. Like humans pigs can live for decades and have a very low rate of spontaneous cancer. This is in contrast to common rodent-based cancer models where life span is limited to a few years and the spontaneous development of cancer is quite high. We now know that 5-6 to six genetic defects are required to convert a normal pig cell into a tumor cell. This is the same as in humans. However mouse cells can be transformed into tumor cells by as little as two genetic lesions. These simple yet profound genetic observations point to pigs as a far superior model system for the human condition.  We propose to use state of the art technology to generate transgenic pigs that can be induced to lose the expression of three major tumor suppressors simultaneously in the breast. These alterations will be coupled with an up-regulation of a growth hormone receptor. These genetic defects are often found in breast cancer and particularly in Triple Negative (TN) breast cancer. TN breast cancer is an especially aggressive and difficult to treat form of breast cancer with a high morbidity rate. We will include a far red fluorescent protein in the system which will allow non-invasive imaging of the status of the induced breast cells.  The project will involve the collaboration of laboratories with extensive experience in the molecular and cellular biology of human breast cancer and laboratories with world renown in the production and husbandry of transgenic pigs.  Animals will be tested to determine if these lesions are sufficient to provoke breast cancer and whether any such cancers have the characteristics of TN breast cancer. We will also use the population to test the effectiveness of cancer chemopreventative agents and whether the pigs respond to front line therapy for TN breast cancer in a similar manner to humans.    PUBLIC HEALTH RELEVANCE: This project will establish a novel model system for evaluating new therapeutic approaches to cancer. The system should be much more predictive for the human condition thus enhancing the ability to identify and characterize effective novel therapeutics. It may also establish a unique model for the study of cancer preventative strategies that cannot be realistically modeled at present. The model is targeted towards breast cancer as over 40 thousand women are expected to die in the United states each year from this disease due to lack of sufficiently effective therapies.

project_terms:
African American;Animal Model;Animals;Arteriosclerosis;BRCA1 gene;Biological Assay;Biological Factors;Biological Models;Biomedical Research;Breast;Cancer Model;Cells;Characteristics;Clinical Trials;Collaborations;Controlled Study;Coupled;Development;Diabetes Mellitus;Disease;Disease model;Effectiveness;Epidermal Growth Factor Receptor;Failure (biologic function);Family suidae;Genetic;Growth Hormone Receptor;Hand;Human;Image;Laboratories;Lesion;Life;Lipids;Lipoproteins;Longevity;Malignant Neoplasms;Metabolism;Metastatic malignant neoplasm to brain;MicroRNAs;Modeling;Molecular;Molecular and Cellular Biology;Monitor;Morbidity - disease rate;Mus;Mutation;Neoplasm Metastasis;Patients;Pharmaceutical Preparations;Pilot Projects;Population;Production;Proteins;Reporting;Rodent;Series;Staging;Study models;System;Technology;Testing;Therapeutic;Time;Tissues;Transgenic Organisms;Translations;Tumor Suppressor Proteins;United States;Up-Regulation (Physiology);Variant;Woman;Work;arterial lesion;base;cancer genetics;cancer prevention;cancer therapy;design;effective therapy;experience;expression vector;genome sequencing;human disease;in vivo;in vivo Model;inhibitor/antagonist;interest;loss of function;malignant breast neoplasm;model development;mouse model;neoplastic cell;novel;novel therapeutic intervention;novel therapeutics;predictive modeling;public health relevance;red fluorescent protein;research study;success;triple-negative invasive breast carcinoma;tumor;tumorigenesis;tumorigenic;vector

public_health_relevance:
Narrative This project will establish a novel model system for evaluating new therapeuticapproaches to cancer. The system should be much more predictive for the humancondition thus enhancing the ability to identify and characterize effective noveltherapeutics. It may also establish a unique model for the study of cancer preventativestrategies that cannot be realistically modeled at present. The model is targeted towardsbreast cancer as over 40 thousand women are expected to die in the United states eachyear from this disease due to lack of sufficiently effective therapies.


application_id: 8266634
project_number: 1R01ES021375-01
project_title: PCBs worsen obesity/metabolic syndrome through 'toxic metabolic endotoxemia'
administering_ic: NIEHS
award_notice_date: 2012-05-08
opportunity_number: PAR-11-170
application_type: 1
activity_code: R01
ic: ES
serial_number: 021375
program_official: COLLINS, JENNIFER B
project_start_date: 2012-05-08
project_end_date: 2017-02-28
study_section: Special Emphasis Panel[ZRG1 EMNR-D (55)]
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): 68% of US adults are either overweight or obese and more than 100 million Americans have diabetes or pre- diabetes. These conditions may lead to cardiovascular disease and cancer. Recent research indicates a potential role for polychlorinated biphenyls (PCBs) which are persistent organic pollutants in obesity and diabetes. PCBs were previously used in electrical transformers. Although they were banned over 30 years ago PCBs are still present in the US food supply and in all adult Americans. Preliminary research performed by our group and others suggests that PCBs cause a "leaky gut" to disrupt the gut:liver:adipose axis. Subsequently intestinal-derived bacterial products enter the bloodstream causing inflammation liver disease and contribute to obesity and diabetes. We call this problem "toxic-metabolic endotoxemia". We hypothesize that PCBs interact with high fat or high carbohydrate diets through toxic metabolic endotoxemia to worsen obesity and diabetes; and studying this hypothesis is the overall objective of this grant. The specific aims of this novel nutrient:toxin interaction translational project are to:!! 1) Determine in mice mechanisms by which PCBs disrupt the gut:liver:adipose axis to increase metabolic endotoxemia and worsen diet-induced obesity/insulin resistance. 2) Determine the potential role of cellular receptors in PCBs-associated toxic-metabolic endotoxemia in mice and cell culture models. 3) Study mechanisms of toxic metabolic endotoxemia in stored blood samples from a large group of highly PCB-exposed humans. We expect to find that PCBs activate receptors perturb the gut:liver:adipose axis and worsen obesity/diabetes via toxic metabolic endotoxemia in mice and in humans. This innovative project is the first to study PCB- related endotoxemia in obesity/diabetes and is expected to lead to a new understanding of these conditions. The proposal is relevant to all overweight/obese people exposed to environmental pollution.   
   
PUBLIC HEALTH RELEVANCE: We expect to find that PCBs worsen obesity/diabetes via toxic metabolic endotoxemia in mice and in humans. This innovative project is the first to study PCB-related endotoxemia in obesity/diabetes and is expected to lead to a new understanding of these conditions. The proposal is relevant to all overweight/obese people exposed to environmental pollution.

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


application_id: 8266015
project_number: 5F31NS074678-02
project_title: Contribution of blast wave components to mild traumatic brain injury
administering_ic: NINDS
award_notice_date: 2012-06-04
opportunity_number: PA-10-108
application_type: 5
activity_code: F31
ic: NS
serial_number: 074678
program_official: JAKEMAN, LYN B
project_start_date: 2011-07-01
project_end_date: 2012-08-16
study_section: Special Emphasis Panel[ZRG1-F01-L(20)L]
contact_pi_person_id: 9821686
contact_pi: RENEER, DEXTER VINCENT
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Blast-induced Traumatic brain injury (bTBI) has become the "signature injury" of Operations Iraqi/Enduring Freedom (OIF/OEF) and is also increasingly frequent in civilians as a result of industrial and terrorist explosions. The mechanisms by which blast shockwaves contribute to bTBI is being investigated using both large and small animal models. Small animal models of bTBI predominantly utilize compressed air-driven shock tubes to generate an injury while large animal models employ chemical explosives (i.e. RDX - the main explosive component of C-4 plastic explosives) in both open-air and a variety of enclosed spaces. The differences in model design and shockwave source make comparison of results from each model difficult. Previous bTBI studies have focused on the relationship between peak blast pressure and brain injury. However we hypothesize that other components of the shock wave may also contribute to the brain injury. In an effort to determine which components of the blast contribute to the injury we developed and characterized the McMillan Blast Device (MBD) a shock tube that can utilize compressed gas (air helium) or chemical explosives (RDX oxyhydrogen) as the shockwave source. Shockwaves produced from compressed gas sources differ substantially from those produced by chemical explosives within the MBD. This proposal seeks to determine which components of the shock wave contribute to brain pathology in rats. The overall hypothesis of this proposal is that positive phase duration in addition to peak overpressure plays a role in the injury produced by blasts. To examine this hypothesis Aim 1 will compare blasts of similar peak overpressures produced by oxhydrogen and compressed air. The oxyhydrogen-driven blasts have a shorter positive phase duration and are therefore anticipated to produce less brain injury. This will be evaluated using a range of peak overpressures. Brain injury will be assessed using markers diffuse axonal injury (DAI) blood-brain barrier (BBB) compromise oxidative stress and neuron death. Aim 2 will expand upon Aim 1 by shortening the positive phase duration of a compressed air-driven shockwave to a length comparable to oxyhydrogen-driven blasts and comparing resultant brain injury. Aim 3 will examine the hypothesis that reflection of the blast waves which extends the duration of the overpressure phase will exacerbate the extent of brain injury produced by a blast.

project_terms:
Acoustics;Air;Animal Model;Animal Testing;Animals;Automobile Driving;Blast Cell;Blast Injuries;Blood - brain barrier anatomy;Brain;Brain Injuries;Brain Pathology;Cessation of life;Chemicals;Conflict (Psychology);Devices;Diffuse Axonal Injury;Electromagnetics;Explosion;Freedom;Frequencies (time pattern);Gases;Goals;Helium;Injury;Length;Lipid Peroxidation;Medical;Methods;Military Personnel;Modeling;Neurons;Oxidative Stress;Pathologic;Phase;Plastics;Play;Population;Positioning Attribute;Proteins;Rattus;Role;Shock;Source;Structure;Testing;Thick;Time;Traumatic Brain Injury;Travel;Triage;Tube;base;design;improved;model design;neuropathology;nitration;operation;pressure;research study

public_health_relevance:
Blast-induced traumatic brain injury (bTBI) is becoming more prevalent among military and civilian populations while the mechanisms underlying the pathologic mechanisms associated with bTBI remain largely unknown. This proposal will evaluate components of the blast wave that contribute to brain injury by using both compressed gas and chemical explosive sources for the blast wave. These results will aid in the design of protective structures and personal protective gear to mitigate the effects of blast wave components which contribute to bTBI.


application_id: 8265680
project_number: 5R01CA091901-10
project_title: Novel Aureolic Acid-Type Antitumor Agents
administering_ic: NCI
award_notice_date: 2012-04-23
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: 2013-07-31
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 2257319
contact_pi: ROHR, JURGEN T
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
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: 8262406
project_number: 5R01AI048850-09
project_title: Fatty Acid Binding Proteins in Macrophage Function
administering_ic: NIAID
award_notice_date: 2012-04-02
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: 8262234
project_number: 1R01HL106843-01A1
project_title: Regulation of Blood Pressure Circadian Rhythm by Vascular Smooth Muscle BMAL1
administering_ic: NHLBI
award_notice_date: 2012-05-07
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: HL
serial_number: 106843
suffix: A1
program_official: LAPOSKY, AARON D
project_start_date: 2012-05-15
project_end_date: 2016-04-30
study_section: Special Emphasis Panel[ZRG1 VH-B (02)]
contact_pi_person_id: 6625920
contact_pi: GONG, MING C
other_pis: GUO, ZHENHENG
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 well-known blood pressure (BP) circadian rhythm is important to human health and BP circadian rhythm disruption in diabetes is emerging as an index for future target organ damage and cardiovascular outcomes. Recent discoveries that clock genes are expressed in all of the tissues examined challenges the dogma that BP circadian rhythm is solely controlled by central pacemaker. However it is completely unknown which specific clock gene(s) in which peripheral tissue(s) are important for BP circadian rhythm. We have generated a novel smooth muscle specific clock gene BMAL1 knockout mice SM-bmal1-/- to investigate the role of vascular smooth muscle in BP circadian rhythm under physiological and diabetic conditions. We found that vascular smooth muscle BMAL1 is essential for normal BP circadian rhythm as well as normal vascular smooth muscle contractile circadian variation. Moreover our preliminary study implicates rho kinase ROCK2 links BMAL1 to contraction. Importantly we found that in type 2 diabetic db/db mice loss of BMAL1 protein and activity circadian oscillations is associated with loss of vascular smooth muscle circadian variation and BP circadian rhythm. Thus we hypothesize that BMAL1 regulates ROCK2 thus controlling vascular smooth muscle contractile circadian variation thereby significantly contributing to normal BP circadian rhythm and its disruption in diabetes. We propose to use in vitro and in vivo approaches to test the hypothesis in three specific aims: 1) test the hypothesis that under physiological conditions BMAL1 regulates the vascular smooth muscle contractile circadian variation and BP circadian rhythm via ROCK2. 2) Test the hypothesis that under diabetic conditions BMAL1 is required for disruptions in vascular smooth muscle contractile circadian variation. 3) Determine the role of vascular smooth muscle BMAL1 in diabetes-associated disruption of BP circadian rhythm. Results from the proposed studies may modify the dogma that central pacemaker is solely responsible for the physiological BP circadian rhythm by providing the first direct experimental evidence that peripheral vascular smooth muscle BMAL1 play an important role. Moreover our results may identify vascular smooth muscle BMAL1 as a potential therapeutic target for control of 24-h BP in diabetic patients by providing evidence that
BMAL1 is a significant contributor linking diabetes to disruptions of BP circadian rhythm.   
   
PUBLIC HEALTH RELEVANCE:  The well-known blood pressure (BP) circadian rhythm is important for human health and the disruption of BP circadian rhythm in diabetes is emerging as an index of future target organ damage and cardiovascular outcomes. However molecular mechanisms linking diabetes with disruption in BP circadian rhythm are unknown. The goals of this application are to elucidate the molecular mechanisms responsible for normal BP circadian rhythm and its disruptions in diabetes.


application_id: 8262107
project_number: 1R01NR013430-01
project_title: Nutrition Intervention to Reduce Symptoms in Patients with Advanced Heart Failure
administering_ic: NINR
award_notice_date: 2011-09-26
opportunity_number: RFA-NR-11-006
application_type: 1
activity_code: R01
ic: NR
serial_number: 013430
program_official: HUSS, KAREN
project_start_date: 2011-09-27
project_end_date: 2015-07-31
study_section: Special Emphasis Panel[ZNR1 REV-T (07)]
contact_pi_person_id: 1906096
contact_pi: LENNIE, TERRY A
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): For a majority of patients with advanced heart failure medical treatment is only partially effective in relieving heart failure symptoms. Therefore it is
recommended that palliative care be initiated soon after diagnosis. There is a need for complementary nonpharmacologic interventions that could be easily implemented by health care providers to provide palliative care. Three major pathologic pathways underlying heart failure symptoms have been identified: fluid overload inflammation and oxidative stress. Prior research has demonstrated that three nutrients-sodium omega-3 fatty acids and lycopene-can alter these pathologic pathways. Clinical trials to date have only tested each nutrient individually. There is strong theoretical rationale that a combined intervention targeting all thre nutrients would have substantial benefit in relieving symptoms in advanced heart failure. Therefore the purposes of this study are to test the effects of a 6-month nutrition intervention o dietary sodium reduction combined with supplementation of lycopene and omega-3 fatty acids on heart failure symptoms health-related quality of life and time to heart failure rehospitalization or all-cause death. The aims of this double blind-placebo controlled study are 1) to determine the effects of a 6-month nutrition intervention on symptom burden (edema shortness of air and fatigue) and health related quality of life at 3 and 6 months and time to heart failure rehospitalization or all-cause death over 12 months from baseline; 2) compare dietary sodium intake inflammation and markers of oxidative stress between the nutrition intervention group and a placebo group at 3 and 6 months; and 3) compare body weight serum lycopene and erythrocyte omega-3 index between the nutrition intervention group and a placebo group at 3 and 6 months. A total of 175 patients with advanced heart failure will be randomized to either the nutrition intervention or placebo group (75 per group). The nutrition intervention group will receive a theory based education and skill building intervention designed to decrease dietary sodium intake to ~2 g per day. A research nurse will make 4 home visits and one follow-up telephone call over 6 months to provide the education-skill building intervention. The intervention group will take 3 omega-3 fatty acid capsules (350 mg eicosahexaenoic acid and 50 mg docosahexaenoic acid) and consume tomato juice or other tomato-based products containing 20-25 mg of lycopene daily for six months. The placebo group will receive the same number of visits and phone calls but only general nutrition information will be provided. They will take 3 placebo capsules containing soybean oil (500 mg/capsule) and consume their choice of fruit juices that do not contain lycopene daily for six months. Data will be collected in person at baseline 3 months and 6 months by a research assistant blinded to the group assignment. Patients will be followed for an additional 6 months by telephone to collect longer term data on symptom burden and quality of life as well as heart failure hospitalization and all-cause mortality at 9 and 12 months.   
   
PUBLIC HEALTH RELEVANCE: Despite optimal drug therapy most patients with heart failure remain symptomatic leading to poor quality of life and frequent rehospitalizations. The proposed study is aimed at improving symptoms and quality of life in patients with advanced heart failure through a low cost easily administered intervention of dietary sodium restriction coupled with lycopene and omega-3 fatty acid supplementation. The knowledge to be gained by defining the role of dietary interventions in heart failure is invaluable and will pave the way for
future research in this area.

public_health_relevance:
Despite optimal drug therapy most patients with heart failure remain symptomatic leading to poor quality of life and frequent rehospitalizations. The proposed study is aimed at improving symptoms and quality of life in patients with advanced heart failure through a low cost easily administered intervention of dietary sodium restriction coupled with lycopene and omega-3 fatty acid supplementation. The knowledge to be gained by defining the role of dietary interventions in heart failure is invaluable and will pave the way for
future research in this area.


application_id: 8261752
project_number: 3R01CA116092-06S1
project_title: Breast tumor exosomal Jak3BP mediated immunosuppression
administering_ic: NCI
award_notice_date: 2011-06-28
application_type: 3
activity_code: R01
ic: CA
serial_number: 116092
suffix: S1
program_official: HOWCROFT, THOMAS K
project_start_date: 2005-08-01
project_end_date: 2012-03-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
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
project_abstract:
DESCRIPTION (provided by applicant):  The goal of this proposal is to identify the mechanisms underlying tumor exosome-mediated suppression of NK cell activity. Our preliminary data indicate that pretreatment of BALB/c mice with exosomes produced by TS/A breast tumor cells results in more rapid tumor growth and earlier metastasis. We have identified a novel breast tumor exosomal protein (Jak3BP) that is capable of binding to Jak3 in the NK cells resulting in the ubiquitination of Jak3. siRNA Jak3BP knockout results indicated however that although Jak3BP is required it is not sufficient for ubiquitination of Jak3. We have now identified two exosomal proteins that interact with Jak3BP Nedd4 and ubiquilin which have the potential to enhance the ubiquitination of Jak3 or protect Jak3BP  against its degradation in IL-2-stimulated NK cells. Our aims are (1) To use siRNA technology to determine if knockout of exosomal Jak3BP in tumor cells is sufficient for reversal of the inhibition of NK-cell activation mediated by TS/A exosomes or whether other exosomal proteins such as Nedd4 and ubiquilin are required. (2) To use siRNA technology to determine if other exosomal proteins that interact with Jak3BP participate in the ubiquitination of Jak3 in NK cells and to identify the molecular determinants of these interaction. We will determine if modification of Jak3BP regulates its choice of interaction partners and in parallel use bioluminescence resonance energy transfer assay technology to identify a peptide that can block the interaction of Jak3 and Jak3BP thus reversing the tumor exosome-mediated inhibition of NK-cell activation. (3) To determine which tumor exosomal proteins contribute to the stabilization of Jak3BP in IL-2 stimulated NK cells and further determine if the elimination of these exosome proteins causes degradation of Jak3BP thus resulting in the attenuation of inhibition of NK cell activation and prevention of tumor growth. (4) To determine if human breast tumor Jak3BP also regulates the ubiquitination of Jak3 of NK cells and to determine if Jak3BP is  over expressed in patients with ductal adenocarcinoma of the breast. The data generated should elucidate the cellular and molecular basis underlying tumor immunosuppression mediated by the exosomes produced by tumor cells and indicate the feasibility of various therapeutic strategies.

project_terms:
A Mouse;Adenocarcinoma;Binding (Molecular Function);Biological Assay;Bioluminescence;Breast Adenocarcinoma;Cells;Complex;Data;Doctor of Philosophy;Ductal;Energy Transfer;Goals;Growth;Human;Immune;Immune response;Immune system;Implant;Inbred BALB C Mice;Interleukin-2;Invaded;Knock-out;Laboratories;Lymphocyte;Mammary Neoplasms;Mediating;Membrane;Modeling;Modification;Molecular;Mus;NK Cell Activation;Natural Killer Cells;Natural immunosuppression;Neoplasm Metastasis;Patients;Peptides;Play;Prevention;Protein Binding;Proteins;Research Personnel;Role;Small Interfering RNA;Technology;Testing;Therapeutic;Tumor-Derived;Ubiquitination;Vesicle;attenuation;base;cancer cell;cytotoxicity;host neoplasm interaction;in vivo;malignant breast neoplasm;neoplastic cell;novel;overexpression;perforin;programs;tumor;tumor growth;ubiquilin;ubiquitin-protein ligase


application_id: 8260585
project_number: 5P01NS058484-05
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: 2011-05-01
budget_end_date: 2013-04-30
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;therapeutic target;tool;working group


application_id: 8260584
project_number: 5P01NS058484-05
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: 2011-05-01
budget_end_date: 2013-04-30
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;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;therapeutic target;treatment strategy


application_id: 8260583
project_number: 5P01NS058484-05
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: 2011-05-01
budget_end_date: 2013-04-30
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;therapeutic target


application_id: 8260582
project_number: 5P01NS058484-05
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: 2011-05-01
budget_end_date: 2013-04-30
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;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: 8260581
project_number: 5P01NS058484-05
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: 2011-05-01
budget_end_date: 2013-04-30
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;In Vitro;Injury;Knock-out;Knockout Mice;Maintenance;Mediating;Membrane Proteins;Memory impairment;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: 8260537
project_number: 5R01DC007176-08
project_title: Neurotrophin Regulation of Taste System Development
administering_ic: NIDCD
award_notice_date: 2012-05-08
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: DC
serial_number: 007176
program_official: SULLIVAN, SUSAN L
project_start_date: 2005-03-01
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1-IFCN-B(03)M]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): During development gustatory innervation is a tightly regulated process in which specific numbers of primary taste afferents project to discrete regions of the oral cavity. Brain-derived neurotrophic factor (BDNF) regulates both the number and location of gustatory innervation during embryonic development. Our current research is designed to determine if and/or how these connections are important for central gustatory development or taste function and whether BDNF regulates development of the postnatal taste system. The proposed studies combine cell counting tract tracing immunohistochemistry electrophysiology and behavioral testing in conditional and inducible transgenic mice to: 1) determine if BDNF influences postnatal changes in geniculate ganglion and taste bud development 2) determine if embryonic or postnatal BDNF is important for central terminal field organization and 3) determine if embryonic or postnatal BDNF is important for adult gustatory function. Together these studies test the hypotheses that: 1) embryonic BDNF determines the number of neurons innervating a taste bud and taste buds increase in size to meet that number postnatally. 2) CNS terminal field formation is regulated by BDNF and the specificity of peripheral connections. 3) Gustatory sensitivity is reduced but that the taste system still functions despite wide-scale reorganization. These studies will determine how early peripheral innervation patterns influence continued development and function of the taste system. In addition we will determine whether BDNF is required for postnatal gustatory development. Because these experiments examine how neurotrophin regulation of sensory innervation influences continued development and adult function this project has important implications for the potential therapeutic use of these powerful signaling molecules in re-establishing gustatory function following neuronal impairment.    PUBLIC HEALTH RELEVANCE: Taste disorders can have detrimental effects on a person's health and quality of life. According to NIDCD more than 200000 people visit a doctor each year for problems with their chemical senses including taste. The underlying mechanism of many gustatory disruptions is not well understood. As a result much emphasis has been placed on a basic understanding of the taste bud. However the neurons innervating taste buds receive little attention and are also required for normal gustatory function. Some adult gustatory disruptions may result from an alteration in factor(s) regulating gustatory system innervation both during development and as a part of normal adult homeostasis. Peripheral neuropathies are relatively common and frequently accompany other illnesses. A basic understanding of the factors that are required to promote innervation during development and possibly maintain it in adulthood may lead to therapeutic approaches that allow taste recovery following its loss.

