A MODEL OF AUTOBIOGRAPHICAL MEMORY & ITS CHANGES IN PTSD
C David, Professor
Duke Universitycity: Durham country: United States (us)
Grant 5R01MH066079-07 from National Institute Of Mental Health
Abstract: We formulate and test a theory of posttraumatic stress disorder (PTSD) based only on mechanisms that have solid support in scientific studies of cognition, personality, and emotion. The theory combines findings from experimental and individual differences research to make predictions that often contradict existing theories of PTSD, but that agree with the existing data. It is the first theory to combine measures of the severity of traumatic events, personality, and memory processes. Moreover, it predicts quantitatively clinical outcomes by assigning numerical weights to the various measures. Two main studies are proposed, which use structural equation models. In the first, 200 adults will be tested, who vary in symptom severity. Of these, at least 50 will meet standard clinical diagnostic inclusion criteria for current PTSD and 50 will meet standard exclusion criteria for lifetime PTSD so that, in addition to the correlational analyses, direct comparisons can be made between the prototypical groups used in the PTSD literature. To provide predictor variables, the participants will complete standardized tests of mood and personality. They will recall and record a narrative version of their most traumatic or stressful events, which will be scored for coherence and event severity. They will also recall their three most positive and three most important events and imagine that three traumatic scenarios occur to them in the future. The imagined future events will probe how the participants view and react to traumatic events in general. For each of their memories and the imagined events, participants will provide measures of emotional intensity and valence, vividness of sensory information, narrative coherence, and degree of reliving of the event. They will also provide ratings of involuntary, often intrusive, memories made as they come to mind for two weeks, recording their responses on personal data assistants. This online technique was developed by our group and its use is still unique to it in PTSD populations. It provides the most accurate measure of intrusive memories, a key symptom of PTSD. The rich data set obtained allows us to disentangle competing