project_terms:
Adult;Attention;Birth;Brain-Derived Neurotrophic Factor;Cell Count;Chemicals;Development;Electrophysiology (science);Embryo;Embryonic Development;Epithelium;Excision;Goals;Health;Homeostasis;Immunohistochemistry;Impairment;Individual;Lead;Location;Mus;National Institute on Deafness and Other Communication Disorders;Nerve;Neurons;Oral cavity;Pattern;Peripheral;Peripheral Nervous System Diseases;Persons;Physiological;Process;Quality of life;Recovery;Regulation;Research;Sensory;Signaling Molecule;Specificity;Stimulus;Structure of geniculate ganglion;System;Systems Development;Taste Buds;Taste Disorders;Taste Perception;Testing;Therapeutic;Therapeutic Uses;Tongue;Transgenic Mice;Visit;behavior test;chorda tympani;critical period;design;meetings;nerve supply;neurotrophic factor;overexpression;postnatal;preference;public health relevance;research study;response

public_health_relevance:
Project Narrative. Taste disorders can have detrimental effects on a person's health andquality of life. According to NIDCD more than 200000 people visit a doctor each year forproblems with their chemical senses including taste. The underlying mechanism of manygustatory disruptions is not well understood. As a result much emphasis has been placed on abasic understanding of the taste bud. However the neurons innervating taste buds receive littleattention and are also required for normal gustatory function. Some adult gustatory disruptionsmay result from an alteration in factor(s) regulating gustatory system innervation both duringdevelopment and as a part of normal adult homeostasis. Peripheral neuropathies are relativelycommon and frequently accompany other illnesses. A basic understanding of the factors thatare required to promote innervation during development and possibly maintain it in adulthoodmay lead to therapeutic approaches that allow taste recovery following its loss.


application_id: 8260467
project_number: 5R01GM087735-04
project_title: Mass Informatics of Two Dimensinoal Gas Chromatography Time-of-flight Mass Spectr
administering_ic: NIGMS
award_notice_date: 2012-04-30
opportunity_number: PAR-07-344
application_type: 5
activity_code: R01
ic: GM
serial_number: 087735
program_official: LYSTER, PETER
project_start_date: 2009-05-01
project_end_date: 2014-04-30
study_section: Enabling Bioanalytical and Biophysical Technologies Study Section[EBT]
contact_pi_person_id: 8487327
contact_pi: ZHANG, XIANG
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): High-throughput omics analysis platforms provide important new technical capabilities to analyze complex biological fluids for disease markers. A particularly important platform for metabolomics is two-dimensional gas chromatography time-of- flight mass spectrometry (GCxGC/TOF-MS) that provides both high precision and extended capacity for molecular detection. However data analysis from this platform is not developed for high sample numbers or for detection of the very large numbers of analytes that this technology detects (more than 1500 per biofluid sample). We will develop an informatics platform for accurate and efficient analysis of data generated from GCxGC/TOF-MS analyses through the following specific aims: (1) Mass informatics for differential metabolomics (2) Interactive visual analysis of metabolite correlation networks and (3) Informatics analysis tools integration. The biological information that our system will deliver is regulation of altered metabolites that relate to phenotypic differences between groups of samples. This information will enable assessment of human health and wellness and will have a direct impact on public health. In the context of existing collaborations our initial large scale application focus will be analyses of metabolomic profiling data from plasma samples of patients with breast and prostate cancer compared with control subjects. Broadly speaking our informatics tools will facilitate efforts in the metabolomics community to perform comparative metabolite profiling with high precision and high volume on the powerful GCXGC-TOF-MS platform. The project consists of the development of algorithms for assessment of metabolite identification accuracy alignment of spectra and normalization of datasets. Separate algorithms will be developed to distinguish specific molecules that are observed to be different between different sample cohorts and to provide a statistical significance context for each differentially expressed molecule. An additional group of algorithms will be developed to enable interactive visual analysis of metabolite correlation networks. Deliverables from this project will include provision of independent software modules that can be remotely invoked via web services and an integrated web-based data analysis pipeline for GCxGC/TOF-MS data.

project_terms:
Algorithms;Area;Biological;Biomedical Research;Blood;Chromatography;Clinical;Collaborations;Communities;Complex;Complex Mixtures;Computational algorithm;Computer software;Data;Data Analyses;Data Files;Data Set;Detection;Development;Disease;Disease Marker;Emerging Technologies;Equilibrium;Gas Chromatography;Health;High temperature of physical object;Human;Informatics;Investigation;Liquid substance;Malignant Neoplasms;Malignant neoplasm of prostate;Marketing;Mass Fragmentography;Mass Spectrum Analysis;Measures;Medicine;Metabolic;Methods;Mission;Modeling;Modification;Molecular;Monitor;Multiple Myeloma;Noise;Online Systems;Output;Pathway Analysis;Patients;Pattern Recognition;Plasma;Preventive;Probability;Process;Regulation;Relative (related person);Research Personnel;Residual state;Running;Sampling;Secure;Series;Signal Transduction;Simulate;Solutions;Source;Speed (motion);Statistical Models;System;Technology;Temperature;Testing;Time;Urine;Variant;Visual;Work;base;biomarker;clinically relevant;cohort;comparative;complex biological systems;data mining;direct application;graphical user interface;human data;improved;instrument;instrumentation;interest;liquid chromatography mass spectrometry;malignant breast neoplasm;metabolomics;open source;programs;public health medicine (field);small molecule;software systems;tool;two-dimensional;web services

public_health_relevance:
PUBLIC HEALTH RELEVANCE: High-throughput molecular omics analysis platforms provide important new technical capabilities to analyze complex biological fluids for disease markers. A particularly important platform for metabolomics is two-dimensional gas chromatography time-of- flight mass spectrometry (GCxGC/TOF-MS) that provides both high precision and extended capacity for molecular detection. This approach usually uses a short polar column after the main analytical column. Typically the second column is operated at a higher temperature than the first column. The metabolites co-eluted from the first GC column are further separated in the second column because of the difference of column temperature and the chromatography matrix. The further separated metabolites are directed to a high capacity time-of-flight mass spectrometry system for detection. Two- dimensional gas chromatography offers significant advantages for analysis of complex samples including: an order-of-magnitude increase in separation capacity significant increase in signal-to-noise ratio and dynamic range and improvement of mass spectral deconvolution and similarity matches. Since GCWGC/TOF-MS can provide more and accurate information it represents powerful tool for the analysis of small molecule metabolites in complex biological systems. However data analysis from this platform is not developed for high sample numbers or for detection of the very large numbers of analytes that this technology detects (more than 1500 per biofluid sample). We will develop a set of computational algorithms for accurate and efficient analysis of data generated from GCxGC/TOF-MS analyses through the following specific aims: (1) Mass informatics for differential metabolomics (2) Interactive visual analysis of metabolite correlation networks and (3) Informatics analysis tools integration. The biological information that our system will deliver is regulation of altered metabolites that relate to phenotypic differences between groups of samples. This information will enable assessment of human health and wellness and will have a direct impact on public health. A direct application of this type of information is metabolite biomarker discovery in clinical biomedical research. In the context of existing collaborations our initial large scale application focus of the developed mass informatics system will be analyses of metabolomic profiling data from human plasma samples of patients with breast cancer and human multiple myeloma compared with corresponding control subjects. With the raw instrument data as input information our informatics tools will perform a series of data mining and discover the metabolites present in the sample and also provide their regulation information. These informatics tools will facilitate efforts in the metabolomics community to perform comparative metabolite profiling with high precision and high volume on the powerful GCXGC-TOF-MS platform. The project consists of the development of algorithms for assessment of metabolite identification accuracy alignment of spectra and normalization of datasets. Separate algorithms will be developed to distinguish specific molecules that are observed to be different between different sample cohorts and to provide a statistical significance context for each differentially expressed molecule. An additional group of algorithms will be developed to enable interactive visual analysis of metabolite correlation networks. Deliverables from this project will include provision of independent software modules that can be remotely invoked via web services and an integrated web-based data analysis pipeline for GCxGC/TOF-MS data.


application_id: 8260004
project_number: 1R21ES021311-01
project_title: Effect of dietary fat on the hepatotoxicity of environmental arsenic
administering_ic: NIEHS
award_notice_date: 2012-05-25
opportunity_number: RFA-ES-11-002
application_type: 1
activity_code: R21
ic: ES
serial_number: 021311
program_official: SHREFFLER, CAROL A
project_start_date: 2012-05-25
project_end_date: 2014-04-30
study_section: Special Emphasis Panel[ZES1 LWJ-J (DI)]
contact_pi_person_id: 1902836
contact_pi: WATSON, WALTER H
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): High intake of dietary fat and chronic exposure to environmental arsenic (As) are independent risk factors for liver disease but there have been no studies on how these two risk factors interact to damage the liver. The majority of obese people in the United States have steatosis (fatty liver) but less than 20% of people with steatosis progress to the much more serious condition of steatohepatitis (fatty liver with inflammation and liver injury) indicating that other environmental factors have an impact on inflammatory liver injury. The current proposal examines the role of environmental As in the progression from steatosis to steatohepatitis. A diet high in fat places a metabolic burden on the liver making it susceptible to injury by a second insult. In the studies proposed here the hypothesis to be tested is that chronic As exposure contributes to liver disease progression by altering metabolic pathways related to inflammation. Specifically this team will examine the basis for their recent observation that As exposure results in inflammatory liver injury in mice fe a high fat diet whereas the same concentration of As is not toxic in mice fed a low fat diet. The plan is to identify pathways altered by high fat As and the combination of the two by measuring changes in liver at the level of metabolomics and proteomics signatures. By constructing a model integrating both the enzymatic activities and metabolites one will be able to identify the pathways where these two stresses interact. These studies are expected to reveal metabolic signaling and regulatory pathways that are associated with inflammatory liver injury in a model of diet-environment interaction that is relevant to the United States population where high fat diets are common and As exposure levels are typically below the threshold for overt hepatotoxicity. This new information will be used as a basis for future studies examining the molecular targets of As that are responsible for increased sensitivity to inflammation. These studies may be applicable to other As- associated illnesses such as cardiovascular disease and cancer that are driven by chronic inflammation.   
   
PUBLIC HEALTH RELEVANCE: Most obese people have fatty liver disease to at least some extent. The proposed studies will examine how environmental As contributes to progression to more serious forms of liver disease.

project_terms:
Address;Affect;Animal Model;Area;Arsenic;Benign;Cardiovascular Diseases;Chronic;Consumption;Data;Development;Diet;Dietary Arsenic;Dietary Fats;Disease;Disease Progression;Environment;Environmental Risk Factor;Exposure to;Fat-Restricted Diet;Fatty Liver;Fatty acid glycerol esters;Figs - dietary;Future;Goals;Hepatotoxicity;Individual;Inflammation;Inflammatory;Inflammatory Response;Injury;Intake;Ions;Knowledge;Label;Liver;Liver diseases;Malignant Neoplasms;Manuscripts;Mass Fragmentography;Measures;Mediating;Meta-Analysis;Metabolic;Metabolic Pathway;Modeling;Molecular Target;Mus;Obesity;Organ;Pathogenesis;Pathway Analysis;Pathway interactions;Peptides;Population;Predisposing Factor;Proteins;Proteome;Proteomics;Regulatory Pathway;Risk;Risk Factors;Role;Sampling;Signal Pathway;Signal Transduction;Steatohepatitis;Stimulus;Stress;Techniques;Testing;Toxic effect;United States;base;biomarker;cell injury;clinically relevant;cytokine;drinking water;feeding;improved;lipid metabolism;liquid chromatography mass spectrometry;metabolomics;mouse model;novel;protein expression;research study;response;sodium arsenite;two-dimensional

public_health_relevance:
Most obese people have fatty liver disease to at least some extent. The proposed studies will examine how environmental As contributes to progression to more serious forms of liver disease.


application_id: 8259428
project_number: 5R03NS075694-02
project_title: Mitochondrial protection of a GDNF propeptide
administering_ic: NINDS
award_notice_date: 2012-03-30
opportunity_number: PA-10-064
application_type: 5
activity_code: R03
ic: NS
serial_number: 075694
program_official: SIEBER, BETH-ANNE
project_start_date: 2011-07-01
project_end_date: 2013-04-30
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 9077753
contact_pi: BRADLEY, LUKE H
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Mitochondrial dysfunction has been identified as one of the key players in Parkinson's disease (PD) pathogenesis. While the etiology is unknown in most cases the development of progressive parkinsonian symptoms has been shown in patients following exposure to various environmental and occupational toxins. Numerous studies demonstrate that these neurotoxins specifically inhibit the mitochondrial respiratory chain complexes of dopaminergic neurons which initiates a cascade of events ultimately leading to cell death. Furthermore the susceptibility to environmental neurotoxins is increased in the aged nervous system. Thus for the long-term treatment of PD and parkinsonian symptoms therapeutic strategies are needed that not only restore dopaminergic neuron function but also provide mitochondrial protection and restoration from various stresses including environmental toxin exposure.  In the past neurotrophic growth factors have received considerable attention as potential therapeutic agents for neurological disorders. However the clinical application of these native molecules has not advanced primarily due to pharmacological disadvantages and challenges associated with directly delivering large protein molecules to the brain. The emergence of physiologically functional propeptides from the neurotrophic factor family provides a wealth of novel smaller sequences for biotherapeutic exploration and evaluation. Examination of the glial cell line-derived neurotrophic factor (GDNF) prosequence predicts internal dibasic endopeptidase sites that would yield a smaller amidated eleven amino acid residue peptide named dopamine neuron stimulating peptide-11 (DNSP-11). Recent evaluation of DNSP-11 has shown that it exhibits similar GDNF-like neurotrophic responses in normal and parkinsonian rat models. However cell culture and proteomic pull-down data suggest that DNSP-11 functions differently than mature GDNF; leading to our hypothesis that DNSP-11's neurobiological actions are through the mitochondria. The research outlined in the current proposal will measure DNSP-11's bioenergetic and protective effects in the MN9D dopaminergic cell line from toxins that specifically target the mitochondrial respiratory complexes. The information obtained in this study will further our understanding of this propeptide's neurobiological activity and provide the basis for future evaluation and biotherapeutic development of DNSP-11.    PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) a chronic neurological disorder that affects over 1 million Americans is characterized by stooped posture balance impairments rigidity resting hand tremors and bradykinesia. While the cause of PD is largely unknown parkinsonian symptoms have been shown to develop following long-term exposure to common environmental toxins that specifically target the mitochondria of dopamine neurons. The goal of this pilot project is to investigate the neuroprotective properties of a novel neurotrophic propeptide DNSP-11 from mitochondrial-specific toxins to pave the way for its downstream evaluation as a potential PD therapeutic.

project_terms:
Affect;Agriculture;American;Amino Acids;Attention;Bioenergetics;Biological Response Modifier Therapy;Bradykinesia;Brain;Cell Culture Techniques;Cell Death;Cell Line;Cells;Chronic;Complex;Data;Development;Disadvantaged;Dopaminergic Cell;Endopeptidases;Etiology;Evaluation;Event;Exhibits;Exposure to;Family;Future;Goals;Growth Factor;Hand;Individual;Measures;Mitochondria;Modeling;Names;Nervous system structure;Neurobiology;Neurotoxins;Occupational;Parkinson Disease;Parkinsonian Disorders;Pathogenesis;Patients;Peptides;Pilot Projects;Posture;Predisposition;Property;Proteins;Proteomics;Rattus;Research;Respiration;Respiratory Chain;Rest;Site;Stress;Symptoms;Testing;Therapeutic;Therapeutic Agents;Toxic Environmental Substances;Toxin;Tremor;aged;base;clinical application;dopaminergic neuron;equilibration disorder;glial cell-line derived neurotrophic factor;mitochondrial dysfunction;nervous system disorder;neurotrophic factor;novel;protective effect;public health relevance;respiratory;response;restoration

public_health_relevance:
PROJECT NARRATIVE Parkinson's disease (PD) a chronic neurological disorder that affects over 1million Americans is characterized by stooped posture balance impairments rigidityresting hand tremors and bradykinesia. While the cause of PD is largely unknownparkinsonian symptoms have been shown to develop following long-term exposure tocommon environmental toxins that specifically target the mitochondria of dopamineneurons. The goal of this pilot project is to investigate the neuroprotective properties of anovel neurotrophic propeptide DNSP-11 from mitochondrial-specific toxins to pave theway for its downstream evaluation as a potential PD therapeutic.


application_id: 8258926
project_number: 4R44HD065388-02
project_title: FastFES Neural Prothesis for Stroke Ambulation and Rehabilitation
administering_ic: NICHD
award_notice_date: 2012-07-05
opportunity_number: PA-10-050
application_type: 4
activity_code: R44
ic: HD
serial_number: 065388
program_official: SHINOWARA, NANCY
project_start_date: 2011-04-01
project_end_date: 2014-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-F(15)B]
contact_pi_person_id: 7771781
contact_pi: HARTMAN, ERIC C
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 129360637
duns_number: 129360637
fips: US
organization_id: 4168101
organization_name: CUSTOMKYNETICS, INC.
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403401290
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-07-05
budget_end_date: 2013-06-30
project_abstract:
DESCRIPTION (provided by applicant):  This FastTrack SBIR proposal aims to disseminate a Functional Electrical Stimulation (FES) technology for stroke ambulation and neuromotor rehabilitation. The FastFES paradigm integrates two rehabilitation approaches fast-paced treadmill walking and FES in a manner that has been shown to both improve gait kinematics when the stimulation is active and to improve performance in clinical tasks with long-term intervention. Precisely timed FES patterns provide: 1) a plantarflexion (PF) assist effect during the terminal double-stance phase of gait; and 2) a dorsiflexion (DF) assist effect during the swing phase. Compared to commercially available DF-only systems the FastFES device will provide improved paretic leg ground reaction forces during push-off as a result of the PF stimulation pattern. This will act to propel the paretic leg through the swing phase of the gait cycle and thus provide more normal gait kinematics. The technology has been developed at the University of Delaware in the laboratory of Dr. Stuart Binder-Macleod PT PhD. The FastFES system will include a leg-worn stimulator that is wirelessly coupled to an instrumented footswitch system. Instrumentation will provide robust and reliable gait cycle measurements to facilitate coordination of the complex FES patterns to the client's volitional gait. A clinician configuration pendant will allow clinicians to program advanced features of the device and to manage multiple users in a clinical environment. The device will also record gait cycle data to summarize its use and to aid the clinician in assessing the device's effectiveness for a particular client. The Phase I project will prove concept feasibility by demonstrating that customKYnetics' stimulator can implement the FastFES's variable frequency train (VFT) stimulation pattern such that contractions of human skeletal muscle are of comparable quality to those produced by the laboratory stimulator. The Phase II project will involve significant engineering efforts to develop the commercialization-ready system and will include a validation study at UD in which individuals with paresis secondary to a stroke iteratively evaluate device prototypes. Efficacy will be demonstrated through a long-term single-blinded randomized controlled clinical intervention study. Outcomes will include kinematic assessment of the client's gait pattern (with and without stim) and assessments of changes in clinical function. The target market for the device will be rehabilitation clinics that serve the stroke market. The device will also be suitable for home/community-use. The product will provide clear differentiation over existing products in the space. The target price for a clinical system will be $5000. The addressable market is estimated at 10000 units for a clinical system and at least 500000 units for a home system.  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;Health Benefit;Hemipareses;Home environment;Human;Individual;Institution;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:
Project Narrative/RelevanceFastFES Neural Prosthesis for Stroke Ambulation and Rehabilitation Applicant Institution: customKYnetics Inc. (PI: Hartman Eric C.) The proposed work may benefit health through development of a functional electrical stimulationsystem indicated for ambulation and neuromotor rehabilitation following stroke (795000 cases per year). Dueto the novel combination of plantarflexion and dorsiflexion stimulation during ambulation the proposedFastFES system may provide improved leg ground reaction forces and provide more normal gait kinematics.


application_id: 8258256
project_number: 5R01CA098664-09
project_title: Repair of oxidative DNA damage in mammalian cells
administering_ic: NCI
award_notice_date: 2013-06-14
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 098664
program_official: OKANO, PAUL
project_start_date: 2003-03-10
project_end_date: 2016-05-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 6617337
contact_pi: IZUMI, TADAHIDE
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): DNA base excision repair (BER) is a ubiquitous and indispensable defense mechanism against cell death mutagenesis and carcinogenesis caused by spontaneously formed DNA damage such as oxidation and alkylation. Apurinic/apyrimidinic endonuclease (APE1 in mammals) arguably determines the BER rate in cells and thus plays a central role in the repair pathway. Recent findings indicate that APE1 is essential for cellular viability and that endogenous DNA damage is lethal if left unrepaired. Independently from its repair activity APE1 interacts with histone deacetylase 1 (HDAC1) to suppress expression of many genes including the parathyroid hormone gene. APE1 also regulates cJun/cFos and other crucial transcription factors. A high of APE1 is often in are expression observed malignant tumor cells which more resistant to radio- and chemotherapeutic treatments suggesting that APE1's repair function increases the chance of survival for cancer cells as well. Thus APE1 may be either beneficial or harmful to humans depending on the type of cells in which it is expressed. Understanding the mechanism for regulation of APE1 activity is therefore crucial for evaluating BER efficiency and its consequences in normal and cancer cells. Indeed cancer predisposition by APE1 deficiency is known and p53 is an upstream regulator of APE1. We have discovered that APE1 is ubiquitinated by mouse double minute 2 (MDM2) and that the ubiquitination is induced by genotoxic stress in a p53-dependent manner. Ubiquitination occurs at specific Lys residues in the APE1 polypeptide and appears to have significant effects on the functions of APE1 and other cellular proteins including XRCC1 (X-ray cross-complementation 1) p53 and HDAC1 that interact directly with APE1. The central hypothesis of this project is that APE1 ubiquitination regulated by MDM2 and p53 modulates the APE1 level and functions in DNA damage response. In order to elucidate the cellular defense mechanism involving this remarkably multifunctional protein we will: (1) determine the effect of APE1 ubiquitination on its enzymatic and DNA binding activities; (2) unravel interaction of ubiquitinated APE1 with factors in BER and p53 signaling network; and (3) establish the regulation of APE1 ubiquitination in vivo. These parameters are crucial to predict susceptibility of cancer cells against therapeutic drugs that generates genomic instability. With the research facilities provided by Louisiana Cancer Research Consortium (LCRC) this project in the long-term should provide insights for developing new modalities for adjuvant cancer therapies and organ preservation and for improving the management of other age-related pathophysiology.

project_terms:
Adjuvant;Affect;Affinity;Alkylation;Base Excision Repairs;Cancer cell line;Cell Death;Cells;DNA;DNA Binding;DNA Damage;Defense Mechanisms;Disease;Double Minutes;Effectiveness;Functional disorder;Genes;Genomic Instability;Genotoxic Stress;Healed;Hormones;Human;Kinetics;Lead;Left;Louisiana;Malignant Neoplasms;Mammalian Cell;Mammals;Methodology;Modality;Monoubiquitination;Mus;Mutagenesis;Mutation;Normal Cell;Oncogene Proteins;Organ Preservation;Oxidative Stress;Parathyroid gland;Pathway interactions;Pharmaceutical Preparations;Play;Predisposition;Protein p53;Proteins;Radiation therapy;Reactive Oxygen Species;Reagent;Regulation;Regulator Genes;Reporting;Resistance;Roentgen Rays;Role;Signal Transduction;Smoke;Suppressor Genes;Testing;Therapeutic;Toxic Environmental Substances;Ubiquitination;age related;anticancer research;cancer cell;cancer therapy;carcinogenesis;cell type;chemotherapy;domain mapping;endonuclease;healing;human APEX1 protein;human HDAC1 protein;improved;in vivo;insight;neoplastic cell;oxidation;oxidative DNA damage;polypeptide;public health relevance;repaired;research facility;response;transcription factor

public_health_relevance:
DNA is continuously damaged by environmental toxicants like smoke and by reactive oxygen radicals generated inside of our bodies. Damaged DNA causes mutations and may ultimately lead to cancer and age- related diseases. This project will help us understand how to enhance natural healing of DNA damage and will help to improve the current methodology for non-surgical cancer treatments including radiotherapy and chemotherapy.


application_id: 8258238
project_number: 5R01HL108621-02
project_title: Mitophagic and anti-angiogenic mechanism of heart failure
administering_ic: NHLBI
award_notice_date: 2011-12-30
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 108621
program_official: ADHIKARI, BISHOW B
project_start_date: 2011-04-15
project_end_date: 2015-12-31
study_section: Special Emphasis Panel[ZRG1-VH-B(02)M]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Although heart failure is inevitable disease its management depends on the understanding of the mechanism of ailing to failing myocardium. During heart failure the heart undergoes compensatory remodeling (i.e. left ventricle hypertrophy (LVH) and vascular angiogenesis. Unfortunately during end-stage heart failure there is dis-coordination between the LVH and angiogenesis (i.e. LVH persists but angiogenesis declines). This leads to continue increase in LV wall stress leading to failure. Remodeling by its very nature implies synthesis degradation and re-arrangement of intra and inter cellular matrix. Matrix metalloproteinases (MMPs) are designer architecture and tailor. The long-term goal of this project is to understand the differential role of MMPs in structural and functional heterogeneity in myocardial remodeling. The selective MMP-2 gene ablation reduces survival and exacerbates cardiac failure-induced by myocardial inflammation. MMP-9 gene ablation is cardioprotective. In human heart end-stage failure MMP-9 activation supersedes the MMP-2 activation. The hypothesis of this proposal is that MMP-2 is constitutive and during compensatory phase activates proteinase activated receptor-1 (PAR-1 a GPCR) and releases growth factors via the activation of anti-stress (PKB/AKT). Chronic stress leads to mitochondrial mitophagy and activation of MMP-9 and MMP-13 (an interstitial collagenase in rodent and MMP-1 in human). TIMP-3 (an apoptotic/autophagic factor) and anti-angiogenic statins are released The hypothesis will be tested by following three specific aims: Specific Aim #1: To determine whether the induction of MMP-2 PAR-1 G1s and AKT causes compensatory hypertrophy and mitochondrial mitophagy causes MMP-9 activation and decreases G1s and AKT in de-compensatory heart failure. Specific Aim #2: To determine whether the MMP-2 releases angiogenic growth factors during compensatory remodeling and MMP-9 releases anti-angiogenic statins in de-compensatory heart failure. Specific Aim #3: To determine whether the mitochondrial mitophagy attenuates angiogenesis in part by activating MMP-9 releasing TIMP-3 and generating statins during de-compensatory heart failure. These studies will delineate the causative role of PAR-1 MMP TIMP G1s and mitophagy in switch from compensatory LVH and angiogenesis to de-compensatory LVH and anti-angiogenesis and will have therapeutic ramifications for chronic heart failure.    PUBLIC HEALTH RELEVANCE: These studies will delineate the differential role of mitochondrial mitophagy and anti- angiogenesis mechanisms in end-stage heart failure. The differential role of different MMPs in angiogenesis and anti-angiogenesis in transition from compensatory hypertrophy to de-compensatory heart failure will be determined. The positive outcome of this project will have therapeutic ramifications for chronic heart failure.

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

public_health_relevance:
Project NarrativeThese studies will delineate the differential role of mitochondrial mitophagy and anti-angiogenesis mechanisms in end-stage heart failure. The differential role of differentMMPs in angiogenesis and anti-angiogenesis in transition from compensatoryhypertrophy to de-compensatory heart failure will be determined. The positive outcomeof this project will have therapeutic ramifications for chronic heart failure.


application_id: 8257040
project_number: 1R01HL107319-01A1
project_title: Mechanisms of thoracic aortic aneurysms
administering_ic: NHLBI
award_notice_date: 2012-03-16
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: HL
serial_number: 107319
suffix: A1
program_official: TOLUNAY, ESER
project_start_date: 2012-04-01
project_end_date: 2016-03-31
study_section: Special Emphasis Panel[ZRG1 VH-B (02)]
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
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): Thoracic aortic aneurysms (TAAs) most commonly develop in the ascending region in an asymptomatic manner. Frequently the first indication of its presence is rupture that commonly leads to death. TAAs are the life-threatening consequence in patients afflicted with a broad range of genetically determined diseases; one of the most common being Marfan's disease. The only current therapeutic strategy for individuals diagnosed with TAAs is surgical options. Consequently there is a pressing need for mechanistic insight into TAAs to develop effective therapeutics.  We have recently demonstrated that AngII infusion also leads to TAAs that are localized to the ascending aorta. AngII-induced TAAs are attenuated by CC Chemokine receptor 2 (CCR2) deficiency. This infers a role for monocyte chemoattractant protein-1 (MCP-1) in TAAs although CCR2 also interacts with other chemokines. We have recently demonstrated that endothelial-specific deficiency of AT1a receptors imparts a similar degree of attenuation of AngII-induced TAAs as whole body CCR2 deficiency. These two observations could potentially be associated via a paracrine mechanism by which AngII stimulates MCP-1 release the ligand that determines the major effects of CCR2 stimulation. The AngII-induced TAAs are characterized by profound medial macrophage accumulation that is predominantly on the adventitial aspect. On the basis of this briefly described background we are proposing to test the central hypothesis that the MCP-1-CCR2 axis promotes AngII-induced TAAs localized to the ascending region through an endothelial-mediated mechanism of macrophage recruitment from the adventitia via aortic region- specific effects. To test this hypothesis the following specific aims will be addressed: Aim 1. Determine the role of the MCP-1-CCR2 axis in development of AngII-induced TAAs. A. Does whole body deficiency of either MCP-1 or CCR2 promote equivalent reductions in AngII-induced TAAs that are persistent and associated with reduced medial macrophage accumulation? B. Is the source of MCP-1 in promoting TAAs due to AngII releasing this chemokine directly from endothelial or indirectly via specific SMC populations? Aim 2. Determine the origin of medial macrophages accumulating in ascending aortas during development of AngII-induced TAAs. A. What is the sequence of leukocytic infiltration in the development of AngII-induced TAAs and does this correlate to the expression of MCP-1 and CCR2? B. Are macrophages that accumulate in media and adventitia of ascending aortas during AngII infusion derived from blood or tissue origin? C. Is leukocyte accumulation in human ascending aortic aneurysmal tissue associated with MCP-1 and CCR2 expression?   
   
PUBLIC HEALTH RELEVANCE: Aortic aneurysmal diseases have devastating health consequences and are increasingly more common. Despite the large impact on public health there is a relatively paucity of investigative efforts on these diseases. Consequently there are no defined medical options developed to provide an alternative to surgical intervention. Further research in aortic aneurysmal diseases is a public health imperative.

project_terms:
Abdomen;Abdominal Aortic Aneurysm;Address;Affect;Angiotensin II;Anterior;Aorta;Area;Attenuated;Blood;CC chemokine receptor 2;CCL2 gene;Cardiac;Cells;Cessation of life;Complex;Defect;Development;Diagnosis;Disease;Embryo;Endothelial Cells;Fibroblasts;Growth;Health;Heart;Human;Individual;Infiltration;Infusion procedures;Leukocytes;Life;Ligands;Literature;Medial;Mediating;Mediator of activation protein;Medical;Monocyte Chemoattractant Protein-1;Mus;Neural Crest;Operative Surgical Procedures;Pathology;Patients;Pericytes;Population;Research;Role;Rupture;Smooth Muscle Myocytes;Source;Specificity;Structure;Surface;Testing;Therapeutic;Thoracic Aortic Aneurysm;Thoracic aorta;Tissues;Tunica Adventitia;Ulcer;ascending aorta;attenuation;base;cell type;chemokine;disease characteristic;insight;macrophage;neutralizing antibody;paracrine;public health medicine (field);receptor


application_id: 8256676
project_number: 5R01CA060872-15
project_title: Mechanism of Apoptosis and Inhibition of Tumor Progression and Metastasis by Par-
administering_ic: NCI
award_notice_date: 2012-04-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 060872
program_official: SPALHOLZ, BARBARA A
project_start_date: 1995-09-30
project_end_date: 2014-04-30
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
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
project_abstract:
DESCRIPTION (provided by applicant): Prostate apoptosis response-4 protein (Par-4; also known as PAWR) is a leucine zipper domain protein that is conserved in vertebrates. During the previous funding period we showed the core effector domain of Par-4 (amino acids 137-195 designated the SAC domain) is necessary and sufficient to induce apoptosis. Interestingly both Par-4 and its SAC domain induce apoptosis selectively in cancer cells but not in normal cells. Although ectopic Par-4 and the SAC domain have long been thought to effect apoptosis by acting within the cell nucleus to inhibit NF-kappaB our recent transient transfection studies unexpectedly displayed apoptosis in neighboring cells that did not express the Par-4 or SAC plasmid. Moreover conditioned medium (CM) from Par-4 transfected cells induced apoptosis when applied to cancer cells but not to normal cells; this implies over-expression of Par-4 leads to the secretion of a pro-apoptotic activity. Both Par-4 and the SAC protein were detected in the CM by Western blot analysis and the apoptotic activity in this CM was neutralized by antibodies against Par-4. The apoptotic activity was diminished in the CM from Par-4 transfectants treated with brefeldin A indicating Par-4 and SAC secretion (or sPar-4 and sSAC respectively) occurs by the classical pathway (i.e. from the endoplasmic reticulum to the Golgi and then to the cell membrane). Importantly CM from normal and cancer cells contains endogenous Par-4 of which the levels increase upon treatment with TRAIL (a short term exposure that is insufficient to produce apoptosis) thereby indicating secretion is physiologically relevant and not an artifact associated with over-expression of the Par-4 and SAC constructs. Based on these data we hypothesize endogenous and exogenous sPar-4 and sSAC exert cancer-specific apoptotic effects via both intracellular and extracellular mechanisms. We will address this hypothesis from a mechanistic perspective characterizing secreted Par-4 and SAC in prostate cancer cells and clarifying the means by which they selectively initiate apoptosis in cancer cells. Specifically we will 1) Delineate the mechanism of Par-4/SAC secretion and apoptosis by sPar-4/sSac in prostate cancer cells; 2) Test the growth suppressive effects of sPar-4 and sSAC domain in prostate cancer models; and 3) Study the inter-dependence of extracellular and intracellular Par-4 in inducing apoptosis in cancer cells. As our recent studies indicate Par- 4 and its SAC domain are secreted and that recombinant (r) Par-4 or rSAC can induce apoptosis when applied exogenously to cells these data may hold significant clinical relevance. Our results introduce the novel prospect of using sPar-4 or sSAC to induce apoptosis not only in local or superficially confined tumors into which Par-4 or SAC can be readily delivered intratumorally but also to distant metastases by intravenous injection or bone-marrow transplantation which we will explore in this proposal. PUBLIC HEALTH RELEVANCE: Our research focuses on the secreted forms of Par-4 and it core effector domain SAC both of which selectively induce apoptosis in cancer cells. We will study these two proteins from a mechanistic perspective both in vitro and in vivo characterizing secreted Par-4 and SAC in prostate cancer cells and clarifying the means by which they selectively initiate apoptosis in cancer cells. The proposed science will explore the novel prospect of using sPar-4 or sSAC to induce apoptosis not only in local or superficially confined tumors into which Par-4 or SAC can be readily delivered intratumorally but also to distant metastases by intravenous injection or bone-marrow transplantation.

project_terms:
Address;Adenocarcinoma;Amino Acids;Animals;Apoptosis;Apoptotic;Binding (Molecular Function);Bone Marrow Transplantation;Brefeldin A;Cancer Model;Cell Nucleus;Cell Surface Receptors;Cell Survival;Cell membrane;Cells;Cessation of life;Conditioned Culture Media;Control Animal;Cyclic AMP-Dependent Protein Kinases;Data;Dependence;Distant Metastasis;Endoplasmic Reticulum;Exposure to;Frequencies (time pattern);Funding;Golgi Apparatus;Growth;Health;In Vitro;Induction of Apoptosis;Inhibition of Apoptosis;Lesion;Leucine Zippers;Liver;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Morphologic artifacts;Mus;NF-kappa B;Neoplasm Metastasis;Normal Cell;PAWR gene;PAWR protein;Pathway interactions;Phosphorylation;Plasmids;Prostate;Prostatic;Prostatic Intraepithelial Neoplasias;Prostatic Neoplasms;Proteins;RNA Interference;Receptor Signaling;Recombinants;Research;Science;Signal Pathway;Spleen;Stromal Cells;TNFSF10 gene;Tertiary Protein Structure;Testing;Therapeutic;Transfection;Transgenes;Transgenic Animals;Transgenic Mice;Transgenic Organisms;Vertebrates;Western Blotting;base;cancer cell;clinically relevant;extracellular;glucose-regulated proteins;in vivo;inhibitor/antagonist;insight;intravenous injection;neutralizing antibody;novel;offspring;prevent;tumor;tumor growth;tumor progression


application_id: 8256671
project_number: 5R01CA140991-04
project_title: Targeting Glucose Metabolism in Cancer
administering_ic: NCI
award_notice_date: 2012-04-25
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 140991
program_official: SPALHOLZ, BARBARA A
project_start_date: 2009-07-01
project_end_date: 2014-04-30
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 9475582
contact_pi: TELANG, SUCHETA
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): A high rate of glycolytic flux even in the presence of oxygen is a central metabolic hallmark of neoplastic tumors. Cancer cells preferentially utilize glycolysis in order to satisfy their increased energetic and biosynthetic requirements. This metabolic phenotype is confirmed by positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxy-glucose which demonstrates that tumors take up 10-fold more glucose than adjacent normal tissues in vivo. Over-expression of HIF-1a and myc ras activation and loss of p53 function stimulate glycolysis by activating a family of four bifunctional 6-phosphofructo-2-kinase/fructose-26-bisphosphatases (PFKFB) which synthesize fructose-26-bisphosphate (F26BP) an allosteric activator of 6-phosphofructo-1- kinase (PFK-1) which is an essential control point in the glycolytic pathway. The PFKFB enzymes are encoded by four genes (PFKFB1-4) reportedly expressed in distinct tissues: liver/skeletal muscle (PFKFB1) heart (PFKFB2) placenta (PFKFB3) and testis (PFKFB4). Previous studies have focused on the PFKFB3 isozyme as the dominant source of F26BP in neoplastic cells due to its high kinase:phosphatase ratio (~740:1) and overexpression in multiple tumors. The identification of the specific PFKFB isozyme responsible for the high rate of glycolysis in cancer cells may allow for the development of novel agents that suppress tumor growth through inhibition of glycolysis. In preliminary studies we measured mRNA expression of the four PFKFB isozymes in 20 tumor tissues by multiplex RT-PCR and found that PFKFB4 mRNA (and not PFKFB3) was markedly increased in 17/20 tumors relative to adjacent normal tissues. We speculated that the high PFKFB4 expression may be caused by disparate oncogenic pathways converging to enhance glycolytic flux. We found that hypoxic exposure of K-rasG12S+ A549 lung adenocarcinoma cells and introduction of H-rasG12V into immortalized human bronchial epithelial cells increased PFKFB4 mRNA and protein expression. Further cell fractionation revealed that the PFKFB4 protein and not PFKFB3 localized to the cytoplasm the cellular compartment of both PFK-1 and glycolysis. Last transient siRNA silencing of PFKFB4 mRNA expression in K- rasG12S+ A549 cells decreased steady-state concentration of F26BP glycolytic flux and anchorage- independent tumor growth in mice. Taken together these preliminary studies provide rationale for further investigation of the PFKFB4 isozyme as a possible novel target for the development of anti-neoplastic agents. We hypothesize that the PFKFB4 isozyme is required for the high glycolytic flux survival growth and spread of transformed cells. We plan to test this hypothesis by pursuing the following specific aims: 1. To examine the requirement for F26BP synthesized by PFKFB4 for glycolytic and mitochondrial metabolism. 2. To determine the requirement for F26BP synthesized by PFKFB4 for growth invasiveness and survival of normal immortalized and ras-transformed epithelial cells. 3. To examine the effect of PFKFB4 genomic deletion on growth and metabolism of ras-dependent tumors in vivo using a Cre-lox inducible mouse knockout of PFKFB4. PUBLIC HEALTH RELEVANCE: We anticipate that shRNA silencing or genomic deletion of the PFKFB4 isozyme will attenuate the neoplastic potential of transformed epithelial cells and conversely that increased F26BP (from overexpression of PFKFB4) will enhance glycolytic flux and augment tumor growth. These findings may validate PFKFB4 as a new target for the inhibition of glycolysis. Accordingly suppression of glycolytic flux in cancer via the development of small molecule inhibitors of PFKFB4 through computational screening for competitive inhibitors of the PFKFB4 substrate-binding domain may reduce the high mortality that is associated with cancer.

project_terms:
6-Phosphofructo-2-kinase;6-Phosphofructokinase;A549;Actins;Adenocarcinoma Cell;Age-Months;Anchorage-Independent Growth;Apoptosis;Attenuated;Basement membrane;Binding (Molecular Function);Brain;Breast;Carbon;Cell Fractionation;Cells;Chickens;Citric Acid Cycle;Colon;Cytoplasm;Data;Development;Enzymes;Epithelial Cells;Exons;Family;Freezing;Fructose;Gel;Genes;Genomics;Glucose;Glycolysis;Glycolysis Inhibition;Growth;Heart;Human;Hypoxia;Immunohistochemistry;In Situ;In Situ Nick-End Labeling;In Vitro;Investigation;Isoenzymes;Knockout Mice;Label;Lactic acid;Lamins;Large T Antigen;Liver;Lung;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Mammary Neoplasms;Mammary gland;Measures;Messenger RNA;Metabolic;Metabolism;Mitochondria;Modeling;Mortality Vital Statistics;Mouse Mammary Tumor Virus;Mus;Mutation;NADH;Normal tissue morphology;Nude Mice;Oncogenic;Open Reading Frames;Organ;Ovary;Oxygen;Oxygen Consumption;Pathway interactions;Phenotype;Phosphoric Monoester Hydrolases;Phosphotransferases;Placenta;Positron-Emission Tomography;Production;Promotor (Genetics);Protein p53;Proteins;Regulation;Relative (related person);Reporting;Resistance;Reverse Transcriptase Polymerase Chain Reaction;Screening procedure;Site;Skeletal muscle structure;Small Interfering RNA;Source;Specimen;Subfamily lentivirinae;TOCSY;Tamoxifen;Telomerase;Testing;Testis;Tissues;Transgenes;Tumor Tissue;Vascularization;Western Blotting;base;cancer cell;cancer type;cell transformation;cellular transduction;design;glucose metabolism;glucose uptake;in vivo;inhibitor/antagonist;mRNA Expression;neoplastic;neoplastic cell;neurotensin mimic 1;novel;overexpression;protein expression;public health relevance;recombinase;shunt pathway;small hairpin RNA;small molecule;tumor;tumor growth;vector

public_health_relevance:
We anticipate that shRNA silencing or genomic deletion of the PFKFB4 isozyme will attenuate theneoplastic potential of transformed epithelial cells and conversely that increased F26BP (from overexpressionof PFKFB4) will enhance glycolytic flux and augment tumor growth. These findings may validate PFKFB4 as anew target for the inhibition of glycolysis. Accordingly suppression of glycolytic flux in cancer via thedevelopment of small molecule inhibitors of PFKFB4 through computational screening for competitive inhibitorsof the PFKFB4 substrate-binding domain may reduce the high mortality that is associated with cancer.


application_id: 8255335
project_number: 5R01CA133171-03
project_title: The role of the Ras effector Nore1a in tumor suppression
administering_ic: NCI
award_notice_date: 2012-04-24
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 133171
program_official: WATSON, JOANNA M
project_start_date: 2010-07-01
project_end_date: 2015-04-30
study_section: Cancer Molecular Pathobiology Study Section[CAMP]
contact_pi_person_id: 8801334
contact_pi: CLARK, GEOFFREY J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Nore1a is a member of the RASSF family of tumor suppressors. It is frequently down- regulated in primary human tumors and is genetically linked to a familial human cancer syndrome. Over-expression of Nore1a can promote apoptosis cell cycle arrest and senescence. Restoration of Nore1a expression to physiological levels blocks the tumorigenic phenotype and shRNA mediated inactivation of Nore1a enhances the transformed phenotype. Thus the evidence that Nore1a is an important human tumor suppressor is strong. Nore1a also directly binds the Ras oncoprotein and appears to serve as a novel effector mediating some of the pro-apoptotic and pro-senescent effects of oncogenic Ras. Thus loss of function of Nore1a may be particularly important to Ras dependent tumors allowing oncogenic Ras to circumvent its apoptotic and senescent functions. However the signaling pathways controlled by Nore1a have not been defined and no animal model for Nore1a function has been investigated. Furthermore the effects of loss of Nore1a function on the transforming effects of oncogenic Ras have not been characterized.  Nore1a lacks obvious enzymatic activity and little is known about its mechanism of action. However it has been hypothesized that it may serve as a scaffolding protein to modulate the formation of tumor suppressor complexes. We have now identified two tumor suppressors in endogenous complex with Nore1a: the Homeodomain Interacting Protein Kinase 2 (HIPK2) protein and the Von Hippel-Lindau protein (VHL) a notorious tumor suppressor which plays a critical role in the development of the majority of Renal Cell Carcinomas (RCC). Both HIPK2 and VHL act in part by directly modulating the master tumor suppressor p53. Defects in p53 have been detected in approximately 50% of human tumors and it may be argued that p53 is the most critical tumor suppressor yet identified. Thus Nore1a may function by modulating p53 by dual pathways and could serve as part of the well known but poorly characterized link between Ras and p53.  We propose a series of experimental aims designed to determine the precise role of Nore1a loss of function in the development of the tumorigenic phenotype and in Ras mediated transformation. This includes a proposal to determine the role of the Nore1a/Ras interaction in vivo using a novel Nore1a knockout mouse model. We will then determine if the mechanism of action of Nore1a involves the modulation of the HIPK2 or VHL tumor suppressors and whether Nore1a acts to integrate their effects upon p53. We anticipate that these experiments will identify Nore1a as an important novel diagnostic and therapeutic target for cancer.    PUBLIC HEALTH RELEVANCE: These studies will serve to define the role of a novel potential tumor suppressor Nore1a in human cancer. They will determine if Nore1a is an important diagnostic/prognostic marker for cancer. They will also determine if Nore1a may be a suitable candidate for the development of epigenetic therapy to restore its normal function in tumor cells.

project_terms:
Animal Model;Apoptosis;Apoptotic;Binding (Molecular Function);Cell Cycle Arrest;Complex;Defect;Development;Diagnostic;Epigenetic Process;Family;Human;Knockout Mice;Link;Malignant Neoplasms;Mediating;Oncogene Proteins;Oncogenic;Pathway interactions;Phenotype;Physiological;Play;Prognostic Marker;Protein Kinase;Protein p53;Proteins;Renal Cell Carcinoma;Role;Scaffolding Protein;Series;Signal Pathway;Signal Transduction;Syndrome;Tumor Suppression;Tumor Suppressor Proteins;VHL protein;Von Hippel-Lindau Tumor Suppressor Protein;design;homeodomain;in vivo;loss of function;member;mouse model;neoplastic cell;new therapeutic target;novel;novel diagnostics;public health relevance;research study;restoration;senescence;small hairpin RNA;tumor;tumorigenic

public_health_relevance:
These studies will serve to define the role of a novel potential tumor suppressor Nore1ain human cancer. They will determine if Nore1a is an important diagnostic/prognosticmarker for cancer. They will also determine if Nore1a may be a suitable candidate forthe development of epigenetic therapy to restore its normal function in tumor cells.


application_id: 8254452
project_number: 5R01CA153227-03
project_title: Trial of mesna to prevent doxorubicin-induced plasma protein oxidation and TNFa r
administering_ic: NCI
award_notice_date: 2012-05-01
opportunity_number: RFA-GM-10-009
application_type: 5
activity_code: R01
ic: CA
serial_number: 153227
program_official: SONG, MIN-KYUNG H
project_start_date: 2010-08-01
project_end_date: 2014-05-31
study_section: ZCA1-SRLB-R(M1)R
contact_pi_person_id: 9360703
contact_pi: HAYSLIP, JOHN
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): Cognitive dysfunction after cancer chemotherapy or 'chemobrain' occurs after anthracycline- containing regimens. Since anthracyclines such as doxorubicin do not enter the central nervous system the mechanism behind this debilitating sequela of therapy has remained obscure. In contrast cardiomyopathy is a well-established toxicity of doxorubicin therapy. We propose two paradigm- shifting hypotheses to 1) explain the cognitive and cardiac toxicities of anthracycline chemotherapy and 2) to propose a remedy. In animal models doxorubicin-induced CNS and cardiac damage can be reversed with anti-TNF-1 antibody and with the antioxidant 3-GCEE. In an initial clinical study we observed a significant decrease in oxidative modification of plasma proteins after doxorubicin administration in children who were coincidentally receiving mesna a drug closely related to 3-GCEE compared to children who were not coincidentally receiving mesna. Mesna has an extracellular mechanism of action and is frequently given in combination chemotherapy regimens to prevent hemorrhagic cystitis associated with the alkylating agents ifosfamide and high-dose cyclophosphamide and is commonly coincidentally co-administered with anthracyclines without affecting cancer therapy outcomes. One of the plasma proteins oxidized by doxorubicin in these patients was APOA1. In further animal studies we found that mesna abrogates doxorubicin-induced oxidative modification of plasma proteins and prevents induction of stress markers in heart and brain tissues and in further in vitro studies we have shown that reduced APOA1 inhibits LPS-induced TNF- 1 release from the J774.4 macrophage cell line while oxidized APOPA1 activates LPS-induced TNF- 1 release from the J774.4 cells. Therefore we hypothesize mesna will prevent doxorubicin-induced oxidative modification of plasma proteins including APOA1 and thus prevent TNF-1 production. We will test this hypothesis in a blinded prospective clinical trial. Eligible participants will be cancer patients with breast cancer scheduled to receive the standard regimen A/C (doxorubicin and cyclophosphamide) and non-Hodgkin lymphoma patients scheduled to receive doxorubicin in CHOP or R-CHOP regimens. Participants will receive one cycle with mesna 360 mg/m2 and another cycle with saline prior to and 3 hours after doxorubicin. The primary endpoint will be determination of difference in oxidation of plasma proteins and TNF-1 levels at 6 hours post doxorubicin between the mesna-containing cycles and the saline-containing cycles. If our initial findings are confirmed in this pilot trial 1) plasma protein oxidation will be established as a novel mechanism of toxicity 2) a hitherto unknown drug interaction between doxorubicin and mesna will be established and 3) a larger randomized trial would be justified to study mesna to prevent the sequelae of doxorubicin therapy.     PUBLIC HEALTH RELEVANCE: Cancer patients receiving chemotherapy regimens that include the anthracycline drugs such as doxorubicin are at risk for developing cognitive and cardiac impairment. We propose a novel hypothesis that these side effects are due to direct oxidative damage of plasma proteins by doxorubicin and we have demonstrated in an animal model that the drug mesna which is used to prevent other complications of other chemotherapy drugs prevents doxorubicin-induced plasma protein oxidative damage and the subsequent induction of markers of neurologic and cardiac injury. Goal: This clinical study will determine whether mesna prevents doxorubicin-induced damage of plasma proteins in cancer patients and will establish plasma protein oxidation as a potential mechanism of anthracycline-induced cognitive and cardiac dysfunction.

project_terms:
Adverse effects;Affect;Alkylating Agents;Animal Model;Animals;Anthracyclines;Antibodies;Antineoplastic Agents;Antioxidants;Back;Blinded;Blood;Blood - brain barrier anatomy;Brain Injuries;Cancer Patient;Cardiac;Cardiomyopathies;Cardiotoxicity;Cell Line;Cells;Chemotherapy-Oncologic Procedure;Child;Clinic;Clinical Research;Clinical Trials;Cognitive;Cyclophosphamide;Cystitis;Dose;Doxorubicin;Drug Interactions;Effectiveness;Functional disorder;Goals;Heart;Hematopoietic;Hour;Ifosfamide;Impaired cognition;Impairment;In Vitro;Injury;Intravenous;Mediating;Mesna;Modeling;Modification;Moscow;Mus;Myopathy;Neuraxis;Neurologic;Non-Hodgkin's Lymphoma;Participant;Patient Schedules;Patients;Pharmaceutical Preparations;Plasma Proteins;Principal Investigator;Production;Proteins;Proteomics;Reactive Oxygen Species;Regimen;Risk;Saline;Schedule;Series;Stress;Syndrome;TNF gene;Testing;Tissues;Toxic effect;Treatment Protocols;brain tissue;cancer therapy;chemobrain;chemotherapy;eligible participant;extracellular;macrophage;malignant breast neoplasm;novel;oxidation;oxidative damage;pilot trial;prevent;programs;prospective;public health relevance;randomized trial;therapy outcome

public_health_relevance:
Program Director/Principal Investigator (Last First Middle): Moscow Jeffrey A.NarrativeRelevance: Cancer patients receiving chemotherapy regimens that include the anthracycline drugssuch as doxorubicin are at risk for developing cognitive and cardiac impairment. We propose a novelhypothesis that these side effects are due to direct oxidative damage of plasma proteins bydoxorubicin and we have demonstrated in an animal model that the drug mesna which is used toprevent other complications of other chemotherapy drugs prevents doxorubicin-induced plasmaprotein oxidative damage and the subsequent induction of markers of neurologic and cardiac injury.Goal: This clinical study will determine whether mesna prevents doxorubicin-induced damage ofplasma proteins in cancer patients and will establish plasma protein oxidation as a potentialmechanism of anthracycline-induced cognitive and cardiac dysfunction.PHS 398/2590 (Rev. 11/07) Page Continuation Format Page


application_id: 8254376
project_number: 5T35DK072923-07
project_title: Summer Endocrine Research Training Program
administering_ic: NIDDK
award_notice_date: 2012-03-28
opportunity_number: PA-08-227
application_type: 5
activity_code: T35
ic: DK
serial_number: 072923
program_official: PODSKALNY, JUDITH M,
project_start_date: 2006-05-01
project_end_date: 2016-04-30
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
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): This is a competing renewal of NIH 5 T35 DK072923 which was originally funded for five years with 6 students supported/year. The principal objectives of the Summer Endocrine Research Training Program are to provide research experience for medical students and to stimulate interest among medical students in becoming clinical research scientists. Trainees engage in research activities with faculty members and participate in projects that are germane to the field of endocrinology and the health concerns of this country. Over the past 3 years we have trained 18 second year medical students who participated in our "Summer Endocrine Research Training Program" research programs in Endocrinology Metabolism and Diabetes at University of Louisville School of Medicine and as this application is submitted 6 new second year medical students will begin their summer research in this program. Approximately 25% of our trainees are members of minority populations and 1/3rd of trainees are female. Our program includes didactic instruction ("Summer Endocrine Research Training Seminar Series" and "Bench-to-Bedside: Introduction to Clinical Research") as well as a hands-on-research experience under the direction of a team of experienced basic and clinical research scientists centered on a core of NIDDK-funded investigators and collaborating faculty. Trainees also attend Endocrine-specific seminars and journal clubs in basic and clinical research. The present application addressses 2 Specific Aims: Aim 1: To provide hands-on training in basic and clinical Endocrine-based research to medical students in a structured mentored environment. Aim 2: To provide an interactive educational experience that introduces medical students the fundamental skills necessary for basic translational and clinical Endocrine-based research. The T35 competing renewal funding will provide stipends for a 10-week summer program for 8-10 second year medical students. Our current T35 grant funds 6 students/year. Given the increase in training faculty mentors and NIDDK-funded research at the University of Louisville School of Medicine documented within the text we request funds to increase to 8 students/year in years 6 and 7 (Yr. one and two of the next funding period) 9 in years 8 and 9 (Yr. three and four of the next funding period and 10 in year 10 (Yr. five of the next funding period).     PUBLIC HEALTH RELEVANCE: This competing renewal T35 application directly addresses the NIH's goal of ensuring that a diverse pool of highly trained scientists are available in the field of Endocrinology to address the Nation's biomedical and clinical research needs.

project_terms:
Address;Basic Science;Biomedical Research;Clinical;Clinical Research;Country;Diabetes Mellitus;Endocrine;Endocrinology;Ensure;Environment;Faculty;Female;Funding;Goals;Grant;Health;Instruction;Journals;Medical Students;Mentors;Minority;National Institute of Diabetes and Digestive and Kidney Diseases;Population;Research;Research Activity;Research Personnel;Research Training;Scientist;Series;Structure;Students;Text;Training;Training Programs;United States National Institutes of Health;Universities;base;bench to bedside;experience;interest;medical schools;member;programs;public health relevance;skills


application_id: 8253142
project_number: 1R42DA032191-01A1
project_title: Transdermal Naltrexone for Opiate Addiction and Alcoholism
administering_ic: NIDA
award_notice_date: 2012-07-26
opportunity_number: PA-11-097
application_type: 1
activity_code: R42
ic: DA
serial_number: 032191
suffix: A1
program_official: PARK, MOO KWANG
project_start_date: 2012-08-01
project_end_date: 2013-11-30
study_section: Special Emphasis Panel[ZRG1 MOSS-D (12)]
contact_pi_person_id: 1866585
contact_pi: STINCHCOMB, AUDRA L.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178031683
primary_uei: EKBZRSBPS8A3
duns_number: 178031683
uei: EKBZRSBPS8A3
fips: US
organization_id: 10006751
organization_name: ALLTRANZ, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): According to the National Survey of Drug Use and Health (NSDUH) of 2008 7.2 million Americans are in need of treatment for Substance-Related Disorders (SRDs) and a large proportion of those need treatment for opiate pain reliever heroin and alcohol addiction. Naltrexone (NTX) an opioid antagonist is currently used in oral tablet form to help maintain opioid addicts in a drug-free state. NTX is also FDA-approved for the treatment of alcohol dependence. Substantial clinical evidence exists for the benefits of NTX treatment in smoking cessation especially in women. Very intriguing clinical trial data has also been observed in amphetamine-dependent individuals which is especially important as methamphetamine dependence has no FDA-approved treatment options. Treatment with NTX in the 90's produced variable success rates in addicts; however current clinical NTX therapy is being optimized based on human pharmacogenetic data. A 30-day depot injection of the drug has been approved for the treatment of opiate addiction and alcoholism; however postmarketing reports of serious injection site reactions (cellulitis abscess and necrosis) have recently required patient warning updates.  Transdermal delivery systems offer a number of improvements over other delivery systems. Patches do not require swallowing eliminating oral side effects; nor do they require skin puncture by syringe needles eliminating pain and patient visits to a physician. Permeation through the skin allows the drug to directly enter the systemic circulation and avoid the first pass effect decreasing gastric side effects and liver damage effects in hepatocompromised drug abusers and alcoholics.  Transdermal delivery of NTX is desirable for addicts and alcoholics in order to help reduce side effects associated with oral/depot injection therapies and improve compliance. NTX itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. Microneedle-enhanced transdermal delivery is an efficient and painless method for increasing the skin permeation of many drugs including NTX. Microneedle products are currently in late-stage clinical trials for vaccine development but this proposed product would be the first microneedle delivery system for multiple day sustained release systemic treatment. We hypothesize that NTX in combination with microneedle treatment will provide a therapeutic transdermal delivery rate of NTX. The initial screening of the prototype patch will be completed in a Yucatan miniature pig pharmacokinetic study to verify that the patch system developed in vitro performs well in vivo (dose ranging study). The final studies for this proposal will be a group of critical GLP dermatotoxicology studies in animals to assess skin irritation and sensitization potential of the final patches. This final data will be used to apply for an IND so that a Phase I clinical trial may begin at the end of this project. We will create a marketable and safe drug that will significantly aid in the treatment of addiction.  
  
PUBLIC HEALTH RELEVANCE: According to the National Survey of Drug Use and Health (NSDUH) of 2008 7.2 million Americans are in need of treatment for Substance-Related Disorders (SRDs) and a large proportion of those need treatment for opiate pain reliever and heroin addiction. Additionally over 8.5% of the U.S. population and 75 million people worldwide meet the diagnostic criteria for alcohol use disorders (AUDs) with alcohol abuse being among the top three preventable public health problems in the U.S. and the world. The proposed preclinical translational research will accelerate testing of naltrexone delivered via a transdermal microneedle system to assess its benefits as a lead candidate in the search for improved alcoholism opiate and other drug addiction pharmacotherapies.

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

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


application_id: 8252790
project_number: 1R41AI098336-01
project_title: Delayed Tolerance Induction in Living Related Donor Renal Transplant Recipients
administering_ic: NIAID
award_notice_date: 2012-03-21
opportunity_number: PA-11-097
application_type: 1
activity_code: R41
ic: AI
serial_number: 098336
program_official: PROGRAIS, LAWRENCE J
project_start_date: 2012-03-21
project_end_date: 2014-02-28
study_section: Special Emphasis Panel[ZRG1 DKUS-L (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: 2012-03-21
budget_end_date: 2014-02-28
project_abstract:
DESCRIPTION (provided by applicant): We have developed a protocol that reproducibly induces transplantation tolerance in individuals undergoing a living related donor kidney transplant. Three subjects have been off all immunosuppression for 10 months 2 months and 1 month respectively and have remained chimeric with stable renal function. Two additional chimeric subjects are in various stages of withdrawal from immunosuppression. The goal of this proposal is to expand this protocol to individuals who have already been transplanted and have a living donor that could subsequently provide a bone marrow stem cell product for their recipient (delayed tolerance).  This work is important because solid organ vascularized composite tissue and islet transplantation currently require nonspecific immunosuppressive agents indefinitely for graft maintenance. These agents have significant toxicities including nephrotoxicity opportunistic infections increased rate of malignancy diabetes and hypertension. It has been known for over 50 years that bone marrow chimerism induces tolerance to transplanted organs cells and tissues. However the requirement for close HLA matching and toxicity of ablative bone marrow transplantation has limited the widespread application of this approach. The induction of donor-specific tolerance through durable chimerism in mismatched recipients while avoiding graft-versus-host disease (GVHD) would impact organ and tissue recipients as well as for individuals with hemoglobinopathies inherited metabolic disorders and autoimmune disorders. We have strong preliminary data in 8 living donor kidney hematopoietic stem cell transplant (HSCT) recipients 1 metachromatic leukodystrophy recipient and 1 sickle cell disease transplant recipient that we can safely establish durable chimerism in highly mismatched donor/recipient pairs. We have successfully established high levels of donor chimerism without GVHD in up to 1/6 HLA matched unrelated donor/recipient pairs. Seven of the eight renal transplant recipients were transplanted with cryopreserved G-CSF mobilized HSCT processed to remove GVHD-producing cells and retain tolerogenic CD8+/TCR- graft facilitating cells (the FCRx).  Unfortunately this successful "simultaneous" stem cell/kidney approach does not address individuals who have already received a transplanted organ and who have a living donor willing to donate bone marrow. This proposal modifies this approach to accommodate induction of "delayed tolerance" in a phase I/II protocol. The findings from this study will directly translate to deceased donor organ transplantation. This is of high priority because most organ donors are deceased. Therefore this novel approach to expand the FCRx technology to delayed tolerance will represent a major milestone in potential commercialization.   
   
PUBLIC HEALTH RELEVANCE: Dependence upon anti-rejection drugs in clinical transplantation is expensive and results in significant morbidity and limitation in graft survival.
Donor specific transplant tolerance would eliminate the need for drug- based immunosuppression but has been an elusive goal in the clinic for over a half century. We have developed a potentially transformative approach to achieving transplant tolerance in solid organ transplant recipients based upon a rationally bioengineered stem cell product termed FCRx. This proposal will determine the safety and efficacy of FCRx for delayed tolerance induction in kidney transplant recipients and will also be directly applicable also to deceased donor organ allograft recipients which comprise the majority of organ transplants.

project_terms:
Achievement;Address;Allografting;Autoimmune Diseases;Biomedical Engineering;Bone Marrow;Bone Marrow Stem Cell;Bone Marrow Transplantation;CD8B1 gene;CSF3 gene;Cells;Chimerism;Clinic;Clinical;Data;Dependence;Diabetes Mellitus;Engraftment;Genetic;Goals;Graft Rejection;Graft Survival;Graft-vs-Host Disease;Hematopoietic;Hematopoietic stem cells;Hemoglobinopathies;Human;Hypertension;Immunosuppressive Agents;Individual;Infusion procedures;Inherited;Islets of Langerhans;Islets of Langerhans Transplantation;Kidney;Kidney Transplantation;Life;Living Donors;Maintenance;Malignant Neoplasms;Metabolic Diseases;Metachromatic Leukodystrophy;Morbidity - disease rate;Natural immunosuppression;Opportunistic Infections;Organ;Organ Donor;Organ Transplantation;Outpatients;Pharmaceutical Preparations;Phase;Postoperative Period;Process;Protocols documentation;Renal function;Risk;Safety;Sickle Cell Anemia;Solid;Staging;Stem cell transplant;Stem cells;Technology;Testing;Tissues;Toxic effect;Translating;Transplant Recipients;Transplantation;Transplantation Tolerance;Transplanted tissue;United States;Withdrawal;Work;base;clinical application;commercialization;conditioning;kidney allograft;nephrotoxicity;novel strategies;optimism;prevent;success

public_health_relevance:
Dependence upon anti-rejection drugs in clinical transplantation is expensive and results in significant morbidity and limitation in graft survival.
Donor specific transplant tolerance would eliminate the need for drug- based immunosuppression but has been an elusive goal in the clinic for over a half century. We have developed a potentially transformative approach to achieving transplant tolerance in solid organ transplant recipients based upon a rationally bioengineered stem cell product termed FCRx. This proposal will determine the safety and efficacy of FCRx for delayed tolerance induction in kidney transplant recipients and will also be directly applicable also to deceased donor organ allograft recipients which comprise the majority of organ transplants.


application_id: 8251289
project_number: 1R43AA021038-01
project_title: Novel flavonoids as anti-inflammatory agents in alcoholism
administering_ic: NIAAA
award_notice_date: 2014-09-02
opportunity_number: PA-11-096
application_type: 1
activity_code: R43
ic: AA
serial_number: 021038
program_official: JUNG, KATHY
project_start_date: 2014-09-05
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1 ETTN-C (11)]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Flavonoids are ubiquitous secondary metabolites in plants with many known health benefits which are mostly ascribed to their potent anti-oxidant activity.  However a search for novel nicotinic ligands using high throughput pharmacological screening of a native plant extract library and subsequently a pure flavonoid library led to the highly surprising conclusion that some methoxylated quercetin-like flavonoid derivatives have partial agonist activity selectively at the alpha7-subtype of nicotinic receptor for acetylcholine (nicAChR).  Activation of these receptors on microglia and macrophages is known to reduce the release of inflammatory mediators by these cells thereby reducing chronic inflammation in the CNS and peripheral tissues.  Since there is a wealth of evidence which implicates chronic inflammatory changes in the neurodegeneration and organ damage associated with alcoholism this implies that these specific flavonoids are of potential value for these therapeutic targets.  The same flavonoids have "added value" specifically for alcoholism in that they retain potent anti-oxidant activity and so should also protect tissues against the oxidative stress induced by alcohol metabolism.  This phase 1 proposal is to investigate the effects of alpha7-nicAChR active flavonoids on bacterial toxin-induced release of inflammatory mediators from microglia and macrophages.  The role of alpha7-nicAChRs in any effects seen will be evaluated using selective agonists and antagonists at these receptors.  The objective is to identify agents with therapeutic potential which will be evaluated in more complex models of alcohol-induced tissue damage in vitro and in vivo in phase 2.  It is important to note that although the most active flavonoids were discovered in native plants some of the alpha7-nicAChR active flavonoids in the library are present in common crop plants such as apples and onions.  This makes regulatory approval for these flavonoids as "nutraceuticals" or "functional foods" relatively easy to obtain and limited toxicity testing in phase 2 will be followed by commercialization with a major global food company which has already indicated strong interest in the anti-inflammatory properties of these natural products.  
  
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.  This organ damage is commonly associated with cellular inflammation and this is also a major contributing factor to alcohol-induced neurodegeneration which may rival Alzheimer's dementia in its prevalence in the US.  Despite this there are currently no accepted approaches to preventing or reversing this tissue damage.  This application proposes a novel approach to organ and brain damage which has major implications for pharmacotherapy of and/or nutritional intervention in these therapeutic targets.

project_terms:
Affect;Affinity;Agonist;Agreement;Alcoholism;Alcohols;Alzheimer's Disease;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Apple;Arthritis;Bacterial Toxins;Binding (Molecular Function);Biological Assay;Biological Factors;Brain;Brain Injuries;Cell Line;Cells;Choline;Chronic;Clinical;Complex;Dependence;Development;Dietary Intervention;Drug Addiction;Endotoxins;Enzyme-Linked Immunosorbent Assay;Ethanol Metabolism;Evaluation;Flavonoids;Flavonols;Food;Fruit;Health Benefit;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Bowel Diseases;Investigation;Legal patent;Libraries;Ligands;Lipopolysaccharides;Lung;Marketing;Measurement;Measures;Mediating;Mediator of activation protein;Medical;Methods;Microglia;Modeling;Mus;Nerve Degeneration;Nicotinic Receptors;Nutraceutical;Onions;Organ;Oxidative Stress;Peripheral;Peritoneal Macrophages;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Phase;Plant Extracts;Plant Sources;Plants;Population;Prevalence;Property;Quercetin;Receptor Activation;Relative (related person);Research;Role;Solidago;Sum;Testing;Therapeutic;Tissues;Toxicity Tests;Vegetables;alcohol exposure;commercialization;cost;design;functional food;in vitro testing;in vivo;interest;macrophage;mouse model;neurotoxicity;novel;novel strategies;phase 2 study;prevent;programs;public health relevance;radioligand;receptor;research and development;screening;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.  This organ damage is commonly associated with cellular inflammation and this is also a major contributing factor to alcohol-induced neurodegeneration which may rival Alzheimer's dementia in its prevalence in the US.  Despite this there are currently no accepted approaches to preventing or reversing this tissue damage.  This application proposes a novel approach to organ and brain damage which has major implications for pharmacotherapy of and/or nutritional intervention in these therapeutic targets.


application_id: 8250521
project_number: 1R01EY022238-01
project_title: Functional studies of DICER1 and Alu RNA in geographic atrophy
administering_ic: NEI
award_notice_date: 2012-01-10
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: EY
serial_number: 022238
program_official: SHEN, GRACE L
project_start_date: 2012-02-01
project_end_date: 2017-01-31
study_section: Biology and Diseases of the Posterior Eye Study Section[BDPE]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Geographic atrophy (GA) is an untreatable advanced form of age-related macular degeneration (AMD) that is characterized by degeneration of the retinal pigmented epithelium (RPE). Neither the mechanisms that promote this RPE degeneration nor the basis for the centrifugal expansion of GA that can ultimately lead to blindness have been resolved. This enigmatic nature of GA pathogenesis has precluded the development of any FDA-approved therapy for the one million Americans diagnosed with GA and the millions more at risk of developing GA. In new and exciting studies we made the surprising observation that there is an abundance of Alu repetitive RNA in the RPE of human eyes with GA that accumulates in response to a dramatic deficiency in the RNase DICER1 and induces RPE degeneration (Kaneko et al. Nature 2011). Our findings which introduce a novel cell survival function for DICER1 independent of its canonical miRNA biogenesis function and the concept that Alu RNA can directly promote human pathology provide new mechanistic insights into GA pathogenesis. However we still lack an integrated understanding of how DICER1 is dysregulated in GA and precisely how Alu RNA induces RPE degeneration. A rigorous definition of these mechanisms is crucial to enhancing our understanding of the molecular drivers of GA and to developing rational treatments. We will provide novel functional insights into how DICER1/Alu RNA dysregulation contributes to GA pathogenesis and develop a novel therapeutic strategy via the following Aims: (1) Generate a spatiotemporal map of DICER1 and Alu RNA in relation to the locus of pathology in GA and early AMD eyes; (2) Decipher the mechanisms by which Alu RNA triggers a new inflammatory cell death pathway we have identified; (3) Define the molecular regulation of DICER1 in the RPE in the context of GA and the function of a novel DICER1 splice variant; (4) Create a new animal model of GA having human-like features of the disease and validate an antisense therapeutic strategy targeting Alu RNA. These studies will illuminate novel aspects of the molecular and biochemical bases of GA and help validate a molecular targeting strategy that could be translated into clinical trials. As such this proposal is perfectly aligned with the 5-year goals of the NEI's Retinal Diseases Program strategic plan.  
  
PUBLIC HEALTH RELEVANCE: There is no FDA-approved treatment for the one million Americans with geographic atrophy (GA) or for the millions more who are at risk of developing GA. We recently discovered an enzymatic deficiency that leads to accumulation of toxic RNA molecules in the eyes of patients with GA. The goal of this project is to understand how this newly discovered pathway causes GA and to test drugs that will be suitable for entry into clinical trials.

public_health_relevance:
There is no FDA-approved treatment for the one million Americans with geographic atrophy (GA) or for the millions more who are at risk of developing GA. We recently discovered an enzymatic deficiency that leads to accumulation of toxic RNA molecules in the eyes of patients with GA. The goal of this project is to understand how this newly discovered pathway causes GA and to test drugs that will be suitable for entry into clinical trials.


application_id: 8250466
project_number: 5R01CA137052-04
project_title: Identifying candidate modifier elements of a breast cancer risk associated allele
administering_ic: NCI
award_notice_date: 2012-04-05
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 137052
program_official: SHARMAN, ANU
project_start_date: 2009-05-08
project_end_date: 2014-04-30
study_section: Cancer Genetics Study Section[CG]
contact_pi_person_id: 6825342
contact_pi: SAMUELSON, DAVID J
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): Identifying candidate modifier elements of a breast cancer risk associated allele Project Summary/Abstract: A woman's risk of developing breast cancer is influenced by genetic epigenetic and environmental factors. Up to 30-40% of the risk of developing breast cancer is likely to be inherited. Breast cancer genetics is complex. The factors controlling disease risk are high penetrant genes with risk alleles that are low in population frequency and low penetrant modifier genes with risk associated alleles that are common in the population. Most of the genetic variation in breast cancer risk is unaccounted and the majority of the genes influencing susceptibility to breast cancer are likely controlled by common genetic variation. The common single nucleotide polymorphism (SNP) rs889312 marks a low penetrant breast cancer risk associated allele on human chromosome 5 (Nature 447 2007). The breast cancer risk associate gene and causal polymorphisms at this locus have not been identified. The human region is orthologous to rat mammary carcinoma susceptibility QTL Mcs1b. The rat Mcs1b locus has been narrowed to 1.2 Mb using congenics. These experiments used the Wistar Furth (WF) strain which is highly susceptible to 712- dimethylbenz[a]anthracene (DMBA)-induced mammary carcinomas as the genetic background. The Mcs1b Copenhagen (COP) allele on a WF background conferred a 60% reduction in DMBA-induced mammary carcinoma development to WF.COP congenics that were COP-homozygous and a 30% reduction to congenics that were COP/WF-heterozygous at Mcs1b. The objective of the proposed work is to use systems genetics in a model organism to identify quality candidate breast cancer risk genetic elements. This will be accomplished through the following specific aims: aim 1: fine map rat Mcs1b to a genomic interval less than 0.5 Mb by testing additional congenic lines carrying shorter segments of the Mcs1b locus as currently defined; aim 2: determine if the Mcs1b COP allele acts in an autonomous manner within the mammary gland by conducting rat mammary gland transplant experiments; and aim 3: identify and evaluate breast cancer candidate genes/genetic elements within rat Mcs1b by determining potential candidates and testing each to identify quality candidates. The final aim will be completed in stages that will incorporate comparative genomics genetic and expression analyses resequencing and in vitro and in vivo validation of candidates. PUBLIC HEALTH RELEVANCE: Breast cancer is a complex disease and the leading cause of death by cancer in US women aged 20- 59 years. Most common susceptibility genes and molecular genetic mechanisms contributing to breast cancer susceptibility are unknown. To work toward decreasing the incidence and mortality due to breast cancer basic research toward better understanding of the genetic etiology of this complex disease is warranted. The proposed research uses a comparative genetic approach to accomplish this and may also identify novel potential targets for breast cancer prevention.

project_terms:
910-Dimethyl-12-benzanthracene;Alleles;Animal Model;Anthracenes;Area;Automobile Driving;BRCA1 gene;BRCA2 gene;Basic Research Breast Cancer;Biological Assay;Biological Models;Breast Cancer Genetics;Breast Cancer Model;Breast Cancer Prevention;Breast Carcinoma;Candidate Disease Gene;Cause of Death;Chromosomes Human Pair 2;Chromosomes Human Pair 5;Complex;DNA Resequencing;Development;Disease;Elements;Environmental Risk Factor;Epigenetic Process;Frequencies (time pattern);Functional RNA;Genes;Genetic;Genetic Markers;Genetic Models;Genetic Polymorphism;Genetic Predisposition to Disease;Genomics;Goals;Health;Human;Human Chromosomes;In Vitro;Inbred Strains Rats;Inbreeding;Incidence;Individual;Inherited;Intercistronic Region;Knowledge;Lead;Location;Malignant Neoplasms;Mammary Tumorigenesis;Mammary gland;Maps;Modeling;Molecular Genetics;Molecular Target;Mortality Vital Statistics;Nature;PTPRJ gene;Phenotype;Population;Predisposition;Principal Investigator;Quantitative Trait Loci;Rat-1;Rattus;Recombinants;Research;Research Project Grants;Risk;STAT5a Transcription Factor;Single Nucleotide Polymorphism;Staging;Susceptibility Gene;System;Testing;Transgenic Model;Translating;Transplantation;Variant;Variation (Genetics);Woman;Work;abstracting;aged;anticancer research;cancer prevention;cancer risk;candidate validation;comparative;comparative genomics;congenic;disorder risk;genetic analysis;genetic element;genome wide association study;in vivo;knockout gene;malignant breast neoplasm;novel;novel strategies;rat genome;research study

public_health_relevance:
Project Narrative: Breast cancer is a complex disease and the leading cause of death by cancer in US women aged 20-59 years. Most common susceptibility genes and molecular genetic mechanisms contributing to breastcancer susceptibility are unknown. To work toward decreasing the incidence and mortality due to breastcancer basic research toward better understanding of the genetic etiology of this complex disease iswarranted. The proposed research uses a comparative genetic approach to accomplish this and may alsoidentify novel potential targets for breast cancer prevention.


application_id: 8250362
project_number: 5R01CA149438-02
project_title: Activation of Cyclin-Dependent Kinases by Fructose-26-Bisphosphate
administering_ic: NCI
award_notice_date: 2012-03-22
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: CA
serial_number: 149438
program_official: SPALHOLZ, BARBARA A
project_start_date: 2011-04-01
project_end_date: 2016-03-31
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 1923745
contact_pi: CHESNEY, JASON A.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The 6-phosphofructo-2-kinase/fructose-26-bisphosphatases (PFKFB) phosphorylate fructose-6-phosphate (F6P) to fructose-26-bisphosphate (F26BP) which is an allosteric activator of 6-phosphofructo-1-kinase a rate-limiting enzyme in the glycolytic pathway. Although there are four PFKFB enzymes PFKFB3 and PFKFB4 are of particular interest since these enzymes have been found to be activated in human cancers to be increased by hypoxic exposure via HIF-1? and in the case of PFKFB3 to be required for the growth of Ras-transformed tumors. In order to better understand the relative contributions of PFKFB2-4 to glycolysis we examined the subcellular localization of these enzymes and were surprised to find that whereas PFKFB2 and PFKFB4 localized to the cytoplasm (the site of glycolysis) PFKFB3 localized to the nucleus. We then over-expressed PFKFB3 in HeLa cells and observed no change in glucose uptake but rather an increase in proliferation. Eukaryotic cell division is controlled by cyclin dependent kinases (CDKs) that bind to regulatory cyclins and phosphorylate hundreds of substrates that control DNA replication transcription and mitosis. We found that over-expression of PFKFB3 stimulated CDK1 activity in HeLa cells and that purified F26BP stimulated recombinant monomeric CDK1 in vitro. We then confirmed the requirement of CDK1 for the pro-proliferative effects of PFKFB3 by demonstrating that CDK1 siRNA but not CDK2 CDK4 or CDK6 siRNA reversed the increased proliferation caused by over-expression of PFKFB3. Importantly transfection of HeLa cells with PFKFB3-specific siRNA decreased endogenous PFKFB3 which in turn reduced CDK1 activity increased p27 expression suppressed G1/S transition induced apoptosis but had no impact on glucose uptake. These data support a distinct role for PFKFB3 in the regulation of cell cycle progression and apoptosis and not glucose metabolism. We propose to test the hypothesis that nuclear F26BP generated by PFKFB3 activates CDKs and promotes cell cycle progression. We anticipate that nuclear F26BP may serve unique roles in regulating CDK1 and other CDKs and that inhibition of PFKFB3 will suppress CDK activities without significantly affecting glucose metabolism in transformed but not in normal cells.    PUBLIC HEALTH RELEVANCE: The research proposed in this application may enable the identification of a novel molecular target - the CDK1 F26BP-binding domain - that is required for the regulation of the cell cycle and cancer progression. This binding pocket then can be used for receptor-based virtual screening to identify novel anti-neoplastic agents.

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

public_health_relevance:
The research proposed in this application may enable the identification of a novel molecular target - theCDK1 F26BP-binding domain - that is required for the regulation of the cell cycle and cancer progression.This binding pocket then can be used for receptor-based virtual screening to identify novel anti-neoplasticagents.


application_id: 8249524
project_number: 5K23AA018399-03
project_title: Zinc supplementation in alcoholic cirrhosis
administering_ic: NIAAA
award_notice_date: 2012-03-30
opportunity_number: PA-09-043
application_type: 5
activity_code: K23
ic: AA
serial_number: 018399
program_official: WANG, JOE
project_start_date: 2010-04-01
project_end_date: 2015-03-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This K23 application will enable Matthew Cave M.D. to achieve his goal of becoming an independent investigator focusing on clinical and translational research in alcoholic liver disease (ALD) and nutrition. Dr. Cave will conduct a mechanistic study evaluating the effects of zinc sulfate therapy in patients with alcoholic cirrhosis (AC). Highlights of Dr. Cave's career development plan include: (i) obtaining a Master of Science degree in Interdisciplinary Studies (I-MS) focusing on toxicology clinical trial design and biostatistics and (ii) board certification in nutrition (ABPNS). These activities will occur in the setting of the recently funded University of Louisville Alcohol Research Center (P01) and will be monitored quarterly by an advisory committee. An estimated two million Americans have ALD and there are no FDA approved medications for any stage of ALD. Our preliminary data document (i) zinc deficiency in human subjects with AC and (ii) improvement in liver injury and in postulated mechanisms of liver injury with zinc supplementation in murine models. Our hypothesis is that zinc sulfate therapy will result in improvement in mechanisms postulated to play a role in the development and progression of human AC. To test this hypothesis we will perform a randomized double blind placebo-controlled "drop in" mechanistic study of zinc sulfate 220 mg daily in 30 subjects with Child-Pugh A-B AC for 24 months. The primary endpoints are reduction in (i) serum endotoxemia and (ii) ex vivo basal and endotoxin-stimulated TNF1 production. Secondary endpoints are (i) improved serum zinc status (ii) increased intestinal tight junctions with decreased permeability (iii) improved serum pro-inflammatory cytokine profile (iv) reduced oxidative stress and improved serum antioxidant status (v) reduced hepatocyte death (vi) decreased fibrosis and (vii) improved clinical status. These studies utilize state- of-the art techniques in a translational approach to develop an enhanced understanding of a potential new therapy for AC.    PUBLIC HEALTH RELEVANCE: This K23 application will enable Matthew Cave M.D. to achieve his goal of becoming an independent investigator focusing on clinical and translational research in alcoholic liver disease (ALD) and nutrition. We will perform a randomized double blind placebo-controlled "drop in" mechanistic study of zinc sulfate 220 mg daily in 30 subjects with Child-Pugh A-B AC for 24 months.

project_terms:
Accounting;Advisory Committees;Alcohol consumption;Alcoholic Liver Cirrhosis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcoholism;American;Animal Model;Antioxidants;Attenuated;Biometry;Blood Circulation;Board Certification;Cell Death;Cell Wall;Cessation of life;Child;Chronic;Cirrhosis;Clinical;Clinical Research;Clinical Trials Design;Data;Development;Development Plans;Disease;Doctor of Medicine;Double-Blind Method;Drops;Endotoxemia;Endotoxins;Epithelial;FDA approved;Fibrosis;Funding;Generations;Goals;Gram-Negative Bacteria;Health Benefit;Hepatocyte;Human;Immune system;Inflammatory;Injury;Interdisciplinary Study;Intestines;Kupffer Cells;Liver;Master of Science;Mediator of activation protein;Modeling;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Mus;Oral;Oxidative Stress;Pathway interactions;Patients;Permeability;Pharmaceutical Preparations;Placebo Control;Play;Primary carcinoma of the liver cells;Principal Investigator;Production;Publishing;Randomized;Reactive Oxygen Species;Reporting;Research;Research Personnel;Research Proposals;Role;Safety;Serum;Staging;Structure;Supplementation;TNF gene;Techniques;Testing;Tight Junctions;Toxicology;Translational Research;United States;Universities;Venous;Work;Zinc;Zinc Sulfate;Zinc deficiency;alcohol research;animal data;base;career development;clinical practice;cytokine;human subject;improved;nutrition;prevent;problem drinker;programs;public health relevance;translational approach

public_health_relevance:
This K23 proposal will enable Matthew Cave MD to achieve his goal of becoming an independent investigator focusing on clinical and translational research in alcoholic liver disease (ALD) and nutrition.  We will perform a randomized double blind placebo-controlled "drop in" mechanistic study of zinc sulfate 220 mg daily in 30 subjects with Child-Pugh A-B AC for 24 months.


application_id: 8249510
project_number: 5R01CA128903-03
project_title: Chemical Probes of Immunoproteasome Function in Cancer
administering_ic: NCI
award_notice_date: 2012-03-15
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 128903
program_official: FU, YALI
project_start_date: 2010-06-07
project_end_date: 2015-04-30
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 8152159
contact_pi: KIM, KYUNG BO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The essential roles of the ubiquitin-proteasome system (UPS) in many cellular processes are now well recognized. However many questions still remain unanswered. Intriguing yet not fully understood are the functions of the immunoproteasome an alternative form of the constitutive proteasome. It has been shown that the roles of the immunoproteasome in cells are not just limited to the generation of antigenic peptides but far more multifaceted. In this regard recent studies have shown that catalytic subunits of the immunoproteasome are implicated in various types of diseases including cancer. Despite these therapeutic implications the immunoproteasome remains largely untapped for cancer drug discovery. A better understanding of immunoproteasome functions would be crucial in developing the optimum LMP2 inhibitor(s). In our continuing efforts to better understand the role of the immunoproteasome in cells we have recently developed a small molecule probe ('UK-101') that specifically targets LMP2 a major catalytic subunit of the immunoproteasome. Further we found that LMP2 is highly expressed in several types of primary tumor tissues and cancer cell lines. Interestingly cancer cells that highly express LMP2 are markedly more sensitive to UK-101 than those expressing low level of LMP2. Consistent with these in vitro results UK-101 inhibits tumor growth in a mouse xenograft model of human prostate tumor that highly expresses LMP2 but not that of tumor that expresses low level of LMP2. These observations further support a potential role of LMP2 in cancer cell growth and survival. The goals of this application are to determine the roles of the immunoproteasome in prostate cancer and to investigate therapeutic potentials of the immunoproteasome-targeting approaches in cancer therapy. Towards this goal we propose to use innovative chemical probes that selectively target and visualize individual catalytic subunits of the immunoproteasome. In order to accomplish this goal four specific aims are proposed: 1) To validate the immunoproteasome as the major pharmacological target of UK-101 2) To determine dynamic cellular distribution of the catalytically active immunoproteasome and 3) To determine the unique functions of the immunoproteasome compared to the constitutive proteasome and 4) To develop an optimum LMP2 inhibitor(s) by generating a structurally diversified small molecule library. The proposed work integrates both chemical and biological approaches. Successful completion of the project will significantly expand our knowledge on the role of the immunoproteasome. In addition the study will yield critical information in developing immunoproteasome-specific inhibitors as a potential therapeutic agent. Finally small molecule probes that will be used in this application will provide valuable research tools for the ubiquitin-proteasome biology community.     PUBLIC HEALTH RELEVANCE: Small molecule probes are valuable tools in deciphering protein functions. We have developed a novel cell permeable small molecule that selectively targets the immunoproteasome. Using this small molecule and other molecular tools we will investigate the roles of the immunoproteasome in cancer cells and therapeutic potentials of the immunoproteasome-targeting approaches in cancer therapy.

project_terms:
Affinity;Antineoplastic Agents;Attention;Binding Proteins;Biological;Biology;Bortezomib;Cancer Cell Growth;Cancer cell line;Catalytic Domain;Cell Death;Cell Line;Cell Survival;Cell physiology;Cells;Chemicals;Clinical;Communities;Complex;Data;Development;Disease;Dominant-Negative Mutation;Down-Regulation;Generations;Goals;Human;In Vitro;Individual;Inflammatory;Inflammatory Bowel Diseases;Interferon Type II;Investigation;Knowledge;Libraries;Malignant Neoplasms;Malignant neoplasm of prostate;Molecular;Multiple Myeloma;Mus;Normal Cell;Organ;Peptide Library;Peptides;Pharmaceutical Preparations;Play;Primary Neoplasm;Prostatic Neoplasms;Proteasome Inhibitor;Proteomics;Publications;Refractory;Research;Role;Screening procedure;Signal Pathway;Small Interfering RNA;Solid Neoplasm;System;Therapeutic;Therapeutic Agents;Toxic effect;Tumor Tissue;Ubiquitin;Up-Regulation (Physiology);Work;Xenograft Model;cancer cell;cancer therapy;drug discovery;imaging probe;in vivo;inhibitor/antagonist;innovation;multicatalytic endopeptidase complex;neoplastic cell;novel;overexpression;protein function;public health relevance;small molecule;small molecule libraries;tool;tumor;tumor growth

public_health_relevance:
Project Narrative:Small molecule probes are valuable tools in deciphering protein functions. We havedeveloped a novel cell permeable small molecule that selectively targets theimmunoproteasome. Using this small molecule and other molecular tools we willinvestigate the roles of the immunoproteasome in cancer cells and therapeutic potentialsof the immunoproteasome-targeting approaches in cancer therapy.


application_id: 8249505
project_number: 5R42DA030001-03
project_title: Intranasal Naloxone: An Opioid Overdose Antidote
administering_ic: NIDA
award_notice_date: 2012-03-29
opportunity_number: PA-09-081
application_type: 5
activity_code: R42
ic: DA
serial_number: 030001
program_official: BOUGH, KRISTOPHER J
project_start_date: 2010-07-15
project_end_date: 2013-01-31
study_section: Special Emphasis Panel[ZRG1-IMST-D(13)B]
contact_pi_person_id: 10086391
contact_pi: WERMELING, DANIEL PAUL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_uei: DC9CX5GXZSU4
duns_number: 831025338
uei: DC9CX5GXZSU4
fips: US
organization_id: 10023078
organization_name: ANTIOP, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405151273
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
project_abstract:
DESCRIPTION (provided by applicant): There is a significant unmet medical need to provide additional pharmacologic treatments for treatment and prevention of opioid overdose. This Fast Track STTR project proposes to apply drug delivery technologies to develop a novel use for a nasally delivered pharmaceutical - naloxone (NLX) hydrochloride - for the emergency treatment of opioid overdose by emergency medical services. Emergency medical service personnel would prefer a non-injection based antidote to avoid accidental needle-sticks in the revival of opioid overdose victims. This approach would markedly reduce the risks of contracting hepatitis or HIV by first responders. It might also reduce time to first treatment by obviating the need to establish an injection site and preparation of the injectable device or intravenous access. The specific objective is to create a nasal spray that offers a novel therapeutic option for a rapid-acting interventional medication intended to acutely reverse the effects of prescription (e.g Oxycontin(R)) and illicit opioids (e.g heroin). The hypothesis of this project is that nasally delivered NLX will have biopharmaceutics comparable to NLX subcutaneous (SC) and intramuscular (IM) injection without the use of a needle. The project hypothesis will be tested by the following Specific Aims: 1. Develop prototype formulations of NLX meeting standards for potency & stability 2. Manufacture the preferred formula and complete product stability testing 3. Manufacture animal and human clinical testing batches of NLX nasal spray 4. Assess upper and lower airway toxicity in vivo to beagle pups 5. Conduct a bioavailability study comparing the nasal spray system to SC and IM injection in healthy  human volunteers For Phase 1 (aim 1) formulation chemistry (see Section 5 Aim 1) will be applied to design chemically stable microbiologically safe nasal delivery formulae for delivery by a unit-dose nasal spray device. For Phase 2 (aim 2) the pilot formula will be manufactured into the sprayer and have formal stability testing completed. For aim 3 the naloxone nasal spray product will be manufactured for animal and human testing. The formula will be administered in vivo to beagle pups in order to test upper and lower airway toxicity (aim 4). For Phase 2 (aim 5) an IND will be filed with FDA and nasally delivered NLX biopharmaceutics will be attained by manufacture of a NLX nasal spray batch of the selected prototype formula and conducting a pilot bioavailability study in healthy human volunteers. Milestones for this project include the development of stable formulae selection of a final formula and stability testing of the manufactured product production of the NLX nasal spray for preclinical and human studies no or reversible irritation in beagle pups and attainment of rapid absorption and bioavailability in human comparable to SC and IM injection.    PUBLIC HEALTH RELEVANCE: There is a significant unmet medical need to provide additional pharmacologic treatments for treatment and prevention of opioid (morphine like medications) overdose. The specific objective is to create a nasal spray that offers a novel therapeutic option for a rapid-acting interventional medication intended to acutely reverse the effects of prescription (e.g Oxycontin(R)) and illicit opioids (e.g heroin).

project_terms:
Acute;Address;Animals;Antidotes;Biological Availability;Biopharmaceutics;Blood;Chemistry;Clinical Research;Contracts;Data;Development;Devices;Dose;Drug Delivery Systems;Drug Formulations;Drug Kinetics;Emergency Situation;Emergency medical service;Emergency treatment;HIV;Health Personnel;Hepatitis;Heroin;Human;Human Resources;Human Volunteers;Injectable;Injection of therapeutic agent;Intramuscular;Intramuscular Injections;Intravenous;Investigation;Investigational Drugs;Investigational New Drug Application;Life;Medical;Morphine;Naloxone;Naloxone Hydrochloride;Needles;Needlestick Injuries;Nose;Opioid;Oryctolagus cuniculus;Outcome;Overdose;Oxycodone;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Preparation;Prevention;Production;Property;Risk;Route;Safety;Site;Small Business Technology Transfer Research;Solutions;System;Technology;Testing;Therapeutic Intervention;Time;Toxic effect;United States Food and Drug Administration;absorption;base;design;emergency service/first responder;in vivo;irritation;meetings;novel;novel therapeutics;opioid abuse;patient population;phase 3 study;pre-clinical;preclinical study;prototype;public health relevance;pup;research clinical testing;stability testing;subcutaneous;volunteer

public_health_relevance:
PROJECT NARRATIVEThere is a significant unmet medical need to provide additional pharmacologic treatments for treatment andprevention of opioid (morphine like medications) overdose. The specific objective is to create a nasal spraythat offers a novel therapeutic option for a rapid-acting interventional medication intended to acutelyreverse the effects of prescription (e.g Oxycontin(R)) and illicit opioids (e.g heroin).


application_id: 8249259
project_number: 3F31ES016719-03S1
project_title: Curcumin inhbits BPDE-induced damage by lowering the threshold of p53 activation
administering_ic: NIEHS
award_notice_date: 2011-04-04
opportunity_number: PA-07-106
application_type: 3
activity_code: F31
ic: ES
serial_number: 016719
suffix: S1
program_official: HUMBLE, MICHAEL C
project_start_date: 2008-05-01
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZRG1-IMM-L(29)L]
contact_pi_person_id: 8797117
contact_pi: ROGERS, ERICA NICOLE
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): Lung cancer the leading cause of cancer-related deaths in America is most commonly caused by long-term exposure to tobacco smoke carcinogens such as benzo[a]pyrene (BaP) which is metabolized into the ultimate metabolite benoz[a]pyrene-78-dihyrodiol-910-epoxide (BPDE). Despite improvements in the treatment and management of lung cancer these methods fail to reduce the overall mortality rate of this disease. While dietary components such as curcumin (turmic spice) show promising effects against BPDEinduced carinogenesis its exact mode of action is not fully understood. The objective of this project is to elucidate whether pretreatment with curcumin inhibits BPDE-induced DMA damage by activating p53. We hypothesize that curcumin may reduce the mutagenic activity of low dose BPDE by lowering the threshold of p53 activation thereby inducing DNA repair and cell cycle arrest at lower BPDE exposures. In Specific aim 1 the expression of p53 and p53-regulated proteins as well as cell cycle progression will be monitored by Western blot and flow cytometric analysis respectively to determine whether curcumin influences cell cycle arrest in response to BPDE exposure. Because global genomic repair (GGR) removes most BPDE-DNA  adducts in a p53-dependent manner Specific aim 2 will use immunoslot blot [32P]-postlabeling and  UvrABC mediated gene and strand-specific southern blot assays to analyze whether curcumin affects p53 activation and thus the relative extent of BPDE-DNA adducts formed and removed in genomic DNA. In Specific aim 3 Northern and Western blot assays will be used to investigate the role of curcumin in the induction of damage recognition proteins of the GGR pathway (XPC DDB2) which are p53-dependent. Furthermore it is believed that conjugation of glutathione (GSH) to BPDE by glutathione-S-transferase (GST) interacts with the expression of p53 to inactivate BPDE. In Specific aim 4 Western blot and GST colorimetric assays will be used to monitor the expression of proteins involved in the GSH detoxification system as well as the overall activity of GST respectively. This aim will provide a better understanding of potential alternative routes that may inactivate BPDE and how curcumin may influence this activity. By investigating the effects of curcumin on p53-mediated responses to DNA damage a better understanding of the potential role of curcumin in preventing tobacco carcinogen-induced mutagenesis and carcinogenesis will be gained. In addition the results from this project will benefit the public by providing easy and inexpensive alternative methods in preventing initial and continuing signs of lung cancer.

project_terms:
78-Dihydro-78-dihydroxybenzo(a)pyrene 910-oxide;Affect;Americas;Benzo(a)pyrene;Biological Assay;Cancer Etiology;Carcinogens;Cell Cycle Arrest;Cell Cycle Progression;Cells;Cessation of life;Curcumin;DNA;DNA Damage;DNA Repair;DNA repair protein;Dietary Component;Disease;Dose;Drug Metabolic Detoxication;Epoxy Compounds;Exposure to;Genes;Genomics;Glutathione;Glutathione S-Transferase;Lesion;Lung;Malignant neoplasm of lung;Mediating;Mediation;Methods;Monitor;Mortality Vital Statistics;Mutagenesis;Northern Blotting;Pathway interactions;Proteins;Pyrenes;Regulation;Relative (related person);Role;Route;Southern Blotting;Spices;System;Tobacco smoke;Tobacco-Associated Carcinogen;Western Blotting;adduct;benzo(a)pyrene-78-dihydrodiol-910-epoxide-DNA;carcinogenesis;prevent;protein expression;repaired;response


application_id: 8249100
project_number: 5R01ES017260-04
project_title: Atherogenic Mechanisms of Arsenic
administering_ic: NIEHS
award_notice_date: 2012-03-28
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: ES
serial_number: 017260
program_official: CARLIN, DANIELLE J
project_start_date: 2009-06-15
project_end_date: 2014-03-31
study_section: Special Emphasis Panel[ZRG1-DIG-C(90)S]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this project is to understand the mechanisms by which exposure to arsenic accelerates or aggravates atherosclerosis. Exposure to arsenic-contaminated water is a global problem and results in the manifestation of multiple cardiovascular symptoms including hypertension stroke and myocardial infarction. Increased atherosclerosis is likely to be the major underlying cause of the increased risk of cardiovascular disease in an arsenic-exposed population. Accordingly the intent of this proposal is to understand the mechanism by which arsenic accelerates or exacerbates atherogenesis in a well-controlled animal model. On the basis of supportive preliminary evidence our central hypothesis is that arsenic promotes atherogenic changes in endothelial cells and in macrophages by inducing endoplasmic reticulum (ER) stress which in turn triggers the unfolded protein response (UPR). To test this hypothesis we will: (1) delineate the contribution of ER stress and UPR to arsenic-mediated endothelial cell and macrophage activation; (2) examine the progression of atherogenesis in arsenic-exposed mice; and (3) elucidate the role of UPR in exacerbation of atherogenesis by arsenic. To accomplish these aims we will examine whether exposure to arsenic induces ER stress and triggers UPR in endothelial cells and macrophages. We will identify which aspects of the UPR are triggered by arsenic and whether ER stress contributes to arsenic-induced activation of endothelial cells and foam cell formation. To assess how arsenic affects atherogenesis we will examine early intermediate and advanced lesions for lipid accumulation cellularity inflammation and oxidative stress in apoE-null mice exposed to arsenic. Bone marrow transplants from arsenic-exposed to non-exposed mice will be performed to delineate the specific contribution of macrophages to arsenic toxicity. To identify the in vivo role of UPR in arsenic toxicity we will examine which components of ER stress and UPR are activated in the lesions of arsenic-exposed animals and whether inhibition of the adaptive phase of UPR by deleting the ATF3 gene accelerates or treatment with chemical chaperones of protein folding inhibits lesion formation. Results of this project may lead to a better understanding of the mechanisms by which arsenic affects atherogenesis and how they could be therapeutically prevented. PUBLIC HEALTH RELEVANCE: Large sections of human population in the US as well as Asia are exposed to high levels of arsenic in drinking water. Previous epidemiological studies show that people exposed to high levels of arsenic have a higher risk of developing cardiovascular disease. Nevertheless the mechanisms by which arsenic elevates cardiovascular disease risk are not known. This project is designed to mimic human exposures to arsenic in an animal model and test whether exposure to arsenic increases the rate and/or the extent of atherosclerotic lesion formation in atherosclerosis-prone mice. The project seeks to understand the underlying molecular mechanisms by which arsenic increases atherosclerosis; which processes are affected; and which cellular and molecular mechanisms mediate the cardiovascular toxicity of arsenic. Results obtained from this project are likely to provide novel models for testing atherogenic effects of arsenic exposure in developing a better understanding of how arsenic worsens atherosclerosis and how the atherogenic effects of arsenic could be ameliorated and treated.

project_terms:
Ablation;Affect;Animal Model;Animal Testing;Animals;Apolipoprotein E;Apoptosis;Arsenic;Arterial Fatty Streak;Arteriosclerosis;Asia;Asses;Atherosclerosis;Blood;Bone Marrow;Bone Marrow Transplantation;Calcium;Cardiovascular Diseases;Cardiovascular system;Carotid Atherosclerotic Disease;Cause of Death;Cell Adhesion Molecules;Cell Death;Cellularity;Cessation of life;Chemicals;Chronic;Collagen;Control Animal;Cytokine Activation;Disease;Endoplasmic Reticulum;Endothelial Cells;Epidemiologic Studies;Exposure to;Foam Cells;Foot Diseases;Genes;Genetic;Goals;Health;Human;Hypertension;Infant;Inflammation;Inflammatory;Ingestion;Knockout Mice;Laboratories;Lead;Lesion;Lipids;Macrophage Activation;Matrix Metalloproteinases;Measures;Mediating;Mitogen-Activated Protein Kinases;Modeling;Molecular;Molecular Chaperones;Mothers;Mus;Myocardial Infarction;Myocardial Ischemia;Oxidative Stress;Pathway interactions;Peripheral arterial disease;Phase;Population;Process;Production;Proteins;Risk Factors;Role;Signal Transduction;Smooth Muscle Myocytes;Staging;Stress;Symptoms;T-Lymphocyte;Testing;Toxic effect;Vascular Endothelial Cell;Water;activating transcription factor;activating transcription factor 3;arterial lesion;atherogenesis;base;biological adaptation to stress;cardiovascular disorder risk;chemokine;cytokine;design;drinking water;endoplasmic reticulum stress;exposed human population;high risk;in vivo;macrophage;novel;prevent;protein folding;response;stroke;transcription factor

public_health_relevance:
Large sections of human population in the US as well as Asia are exposed to high levels of arsenic in drinkingwater. Previous epidemiological studies show that people exposed to high levels of arsenic have a higher riskof developing cardiovascular disease. Nevertheless the mechanisms by which arsenic elevatescardiovascular disease risk are not known. This project is designed to mimic human exposures to arsenic inan animal model and test whether exposure to arsenic increases the rate and/or the extent of atheroscleroticlesion formation in atherosclerosis-prone mice. The project seeks to understand the underlying molecularmechanisms by which arsenic increases atherosclerosis; which processes are affected; and which cellular andmolecular mechanisms mediate the cardiovascular toxicity of arsenic. Results obtained from this project arelikely to provide novel models for testing atherogenic effects of arsenic exposure in developing a betterunderstanding of how arsenic worsens atherosclerosis and how the atherogenic effects of arsenic could beameliorated and treated.


application_id: 8248797
project_number: 5R01CA049797-21
project_title: Mechanisms of MnSOD expression in normal and tumor cells
administering_ic: NCI
award_notice_date: 2012-04-27
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 049797
program_official: MIETZ, JUDY
project_start_date: 1989-12-01
project_end_date: 2015-04-30
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
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 identify novel redox base mechanisms that lead to the development of cancer. Our studies have identified the mitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) as an important regulator that can both modulate the development of cancer and be modulated during the progression of cancer. Our studies in the previous funding period demonstrate that reduction of MnSOD levels occurs very early in the development of skin cancer and that the level of p53 regulates the expression of MnSOD. We also found that the level of the mitochondrial uncoupling protein 1 (UCP1) is significantly increased in skin tissues of MnSOD-deficient mice. We hypothesize that the activities of p53 MnSOD and UCP1 are regulated to minimize reactive oxygen species (ROS) production in mitochondria.  We propose that: 1) as a critical transcription factor p53 cooperates with transcriptional activators and suppressors to regulate MnSOD transcription (Aim 1) and 2) the reduction of MnSOD levels in mitochondria leads to UCP1 induction as a result of compromised mitochondrial function which induces transcriptional responses to reduce superoxide production from mitochondrial respiration (Aim 2). The positive and negative feedback loops between nuclei and mitochondria help to ensure that superoxide levels are minimized to prevent mitochondrial dysfunction and subsequent neoplastic transformation. We will use state-of-the-art molecular biology biochemistry and free radical biology approaches to address these specific aims.  Because mitochondria are major sites of cellular energy production and cellular ROS homeostasis and are integrators of apoptosis signaling that are altered in cancer cells understanding the regulation of mitochondrial ROS levels is important and will provide a unique opportunity to design novel interventions that maximize the benefits to normal tissues and prevent cancer development. Given that cellular redox status contributes to almost all aspects of biological function and that MnSOD and p53 are critical for normal cellular function and for cancer prevention the results from this study of cancer will have a broad impact on human health and the prevention of other diseases including obesity and metabolic disorders.    PUBLIC HEALTH RELEVANCE: Skin cancer is the most common human malignancy in the United States. Many chemicals and Ultraviolet radiation (UV) are well-established agents that cause skin cancer. We have found that the mitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) is an important regulator that can modulate the development of cancer as well as be modulated during the progression of cancer. Our studies demonstrate that reduction of MnSOD levels occurs very early in the development of skin cancer and that expression of MnSOD is regulated by p53. We also found that the levels of the mitochondrial uncoupling protein (UCPs) are altered in skin tissue of MnSOD-deficient mice. In this application we will extend from this novel finding to determine how UCPs acts to prevent skin cancer and will perform proof-of-concept experiments to verify the feasibility of using the knowledge to be learned to prevent the development of skin cancer resulting from exposure to UV and/or alteration of mitochondrial function.

project_terms:
Address;Antioxidants;Apoptosis;Binding (Molecular Function);Binding Sites;Biochemistry;Biogenesis;Biological Process;Biology;Cell Nucleus;Cell physiology;Cells;Chemicals;DNA Structure;Data;Development;Disease;Ensure;Enzymes;Exhibits;Family;Feedback;Free Radicals;Funding;Gene Expression;Genes;Genetic Transcription;Goals;Health;Homeostasis;Human;In Vitro;Intervention;Knowledge;Lead;Learning;Link;Luciferases;Malignant - descriptor;Malignant Neoplasms;Manganese;Mediating;Messenger RNA;Metabolic;Metabolic Diseases;Mitochondria;Mitochondrial Proteins;Molecular Biology;Monitor;Mus;Neoplastic Cell Transformation;Normal Cell;Normal tissue morphology;Obesity;Oxidation-Reduction;Oxidative Phosphorylation;Physiological;Prevention;Prevention strategy;Production;Promotor (Genetics);Proteins;RNA-Binding Proteins;Reactive Oxygen Species;Regulation;Regulatory Element;Reporter Genes;Reporting;Respiration;Ribonucleoproteins;Role;SOD2 gene;Signal Transduction;Site;Skin Cancer;Skin Carcinogenesis;Skin Tissue;Structure;Superoxide Dismutase;Superoxides;Testing;Transcription Coactivator;Transgenic Mice;Tumor Suppressor Proteins;UV Radiation Exposure;Ultraviolet Rays;United States;base;cancer cell;cancer prevention;design;disorder prevention;fascinate;in vivo;insight;link protein;liposarcoma;member;mitochondrial dysfunction;mitochondrial uncoupling protein;mouse model;neoplastic cell;novel;nucleophosmin;prevent;programs;public health relevance;research study;response;skin cancer prevention;transcription factor;tumor progression;uncoupling protein 1

public_health_relevance:
Program NarrativeSkin cancer is the most common human malignancy in the United States. Many chemicals andUltraviolet radiation (UV) are well-established agents that cause skin cancer. We have found that themitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) is animportant regulator that can modulate the development of cancer as well as be modulated during theprogression of cancer. Our studies demonstrate that reduction of MnSOD levels occurs very early inthe development of skin cancer and that expression of MnSOD is regulated by p53. We also found thatthe levels of the mitochondrial uncoupling protein (UCPs) are altered in skin tissue of MnSOD-deficientmice. In this application we will extend from this novel finding to determine how UCPs acts to preventskin cancer and will perform proof-of-concept experiments to verify the feasibility of using theknowledge to be learned to prevent the development of skin cancer resulting from exposure to UVand/or alteration of mitochondrial function.


application_id: 8248288
project_number: 7R01CA084374-13
project_title: STUDIES ON CALICHEAMICIN BIOSYNTHESIS AND SELF RESISTANCE
administering_ic: NCI
award_notice_date: 2012-03-30
opportunity_number: PA-07-070
application_type: 7
activity_code: R01
ic: CA
serial_number: 084374
program_official: FU, YALI
project_start_date: 2000-05-01
project_end_date: 2014-04-30
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
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): Natural products (NPs) and NP derivatives are an unrivaled but highly under-represented resource. Arguably among the most notable natural products discovered to date the 10-membered enediynes - exemplified by the saccharide-fused calicheamicins (CLM) and the anthraquinone-fused dynemicins (DYN) - offer unprecedented molecular architecture spectacular biological activity and demonstrated clinical utility. The objective of the first phase of this study (CA84374 years 1-4) was to i) clone and characterize the CLM gene cluster from M. echinospora ii) develop the genetic tools to address CLM biosynthesis in M. echinospora iii) investigate the mechanism(s) of CLM self-resistance and iv) initiate aryltetrasaccharide biosynthetic studies. With these goals largely achieved and new tools/information in place the second phase of this program (CA84374 years 5-9) was focused upon i) cloning and characterization of the DYN gene cluster from M. chersina ii) development of genetic tools to address DYN biosynthesis in M. chersina iii) initiating enediyne core biosynthetic studies iv) structurally characterization of the CLM self-sacrifice resistance protein CalC and v) the elucidation of key aryltetrasaccharide biosynthetic transformations (sugar N-oxidation thiosugar formation and GT-catalyzed aryltetrasaccharide assembly). The successful completion of the majority of phase II aims enables the proposed course of study for this competitive renewal. Specifically we will focus upon i) extending our understanding of enediyne core biosynthesis ii) delineating the potential role of CalC in regulating CLM production in M. echinospora iii) completing the study of key aryltetrasaccharide sugar nucleotide transformations (sulfur installation and sequential C-C alkylation of the N-alkyl dideoxypentose) iv) initiating an enediyne structural biology program and v) synthesizing and evaluating (neo)glycorandomized libraries of CLM and DYN.    PUBLIC HEALTH RELEVANCE: This is a second competitive renewal of a productive program ((CA84374) targeting the biosynthesis of 10-membered enediynes (calicheamicin and dynemicin) - a novel class of anticancer natural products. The program is anticipated to provide pioneering discoveries in enzyme-catalyzed chemistries new tools for the chemical diversification of complex natural products and unique anticancer lead compounds.

project_terms:
Address;Alkylation;Anabolism;Anthraquinones;Architecture;Biochemical;Biological;Biological Factors;Chemicals;Chemistry;Clinical;Cloning;Complex;Coupled;Crystallization;DNA;DNA Binding Domain;Development;Dynemicin;Enzymes;Escherichia coli;Evaluation;Fermentation;Gene Cluster;Gene Proteins;Gene Silencing;Genetic;Goals;In Vitro;Lead;Libraries;Molecular;Participant;Phase;Production;Proteins;Recombinants;Resistance;Resources;Role;Sensory;Series;Solubility;Specificity;Structure;Sulfur;analog;assay development;catalyst;glycosylation;glycosyltransferase;in vitro Assay;in vivo;novel;oxidation;programs;protein expression;public health relevance;research study;structural biology;structural genomics;sugar;sugar nucleotide;thiosugar;tool

public_health_relevance:
NARRATIVEThis is a second competitive renewal of a productive program ((CA84374) targeting the biosynthesis of 10-membered enediynes (calicheamicin and dynemicin) - a novel class of anticancer natural products. Theprogram is anticipated to provide provide pioneering discoveries in enzyme-catalyzed chemistries new toolsfor the chemical diversification of complex natural products and unique anticancer lead compounds.


application_id: 8247668
project_number: 5R01MD004598-04
project_title: Does Violence Against Women result in disparities in cancer care for women with b
administering_ic: NIMHD
award_notice_date: 2012-04-17
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:
Background: Violence against women (VAW) is defined by the United Nations as "any act of gender based violence thatresults in physical sexual or psychological harm or suffering to women." In Kentucky almost 40% of women hadexperienced some form of VAW in their lifetime. The frequency of VAW poses a serious public health challenge not onlydue 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 ahigh cancer burden with the highest cancer mortality rate of all US states. Incidence rates of cancer and the proportion ofwomen diagnosed at a later stage are higher in the Appalachian region of Kentucky. VAW frequently co-occurs withsocial factors leading to health disparities including unemployment less education and minority race. Overall objectivesof this project are to determine the extent to which VAW may explain noted disparities in cancer care based on women'srace/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 (aim2) and cervical cancer (aim 3) care outcomes to include not receiving cancer screening at recommended intervals beingdiagnosed with cancer at a later stage not receiving recommended cancer treatment including supportive/palliative careand poorer cancer specific survival among women diagnosed with these cancers in Kentucky and adjusting for relevantconfounders including race socioeconomic status having health insurance rural residence and specific regions of highpoverty (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 cases1575 colorectal cancer cases and 525 cervical cancer cases. These 5250 women will be interviewed by phone to determinetheir lifetime exposure to VAW and comorbid conditions. These data will be linked with state level Medicare claims datafor women completing phone surveys who are 65 or older. The Medicare claims data administered by the Center forMedicare and Medicaid Services include comprehensive coverage of medical services regardless of where the patientsseek care in the nation which would allow the detailed examination of the proposed cancer care continuum: cancerscreening stage at diagnosis treatment supportive or palliative care and survivorship. Both logistic regression and Coxproportional hazards modeling will be used to determine the role of VAW (by frequency duration severity recency andtype) and socioeconomic attributes influencing disparities in cancer care. These associations will be investigated for eachof the hypothesized five cancer care outcomes and by specific cancer. The mediating or moderating role of socioeconomicfactors will also be explored using structural equation modeling. Relevance: This will be the first population-based cohortof the influence of VAW on the life course of cancer care in a state with high cancer burden and regions of extremepoverty. Findings will have significant public health impact in reducing disparities and improving cancer prevention andcontrol 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: 8246445
project_number: 5R01DC009418-04
project_title: Neurotrophin receptor regulation of taste development
administering_ic: NIDCD
award_notice_date: 2012-02-14
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DC
serial_number: 009418
program_official: SULLIVAN, SUSAN L
project_start_date: 2009-04-01
project_end_date: 2014-03-31
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: MINICHIELLO, LILIANA
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:
Project Summary: During development sensory innervation to taste buds is tightly regulated by theactions of two neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4).Although both of these factors regulate gustatory innervation their specific functions are different fromone another. BDNF is expressed in gustatory epithelium and determines whether gustatory neurons willlocate and innervate taste placodes during development while NT4 does not. Both BDNF and NT4regulate gustatory neuron and taste bud number but they have their influences at different times duringdevelopment. The long range goal of this research is to understand the cellular and molecularmechanisms that regulate the neural innervation to and the maintenance of taste buds duringdevelopment. The proposed studies focus on mechanisms by which these two neurotrophins BDNFand NT4 can influence various aspects of neural innervation through the same receptors TrkB andp75. The proposed studies use cell counting tract tracing immunohistochemistry and scanningelectron microscopy in gene knockout mice to determine when TrkB and p75 are required for specificaspects of gustatory development including axonal extension into the tongue target selection andgeniculate neuron/taste bud survival. Furthermore these studies combine these anatomicalapproaches with sophisticated genetic tools allowing the function of single phosphorylation sites on theTrkB receptor protein to be blocked in vivo. These experiments will determine which TrkB intracellularsignaling pathways are required for axonal extension into the tongue target selection and geniculateneuron/taste bud survival. Together these studies test the hypotheses that TrkB mediates the effects ofboth BDNF and NT4 but that each function of these neurotrophins requires a different intracellularsignaling pathway. While p75's more subtle role is to modulate the regulation of gustatorydevelopment by neurotrophins. Because these experiments examine the fundamental mechanisms ofhow neurotrophins regulate neuronal survival and axon targeting via Trk receptors this project hasimportant implications for the therapeutic use of these signaling mechanisms in controlling neuronsurvival and axon targeting during regeneration..

project_terms:
Adult;Afferent Neurons;Axon;Binding (Molecular Function);Birth;Brain-Derived Neurotrophic Factor;Cell Count;Cell Cycle;Data;Development;Developmental Process;Docking;Embryonic Development;Epithelium;Fiber;Fungiform Papilla;Genes;Genetic;Goals;Growth;Growth Factor;Immunohistochemistry;Injury;Intracellular Signaling Proteins;Knockout Mice;Maintenance;Mediating;Microscopy Electron Scanning;Molecular;Mus;Mutate;NTF3 gene;Natural regeneration;Nerve;Nerve Growth Factor Receptors;Nerve Regeneration;Nervous System Trauma;Neurites;Neuronal Differentiation;Neurons;Neurotrophic Tyrosine Kinase Receptor Type 2;Palate;Pathway interactions;Pattern;Peripheral;Phospholipase;Phosphorylation Site;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Regulation;Research;Role;Sensory;Sensory Ganglia;Signal Pathway;Signal Transduction;Site;System;Systems Development;Taste Buds;Taste Perception;Techniques;Testing;Therapeutic Uses;Time;Tongue;Tyrosine;Wild Type Mouse;adapter protein;axon regeneration;improved;in vivo;nerve supply;neuron development;neuron loss;neuronal survival;neurotrophic factor;neurotrophin 4;postnatal;receptor;reinnervation;relating to nervous system;research study;response;somatosensory;synaptogenesis;tool;transcriptional coactivator p75

public_health_relevance:
The taste system is an ideal and commonly used system for examining axonregeneration following injury. We are examining the signaling mechanisms for twofactors (neurotrophins) that influence axon targeting and neuron survival duringdevelopment. By understanding of how these signaling mechanisms normally functiontechniques can be developed to manipulate these important signaling factors duringnerve regeneration which will improve reinnervation and function following nervoussystem injury.


application_id: 8246441
project_number: 5K01DK080951-04
project_title: Endoplasmic Reticulum-Induced Stress and Apoptosis in the Renal Tubule
administering_ic: NIDDK
award_notice_date: 2012-03-30
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: 8245698
project_number: 5R03AG038909-02
project_title: Mechanism of Age-Related Change in Estrogen Receptor Beta Expression in Rat Brain
administering_ic: NIA
award_notice_date: 2012-03-21
opportunity_number: PA-10-064
application_type: 5
activity_code: R03
ic: AG
serial_number: 038909
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2011-04-01
project_end_date: 2013-03-31
study_section: Molecular Neurogenetics Study Section[MNG]
contact_pi_person_id: 9097391
contact_pi: WESTBERRY, JENNE MITCHELL
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): Estrogen plays a crucial role in coordinating the neuroendocrine events that control sexual development sexual behavior and reproduction. Additionally estrogen modulates numerous additional facets of brain function. In humans the primary biologically active form of estrogen is 172-estradiol (E2). E2 has been implicated in several non-reproductive brain functions such as protection against brain injury involvement in learning and memory as well as promoting the formation of synapses. Additionally a growing body of literature has shown that E2 treatment may alleviate neuronal dysfunctions from Alzheimer<s disease through multifaceted molecular and cellular mechanisms. During aging cognitive and neurodegenerative conditions increase. In particular postmenopausal women are increasingly vulnerable as their E2 levels precipitously decline. As women spend a larger proportion of their lives in a hypoestrogenic state it is critical to understand the underlying mechanisms of estrogen action in the brain. Data from the Women<s Health Initiative suggest that current hormonal therapies however do not prevent cognitive decline. One potential reason for this observation is that the timing of hormone replacement is critical and thus changes in estrogen receptor expression in the brain may over-ride any potential hormonal intervention. Estrogen receptor-alpha splice variants have been shown to be associated with neurological disorders in the aging human brain however little is known about estrogen receptor-beta expression in the aging human brain. In rodents however ER2 mRNA expression is modified by age. ER2 expression decreases in a brain region specific manner although the cause of this decline is not known.  ER2 expression in the cortex and other brain regions could be regulated by a variety of mechanisms. One potential mechanism of ER2 gene regulation is through epigenetic modification of C-G rich regions of the ER1 promoter by methylation or acetylation of histones associated with the gene. Gene silencing occurs when methyl-binding proteins become associated with the methylated region of DNA which prevents transcription machinery from binding. Examples of epigenetic regulation of ER2 are seen in breast and prostate cancer where ER2 expression has been correlated with changes in methylation. Although regulation of ER2 expression has been heavily studied in cancer models very little is known about epigenetic regulation of ER2 in the brain during aging. Understanding how methylation alters gene expression in the brain may lead to the development of interventional strategies to influence gene expression related to human neurological disease. This proposal tests the hypothesis that estrogen receptor-beta gene expression is regulated by epigenetic mechanisms in the aging female brain.    PUBLIC HEALTH RELEVANCE: These studies will begin to determine the novel mechanisms of changes in gene expression caused by age on a critical gene in the female brain. These insights could lead to development of therapeutics that result in improved cognition in the postmenopausal woman by potentially preventing changes in ER2 gene expression. Furthermore we will develop a new methodology that will be critical for examining epigenetic changes in gene expression in a temporal and spatial manner in neural tissue with heterogeneous cell populations.

project_terms:
Age;Aging;Alzheimer's Disease;Area;Binding (Molecular Function);Binding Proteins;Brain;Brain Injuries;Brain region;Cancer Model;Cells;Cognition;Cognitive aging;DNA;Data;Development;Epigenetic Process;Estradiol;Estrogen Receptor alpha;Estrogen Receptor beta;Estrogen Receptors;Estrogens;Event;Female;Gene Expression;Gene Expression Regulation;Gene Silencing;Genes;Genetic Transcription;Health;Histone Acetylation;Hormonal;Hormones;Human;Impaired cognition;In Situ;Intervention;Lead;Learning;Literature;Malignant neoplasm of prostate;Memory;Methodology;Methylation;Modification;Molecular;Nerve Degeneration;Neuronal Dysfunction;Neurosecretory Systems;Ovariectomy;Play;Population;Postmenopause;Promotor (Genetics);Proteins;RNA Splicing;Rattus;Regulation;Reproduction;Rodent;Role;Sex Behavior;Sexual Development;Techniques;Testing;Time;Tissues;Variant;Woman;Women's Health;age effect;age related;brain cell;cancer cell;cell type;design;hormone therapy;improved;in vivo Model;insight;mRNA Expression;malignant breast neoplasm;nervous system disorder;novel;prevent;protein expression;public health relevance;receptor expression;relating to nervous system;synaptogenesis;therapeutic development

public_health_relevance:
PROJECT NARRATIVEThese studies will begin to determine the novel mechanisms of changes in geneexpression caused by age on a critical gene in the female brain. These insights couldlead to development of therapeutics that result in improved cognition in thepostmenopausal woman by potentially preventing changes in ER gene expression.Furthermore we will develop a new methodology that will be critical for examiningepigenetic changes in gene expression in a temporal and spatial manner in neuraltissue with heterogeneous cell populations.


application_id: 8245575
project_number: 5R01NS070899-03
project_title: Regulation signaling and dynamics of glucan phosphatases.
administering_ic: NINDS
award_notice_date: 2012-03-27
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.

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


application_id: 8245164
project_number: 5R01AI025098-23
project_title: Plague biofilm formation--regulation and function
administering_ic: NIAID
award_notice_date: 2012-03-16
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 025098
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 1993-09-30
project_end_date: 2014-03-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 1864186
contact_pi: PERRY, ROBERT DONALD
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Yersinia pestis is the causative agent of plague which has caused widespread loss of human life during recurrent pandemics. On average approximately 2500 cases of human plague occur world-wide each year. Recently over 98% of the plague cases are found in Africa. In nature the bacterium cycles between mammals (mainly rodents) and fleas. The interaction of plague with fleas is facilitated by the formation of a biofilm. In the oriental rat flea Xenopsylla cheopis formation of the biofilm leads to blockage of the valve between the esophagus and stomach of the flea known as the proventriculus. Blockage of the proventriculus may extend the transmission time. The hemin-storage genes (hms) of Y. pestis are responsible for the production of a biofilm which is essential for flea blockage. The Hms+ phenotype was initially characterized as the ability of cells grown at 26:C but not 37:C to bind exogenous hemin or the dye Congo red and is due to the production of an exopolysaccharide matrix or biofilm. There are at least 5 genes involved in the synthesis of the Hms- dependent biofilm; hmsHFRS hmsT and hmsP. Two of these gene products HmsP and HmsT are responsible for the synthesis and turnover of the signaling molecule cyclic di-guanylic acid. Over-production of HmsT a diguanylate cyclase or the absence of HmsP a phosphodiesterase leads to increased biofilm formation. Polyamines also play a role in the creation of a Y. pestis biofilm. Mutants that are unable to synthesize polyamines can not form a biofilm unless supplied with exogenous putrescine. This proposal will continue studies on the mechanisms that control biofilm development and the protein-protein interactions needed for biofilm formation. The biochemical functions of the Hms proteins as well as the role of the biofilm in fleas and mice will be addressed. In specific aim 1 the interaction between Y. pestis wild-type cells as well as various hms mutants and different flea species will be investigated. The role of c-di-GMP in virulence of plague will also be examined. Specific factors which regulate biofilm development will be studied in specific aim 2. In specific aim 3 the interactions between the Hms proteins as well as their biochemical and enzymatic characteristics will be addressed. The proposed studies will provide new insights into the regulation of plague biofilm formation and its role in the transmission of the disease from fleas to mammals. Systems similar to that responsible for plague biofilm are present in a number of diverse bacteria. Biofilms are often associated with the ability to survive harsh conditions as well as increased resistance to antibiotics. Understanding the mechanisms involved in producing the plague biofilm as well as the factors that regulate its production will likely be relevant for biofilm formation in other pathogens. PUBLIC HEALTH RELEVANCE: pestis the bacterium that causes bubonic and pneumonic plague produces a sticky substance known as a biofilm. Biofilms are made by several different kinds of bacteria and are often associated with their ability to survive harsh environments and in some cases cause disease. Understanding how the plague bacterium makes biofilm may eventually lead to ways to prevent biofilm formation in other bacterial pathogens.

project_terms:
Address;Affect;Africa;Amino Acids;Antibiotic Resistance;Asians;Bacteria;Binding (Molecular Function);Biochemical;Bioterrorism;Blood;Bubonic Plague;Cells;Characteristics;Congo Red;Development;Dinucleoside Phosphates;Disease;Disease Outbreaks;Dyes;Environment;Escherichia coli;Esophagus;Fleas;Genes;Guanosine Monophosphate;Health;Hemin;Human;In Vitro;Individual;Lead;Life;Mammals;Microbial Biofilms;Modeling;Montana;Mus;Mutagenesis;Mutation;Nature;Pathogenesis;Peptide Hydrolases;Phenotype;Plague;Play;Pneumonic Plague;Polyamines;Production;Proteins;Proventriculus;Putrescine;Rattus;Recurrence;Regulation;Rodent;Role;Signaling Molecule;South America;Southeastern Asia;Spermophilus;Squirrel;Stomach;System;Temperature;Testing;Time;Translations;Virulence;Yersinia pestis;bis(3'5')-cyclic diguanylic acid;cell type;diguanylate cyclase;disease transmission;glycosyltransferase;in vivo;insight;macrophage;mutant;pandemic disease;pathogen;periplasm;phosphoric diester hydrolase;prevent;protein protein interaction;transmission process;vector

public_health_relevance:
Project NarrativeYersinia pestis the bacterium that causes bubonic and pneumonic plague produces a sticky substance knownas a biofilm. Biofilms are made by several different kinds of bacteria and are often associated with their abilityto survive harsh environments and in some cases cause disease. Understanding how the plague bacteriummakes biofilm may eventually lead to ways to prevent biofilm formation in other bacterial pathogens.


application_id: 8245103
project_number: 5R01HD057501-05
project_title: The Mechanism of Cryptorchidism in LH Receptor Knockout Animals
administering_ic: NICHD
award_notice_date: 2012-03-19
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HD
serial_number: 057501
program_official: TAYMANS, SUSAN
project_start_date: 2008-04-01
project_end_date: 2015-03-31
study_section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER]
contact_pi_person_id: 2220008
contact_pi: LEI, ZHENMIN
other_pis: Not Applicable
congressional_district: 03
department: OBSTETRICS & GYNECOLOGY
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):  Cryptorchidism is by far the most common defect of sexual differentiation in humans. Testicular descent can be anatomically divided into two stages i.e. transabdominal and inguinoscrotal phases. It is known that both insulin-like peptide 3 (INSL3) and androgen signaling pathways play critical roles in the control of the transabdominal phase of testis descent. However the mechanism that regulates the inguinoscrotal phase is not completely understood even though the incidence of this defect is much more common clinically. Targeted disruption of luteinizing hormone receptor (LHRKO) in mouse impaired development of adult-type Leydig cells which resulted in a dramatic reduction of INSL3 and testosterone levels. Surprisingly serum estradiol levels were significantly increased. LHRKO males exhibited a bilateral cryptorchid phenotype resulting from a defect in inguinoscrotal testis descent. Histology morphometry cell proliferation and differentiation analyses demonstrated the defect was due to a reduction in mesenchymal cell division and differentiation into cremaster muscle cells during the second stage of testis descent. The expression of several genes in the gubernaculum that are known to be involved in gubernacular development such as Hoxa10 Hoxa11 Wt1 Dll1 and Desrt were not altered in mutant mice while Lgr8 Notch1 and Numb mRNA levels were drastically deceased as compared with age-matched wild type siblings. In contrast the expressions of Esr1 (ER1) and Esr2 (ER2) were significantly elevated. Postnatal testosterone replacement therapy (TRT) completed testicular descent into the scrotum and concomitantly normalized estradiol concentrations in the circulation and Esr1 Esr2 Lgr8 Notch1 and Numb mRNA levels in the gubernaculum. Remedy of the defect by TRT was neither dependent on recovery of adult-type Leydig cells nor the genitofemoral nerve but required androgen receptor activity in the gubernaculum. Using organ culture of the gubernaculum in vitro androgen alone did not significantly stimulate proliferation of gubernacular mesenchymal cells without activation of the leucine-rich repeat-containing G-protein coupled receptor 8 (LGR8) signaling pathway by addition of INSL3 or relaxin. Co-treatment of estrogen with androgen prevented androgen-induced Lgr8 expression. Cotreatment of INSL3 and androgen increased Notch1 but not Numb mRNA levels. Taking these results together we hypothesize that induction of the Lgr8 gene expression by androgen and activation of LGR8 signal impinging on the Notch system to stimulate gubernacular cell proliferation differentiation and myogenesis are the essential molecular pathways in the control of gubernacular development to facilitate inguinoscrotal testis descent. In addition to androgen deficiency unbalanced androgen/estrogen signals also play a role in contributing to the cryptorchid phenotype in LHR null animals. In this grant application we propose four specific aims to verify our hypotheses: (1) to define the underlying mechanism by which androgen modulates the Lgr8 gene expression in the gubernaculum; (2) to assess the role of the LGR8 signaling pathway in androgen-induced inguinoscrotal testis descent in LHR null males; (3) to determine the importance of the Notch signaling pathway in mediating androgen and LGR8 signals to regulate gubernaculum development during inguinoscrotal testis descent and (4) to investigate the effect of estrogen on androgen-induced inguinoscrotal testis descent in LHR null males. Cryptorchidism is by far the most common birth defect in males. Although inguinoscrotal testis descent is known to be androgen dependent the underlying mechanism remains unclear. The current proposal is focusing on determining androgen downstream target genes and subsequent signaling network during the process of inguinoscrotal testis descent which may provide new insight into the causes of testis maldescent.

project_terms:
Adult;Age;Androgen Receptor;Androgens;Animals;Applications Grants;Bilateral;Blood Circulation;Cell Differentiation process;Cell Proliferation;Cell division;Cells;Congenital Abnormality;Cryptorchidism;Defect;Development;Estradiol;Estrogens;Exhibits;G-Protein-Coupled Receptors;Gene Expression;Gene Targeting;Genes;Histology;Human;In Vitro;Incidence;Insulin;LH Receptors;Leucine-Rich Repeat;Mediating;Mesenchymal;Messenger RNA;Molecular;Mus;Muscle Cells;Mutant Strains Mice;Nerve;Notch Signaling Pathway;Organ Culture Techniques;Pathway interactions;Peptides;Phase;Phenotype;Play;Process;Recovery;Relaxin;Role;Scrotum;Serum;Siblings;Signal Pathway;Signal Transduction;Staging;System;Testis;Testosterone;cremaster muscle;insight;knockout animal;leydig interstitial cell;male;morphometry;myogenesis;notch protein;postnatal;prevent;testosterone replacement therapy


application_id: 8244994
project_number: 5T32HL086341-05
project_title: Research Training in Muscle Biology of Cardiopulmonary Disease
project_terms: Biology;Cor pulmonale;Muscle;Research Training
administering_ic: NHLBI
award_notice_date: 2012-03-29
application_type: 5
activity_code: T32
ic: HL
serial_number: 086341
program_official: TIGNO, XENIA
project_start_date: 2008-04-01
project_end_date: 2014-03-31
study_section: ZHL1-CSR-M(O2)
contact_pi_person_id: 6197585
contact_pi: ANDRADE, FRANCISCO H
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
The progression of cardiopulmonary disease and the efficacy of therapeutic interventions are critically dependent on the response of cardiac smooth and skeletal muscles in the cardiovascular and pulmonary systems. All three muscle types are essential for normal cardiopulmonary function all three play key roles in cardiovascular and pulmonary disease and all are targets for therapeutic development. The current program targets this area of biomedicine by training predoctoral and medical students for muscle research in the context of cardiopulmonary disease. The University of Kentucky (UK) is ideally suited for the program. UK is a public research institution with 33692 undergraduate and graduate students 1920 faculty members extramural research support of $290 million in 2006 and a medical center comprising six different health- related Colleges. A recently-adopted strategic plan calls for rapid growth of UK research via added faculty expanded graduate programs and new research facilities. Within this dynamic academic environment the UK program for Research Training in Muscle Biology of Cardiopulmonary Disease will builds on institutional strengths to train exceptional students for careers in basic and translational research. In a highly-selective vetting process program leadership will identify and recruit the best-qualified applicants for participation in two elite programs. Graduate students from eight different PhD programs will compete for two-year full-time appointments in the Postdoctoral Scholar program. A similar competition will identify research-oriented medical students for an eight-week Summer Scholar program. Both groups of Scholars will be mentored by twenty-two faculty members from ten basic science and clinical departments. Multidisciplinary mentoring teams will train Scholars in relevant areas of cardiac vascular smooth and respiratory skeletal muscle biology. Individualized curricula will combine coursework laboratory training and a structured clinical experience to achieve three specific aims: 1.) To prepare basic scientists at the predoctoral level for successful long-term careers in cardiopulmonary research; 2.) To engage predoctoral medical students in a summer laboratory experience that stimulates ongoing interest in basic and translational research; and 3.) To foster excellence in the mentoring skills of both program faculty and predoctoral scholars.


application_id: 8244979
project_number: 5R21HD068844-02
project_title: Combating Produce Consumption Disparity: Appalachian Farm to School Intervention
administering_ic: NICHD
award_notice_date: 2012-04-30
opportunity_number: PA-07-391
application_type: 5
activity_code: R21
ic: HD
serial_number: 068844
program_official: RAITEN, DANIEL J
project_start_date: 2011-05-01
project_end_date: 2015-04-30
study_section: Health Disparities and Equity Promotion Study Section[HDEP]
contact_pi_person_id: 8931964
contact_pi: SWANSON, MARK
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Located in rural Appalachian Kentucky a region with significantly lower fruit and vegetable intake and higher rates of a range of diet related diseases than the US as a whole the proposed project in Lee County KY examines the feasibility of using a farm to school program which provides locally-raised produce to the school cafeteria as a health intervention. The proposed project will be sited in one of the two elementary schools in the county both of which have free and reduced lunch qualification rates exceeding 78 percent with the other school serving as a matched control site. Farm to school projects seek to increase student consumption of fruits and vegetables by linking local farms to school cafeterias; currently however there are no known empirically-based examinations of this promising ecologically oriented approach to improving child nutrition. A multidisciplinary team including an anthropologist a health communications specialist a biostatistician and a public health nutritionist will partner with school personnel students parents and farmers in a Community Based Participatory Research program designed to develop implement and assess a farm to school program in a low-income county in Central Appalachia. The Specific Aims of this project are 1) To tailor existing farm to school programs using formative research including the development of promotional media for use in a low-income high disparity Appalachian community; and (2) To implement and evaluate a pilot F2S program as a means of improving FandV consumption in a low-income Appalachian elementary school. During Phase I the developmental phase key informant interviews and focus groups will be conducted to gain insights into how to tailor existing farm to school programs from elsewhere in the US to the Central Appalachian setting. Formative research with school administrators and food service personnel teachers area farmers students and parents will guide modifications to model farm to school programs. Research team members will collaborate closely with community members in structuring key program components farmer recruitment and selection of produce. We will use social marketing techniques to design in-school promotional media based on student suggestions and feedback from pilot testing. During Phase II we will administer the intervention using a nonequivalent control group design with pre and post tests. The primary outcome measure is the level of consumption of fruits and vegetables measured using an innovative technique based on digital photographic assessment of cafeteria consumption. Outcome evaluation is complemented with extensive process evaluation. Upon project completion we will apply and expand the findings of this ecologically oriented CBPR project to create a large scale R01 project capable of reducing childhood obesity in a way enriching and acceptable to the community.    PUBLIC HEALTH RELEVANCE: An important health risk faced by children in Appalachia is low intake of fruits and vegetables. This dietary deficiency can lead to a range of serious health consequences throughout life. Given the high levels of participation particularly in lower income schools the school lunch program is an important avenue to address this problem. The proposed project works with one Appalachian elementary school in Kentucky as well as its surrounding community to develop implement and assess a Farm to School program that brings locally grown produce into the cafeteria.

project_terms:
Achievement;Address;Administrator;Agriculture;American;Appalachian Region;Area;Attention;Behavior;Child;Child Nutrition;Communities;Complement;Complex;Consumption;Control Groups;County;Data;Development;Diet;Digital Photography;Disease;Eating;Effectiveness;Ensure;Evaluation;Farming environment;Feedback;Focus Groups;Food;Food Services;Funding;Grant;Health;Health Benefit;Health Communication;Housing;Human Resources;Intake;Intervention;Interview;Investments;Kentucky;Lead;Life;Light;Link;Low income;Malnutrition;Measurement;Measures;Modeling;Modification;North Carolina;Nutritionist;Outcome;Outcome Measure;Parents;Phase;Poverty;Pre-Post Tests;Price;Process;Program Effectiveness;Qualitative Methods;Qualitative Research;Reporting;Research;Research Design;Research Project Grants;Risk;Role;Rural;Schools;Site;Social Marketing;Specialist;Structure;Students;Suggestion;Techniques;Testing;Underrepresented Minority;Underserved Population;Vermont;Work;base;combat;community based participatory research;cost effectiveness;design;digital;elementary school;farmer;fruits and vegetables;health disparity;improved;informant;innovation;insight;member;multidisciplinary;obesity in children;primary outcome;programs;public health medicine (field);public health relevance;success;teacher;tool

public_health_relevance:
An important health risk faced by children in Appalachia is low intake of fruits and vegetables.This dietary deficiency can lead to a range of serious health consequences throughout life. Giventhe high levels of participation particularly in lower income schools the school lunch programis an important avenue to address this problem. The proposed project works with oneAppalachian elementary school in Kentucky as well as its surrounding community to developimplement and assess a Farm to School program that brings locally grown produce into thecafeteria.


application_id: 8244565
project_number: 5R01DK071349-08
project_title: Mechanisms Underlying Metabolic Syndrome in Obesity
administering_ic: NIDDK
award_notice_date: 2012-05-17
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 071349
program_official: ABRAHAM, KRISTIN M
project_start_date: 2005-06-01
project_end_date: 2014-03-31
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: KERN, PHILIP A
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):  Resident macrophages in adipose tissue account for much of the cytokine expression with obesity. We described the expression of thrombospondin (TSP1) a pleiotropic adipokine in insulin resistant subjects. Through its anti-angiogenic properties and its ability to activate TGF2 TSP1 may be an important part of the adipocyte/macrophage interaction that results in simultaneous impairment of angiogenesis and increased TGF- 2-mediated fibrosis and inflammation. We recently demonstrated that macrophages also infiltrate skeletal muscle with obesity that is strongly correlated with insulin resistance. Furthermore the presence of macrophages in co-culture with muscle cells in the presence of palmitic acid to mimic an obese environment results in a synergistic increase in the expression and secretion of inflammatory cytokines from muscle cells all of which impair insulin action. We hypothesize that macrophages in both muscle and adipose tissues promote the development of metabolic syndrome during obesity. To test this hypothesis adipose (Aim 1) and muscle tissue (Aim 2) from obese insulin resistant compared to normal human subjects will be characterized. Macrophage number the proportion of macrophages that are classically versus alternatively activated and the proportion of macrophages in crown-like structures (in adipose) will be quantified along with markers of the TGF2 pathway fibrosis hypoxia tissue remodeling and vascularity. To specifically determine the role of TSP1 and the TGF2 pathway in insulin resistance adipose and muscle tissue fibrosis hypoxia and macrophage function will be analyzed in high fat fed TSP1 null mice in Aim 3. A peptide that specifically blocks TSP1- mediated TGF2 activation will also be used in wild type high fat fed mice to test the hypothesis that macrophage infiltration and fibrosis in adipose and muscle will be ameliorated in the absence of TSP1 resulting in improved insulin sensitivity. Aim 4 is the intervention aim in which the mechanisms underlying the beneficial effects of aerobic exercise training on insulin sensitivity will be determined. Following 12 weeks of training in obese and lean subjects changes in muscle and adipose macrophage number activation state the TSP1/TGF2 pathway and inflammation in response to a single bout of eccentric exercise will be quantified relative to insulin sensitivity. Finally in Aim 5 the effects of different macrophage populations on adipocytes and muscle cells will be studied in vitro. The expression of genes involved in adipogenesis extracellular matrix and the TGF2 pathway will be monitored in adipocytes following macrophage co-culture. These will also be quantified in muscle cells as well as the response to insulin. We will determine whether mechanical stimulation of myotubes to mimic exercise will alter the muscle cell response to macrophages.    PUBLIC HEALTH RELEVANCE:  The American population is experiencing an explosion in obesity metabolic syndrome and diabetes and this national trend is magnified in Kentucky and the Southeast. The cost of caring for diabetes and its complications is enormous. Impaired glucose tolerance and metabolic syndrome are preludes to the development of type 2 diabetes represent a risk factor for coronary artery disease and are more prevalent than diabetes itself. These studies are intended to examine fundamental mechanisms of insulin resistance and inflammation and involve studies in humans mice and cell culture. New insight into these fundamental mechanisms may form the basis for new treatments.

project_terms:
Accounting;Adipocytes;Adipose tissue;Aerobic Exercise;American;Anti-Inflammatory Agents;Anti-inflammatory;Area;Arkansas;Award;Budgets;Caring;Cell Culture Techniques;Chronic;Clinical;Coculture Techniques;Collaborations;Coronary Arteriosclerosis;Data;Dental crowns;Development;Diabetes Mellitus;Doctor of Philosophy;Environment;Etiology;Exercise;Explosion;Extracellular Matrix;Fatty acid glycerol esters;Fibrosis;Functional disorder;Funding;Funding Mechanisms;Gene Expression;Goals;Grant;Human;Hypoxia;Impairment;In Vitro;Individual;Infiltration;Inflammation;Inflammatory;Insulin;Insulin Resistance;Interleukin-1;Interleukin-6;Intervention;Kentucky;Knockout Mice;Link;Mechanical Stimulation;Mediating;Medical;Metabolic syndrome;Monitor;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle function;Necrosis;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Palmitic Acids;Pathway interactions;Phenotype;Population;Process;Property;Relative (related person);Research Personnel;Risk Factors;Role;Science;Signal Pathway;Skeletal muscle structure;Stretching;Structure;System;TNF gene;Talents;Testing;Thrombospondin 1;Time;Tissues;Training;United States National Institutes of Health;Universities;Update;Vascularization;Work;adipokines;adiponectin;angiogenesis;base;cost;cytokine;experience;feeding;human subject;impaired glucose tolerance;improved;in vitro Model;innovation;insight;insulin sensitivity;insulin signaling;lipid biosynthesis;lipid metabolism;macrophage;peptide A;programs;public health relevance;repaired;response;stem;trend

public_health_relevance:
Project NarrativeThe American population is experiencing an explosion in obesity metabolic syndrome and diabetes and thisnational trend is magnified in Kentucky and the Southeast. The cost of caring for diabetes and itscomplications is enormous. Impaired glucose tolerance and metabolic syndrome are preludes to thedevelopment of type 2 diabetes represent a risk factor for coronary artery disease and are more prevalentthan diabetes itself. These studies are intended to examine fundamental mechanisms of insulin resistance andinflammation and involve studies in humans mice and cell culture. New insight into these fundamentalmechanisms may form the basis for new treatments.


application_id: 8244527
project_number: 5R01CA133429-05
project_title: The Role of PHLPP in Colon Cancer
administering_ic: NCI
award_notice_date: 2012-06-01
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 133429
program_official: YASSIN, RIHAB R
project_start_date: 2009-04-01
project_end_date: 2015-02-28
study_section: Molecular Oncogenesis Study Section[MONC]
contact_pi_person_id: 7353657
contact_pi: GAO, TIANYAN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Colorectal cancer is the second leading cause of cancer-related deaths in the United States with 112000 new cases diagnosed per year and approximately 52000 deaths estimated in 2007. Dysregulation of Akt and protein kinase C (PKC) contributes to tumorigenesis by promoting cell proliferation and inhibiting apoptosis. The signaling activation process of Akt and PKC has been studied in great detail. However little is known about how the signals are turned off once activated. Recently we have identified a family of novel protein phosphatases PHLPP (PH domain Leucine-rich-repeats Protein Phosphatase) that directly dephosphorylates Akt and PKC. However the role of PHLPP in cancer has not been defined. In the preliminary studies we found that loss of PHLPP expression occurs with high frequency in human colorectal cancer specimens. Furthermore our studies have suggested that PHLPP plays a role in regulating cell polarity. In light of our findings the central hypothesis driving this proposal is that PHLPP serves as a tumor suppressor by regulating cell polarity in addition to its ability of turning off the growth signaling activated by Akt and PKC. The long-term goal of our studies is to better understand the physiological role of PHLPP and its contribution to colon cancer development and progression in vivo. The Specific Aims are: Aim 1: To define the molecular mechanism of PHLPP downregulation. The goal of this aim is to investigate the potential mechanism leading to PHLPP downregulation in cancer. We will test the hypothesis that the expression level of PHLPP is controlled by the ubiquitin proteasome pathway in cells and preventing PHLPP degradation leads to upregulation of the protein. Aim 2: To determine the role PHLPP in maintaining cell polarity. We hypothesize that PHLPP exerts its function as a tumor suppressor by regulating cell polarity and cell growth. The functional effect of PHLPP on establishing epithelial cell polarity will be determined. To elucidate the underlying mechanism we will test the hypothesis that PHLPP is required for epithelial junction formation by modulating PKC activity via binding to the polarity protein Scribble. Aim 3: To delineate the role of PHLPP in tumorigenesis in vivo. The hypothesis driving this aim is that loss of PHLPP expression contributes to the initiation and progression of colorectal tumors. We will address the question whether there is an increase of tumor incidence when PHLPP is knocked out both basally and in combination with other carcinogenic factors. Furthermore we will assess the contribution of altered cell polarity in normal development of gut epithelium and tumor initiation using the knockout mice. PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer-related deaths in the United States with 148000 new cases diagnosed per year and approximately 50000 deaths estimated in 2007 and among many contributing factors aberrant protein phosphorylation resulting from hyperactivation of oncogenic signaling mediated by protein kinases such as Akt and PKC is a key cause of colorectal cancer. We recently identified a novel protein phosphatase PHLPP that directly dephosphorylates Akt and PKC and terminates the growth signals activated by these kinases. We propose to determine the functional importance of PHLPP as a tumor suppressor in colorectal cancer and the results from this study will provide significant insights into the development of potential cancer therapy using PHLPP as a novel target.

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

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


application_id: 8244231
project_number: 1R21NS071299-01A1
project_title: Electrophysiological reporter for monitoring gene manipulations
administering_ic: NINDS
award_notice_date: 2011-08-15
opportunity_number: PA-10-069
application_type: 1
activity_code: R21
ic: NS
serial_number: 071299
suffix: A1
program_official: TALLEY, EDMUND M
project_start_date: 2011-09-01
project_end_date: 2013-08-31
study_section: Neurotechnology Study Section[NT]
contact_pi_person_id: 9011081
contact_pi: PETRUSKA, JEFFREY C
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):  This proposal is an innovative effort to develop a novel tool that could revolutionize the execution and application of in vivo sharp electrode intracellular electrophysiology the fundamental approach for examining cellular and synaptic mechanisms of systems-level functions.  This tool is a reporter gene that will be detectible by electrophysiological methods in real-time by sharp electrodes in vivo without the need for secondary factors (i.e. light stimulus or exogenous ligands).  This could provide a necessary link to enable a more thorough incorporation of classic-type systems physiology with the reduced preparations and lower species that make up the majority of current experimental approaches used to understand genetic manipulations.  An ideal electrophysiological reporter is one that is genetically-encoded is "visible" to electrophysiological methods has a signal that is easily recognized and distinguished from native processes in real time and does not interfere with normal physiological function.  We have identified a lab-generated mutant ion channel that fits these criteria and appears to be an excellent candidate.  We will make use of new viral vector technology to deliver candidate gene to adult rats.  Aim 1 will use both in vivo and in vitro single-cell electrophysiological approaches to determine if the signal from the reporter gene can be detected against the well characterized background of the model systems (dorsal root ganglion sensory neurons and spinal motoneurons).  Aim 2 is hypothesis driven and will determine if constitutive signaling by trkC the receptor for neurotrophin-3 plays a necessary role in maintenance of the cellular and synaptic properties of adult motoneurons.  The issue of maintenance of cellular properties by target-derived factors is in a question of fundamental importance in terms of the principles of neuroscience/neurobiology and also in terms of biomedical issues in the adult nervous system such as aging neurodegeneration traumatic injury and learning and memory.  
  
PUBLIC HEALTH RELEVANCE:  This project is aimed at developing a new tool for research - a gene that will report the status of genetic manipulations to electrophysiological probes.  If successful it will greatly facilitate the execution of and interpretation of data from systems-level in vivo neurophysiology an experimental approach that is particularly relevant to functional studies of the role of specific genes/cell-types in systems-level processes such as aging locomotion sensori-motor integration models of psychiatric disorders and addiction/substance abuse and nervous system disease/injury/insult and the responses to treatments.  This project also Aims to determine the effect of altering the expression of trkC (the receptor for neurotrophin-3) on the cellular and synaptic electrophysiological properties of a subpopulation of neurons which is relevant to conditions or disease states that may include reduced neurotrophin-receptor signaling in the pathophysiology such as aging diabetic neuropathy traumatic nervous system injury and neurodegeneration.

project_terms:
Address;Adult;Afferent Neurons;Aging;Animals;Biological Models;Candidate Disease Gene;Cell Line;Cells;Characteristics;Code;Complex;Data;Diabetes Mellitus;Diabetic Neuropathies;Disease;Electrodes;Electrophysiology (science);Functional disorder;Gene Delivery;Genes;Human;In Vitro;Individual;Information Systems;Injury;Ion Channel;Kinetics;Learning;Ligands;Light;Link;Locomotion;Maintenance;Mammalian Cell;Mediating;Memory;Mental disorders;Methods;Modeling;Molecular Genetics;Monitor;Motor;Motor Neurons;Nerve Degeneration;Nerve Growth Factor Receptors;Nervous System Trauma;Nervous system structure;Neurobiology;Neurodegenerative Disorders;Neurons;Neurosciences;Neurotrophic Tyrosine Kinase Receptor Type 3;Neurotrophin 3;Newborn Animals;Pathology;Physiologic pulse;Physiological;Physiology;Play;Preparation;Process;Production;Proline;Property;Publishing;Rattus;Receptor Signaling;Reporter;Reporter Genes;Reporting;Research;Research Personnel;Role;Signal Transduction;Spinal;Spinal Ganglia;Stimulus;Substance abuse problem;Synapses;System;Technology;Time;Viral Vector;Virus;Work;addiction;cell type;fighting;genetic manipulation;improved;in vivo;injured;innovation;interest;knock-down;mutant;nervous system disorder;neurophysiology;novel;receptor;relating to nervous system;research study;response;small hairpin RNA;therapeutic target;tool;voltage

public_health_relevance:
This project is aimed at developing a new tool for research - a gene that will report the status of genetic manipulations to electrophysiological probes.  If successful it will greatly facilitate the execution of and interpretation of data from systems-level in vivo neurophysiology an experimental approach that is particularly relevant to functional studies of the role of specific genes/cell-types in systems-level processes such as aging locomotion sensori-motor integration models of psychiatric disorders and addiction/substance abuse and nervous system disease/injury/insult and the responses to treatments.  This project also Aims to determine the effect of altering the expression of trkC (the receptor for neurotrophin-3) on the cellular and synaptic electrophysiological properties of a subpopulation of neurons which is relevant to conditions or disease states that may include reduced neurotrophin-receptor signaling in the pathophysiology such as aging diabetic neuropathy traumatic nervous system injury and neurodegeneration.


application_id: 8242441
project_number: 1R01DA032910-01
project_title: Development of a Cocaine-Metabolizing Enzyme for Drug Overdose Treatment
administering_ic: NIDA
award_notice_date: 2012-02-17
opportunity_number: RFA-DA-12-001
application_type: 1
activity_code: R01
ic: DA
serial_number: 032910
program_official: SHIH, MING L
project_start_date: 2012-03-01
project_end_date: 2015-02-28
study_section: Special Emphasis Panel[ZDA1 JXR-D (06)]
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Development of a truly effective anti-cocaine medication has been very challenging particularly for treatment of cocaine overdose. There is still no FDA-approved anti-cocaine medication. Enhancing cocaine metabolism by administration of butyrylcholinesterase (BChE) has been recognized as a promising treatment strategy for cocaine abuse. However the catalytic activity of this plasma enzyme is low against the naturally occurring (-) - cocaine. Our recent integrated computational-experimental effort has led to discovery of high-activity mutants of human BChE known as cocaine hydrolases (CocHs) with >1000-fold improved catalytic efficiency against cocaine compared to wild-type BChE. In vivo evidences indicate that our discovered CocHs are promising candidates for development of an anti-cocaine medication especially for the overdose treatment. In this proposed project we focus on the selection and optimization of the most promising CocH as a novel therapeutic candidate for cocaine overdose treatment through a combined use of various in silico in vitro and in vivo approaches. The specific aims are: (1) To prepare and characterize the discovered CocHs in vitro for their catalytic activity and stability; (2) To characterize the CocHs in vivo for their potency biological/circulatory half-lives and immunogenicity by using the CocH materials prepared in Aim 1; (3) To design prepare and characterize new CocH entities that have not only a high in vivo potency but also a higher thermal stability and a longer circulatory half-life without immunogenicity. Accomplishment of this proposed investigation will result in the identification and development of the most promising CocH entity that has a high in vivo potency in the protective and rescuing effects a high stability and a sufficiently long biological half-life without immunogenicity. The CocH entity optimized in this investigation is expected to be highly effective and safe as an exogenous enzyme for cocaine overdose treatment in humans.  
  
PUBLIC HEALTH RELEVANCE:  Accelerating cocaine metabolism has been recognized as a promising treatment strategy for anti-cocaine medication. Accomplishment of the proposed investigation will result in the identification of reliable candidates of a novel enzyme therapy for cocaine overdose.


application_id: 8242152
project_number: 1K23AR060275-01A1
project_title: Clinical and Biochemical Predictors of Outcome after Knee Injury in Young Patient
administering_ic: NIAMS
award_notice_date: 2012-03-05
opportunity_number: PA-10-060
application_type: 1
activity_code: K23
ic: AR
serial_number: 060275
suffix: A1
program_official: PANAGIS, JAMES S
project_start_date: 2012-03-05
project_end_date: 2017-02-28
study_section: Arthritis and Musculoskeletal and Skin Diseases Special Grants Study Section[AMS]
contact_pi_person_id: 9042382
contact_pi: LATTERMANN, CHRISTIAN
other_pis: Not Applicable
congressional_district: 06
department: ORTHOPEDICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Posttraumatic osteoarthritis is an acknowledged outcome of contact-related sports injuries but is an underestimated and understudied problem occurring after non-contact rupture of the anterior cruciate ligament (ACL).  It is estimated that approximately 40-50% of young athletes are at significant risk for developing progressive osteoarthritis (OA) 10-20 years after ACL injury suffered during high school sports participation. Unfortunately reliable predictors of which athletes are at highest risk for developing OA after ACL injury do not exist.   We propose to establish for the first time baseline serum measures of specific biomarkers in 350 injury- free adolescent high school athletes before during and after their competitive season (Aim 1). We will follow this cohort of subjects prospectively for 4 years. Simultaneously we will study a second age- matched cohort of young high school athletes with documented ACL tears. Biomarkers will be measured in these subjects post-injury until biomarker values normalize.  These subjects will be followed for two years post-operatively using patient reported outcome (PRO) instruments. We hypothesize that biomarker levels will increase after ACL injury relative to a normative population. In addition we hypothesize that biomarkers will be highest in subjects with more severe bone bruising after ACL injury (Aim 2).  Finally we will determine outcomes of subjects with severe bone bruises following ACL injury (Aim 3). The presence of bone bruise is not known to be a predictor of posttraumatic OA and lower clinical outcomes scores however bone bruises have been implicated in the progression of osteoarthritis after ACL injury. We will examine if any correlation exists between the magnitude distribution or severity of bone bruise lower patient reported outcomes and evidence of posttraumatic OA initiation at 2 year follow-up. We will also re-examine pre-operative MRI scans pre and post-operative standardized  x-ray and patient reported outcomes followed over 2 years (with a follow-up rate of 85%) in a  prospective longitudinal cohort of 112 isolated ACL injured patients with no additional comorbidities.   Typically 90-100% of these patients may be expected to have a bone bruise after ACL injury.   The impact of these studies is expected to be significant. The identification and validation of biomarkers with and without supporting correlating data from the extent of bone bruise associated with ACL rupture  will provide clinicians with the means to identify adolescents at high risk for the development of  disabling and crippling posttraumatic osteoarthritis and tailor treatment and rehabilitation protocols  that may prevent or delay early onset osteoarthritis in this vulnerable population.    
   
PUBLIC HEALTH RELEVANCE: Non-contact injuries to the knee in the young are becoming prevalent at an alarming rate as participation in high school sports increases. Anterior cruciate ligament (ACL) injuries with bone bruises may hasten cartilage loss predisposing some individuals to early onset osteoarthritis. This study investigates the ability of a serum biomarker
and magnetic resonance imaging to predict (separately or in combination) progressive unremitting cartilage loss in high school athletes at the time of ACL injury. The result of this study may significantly impact the design and implementation of new better treatment and rehabilitation protocols in these young athletes.

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

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


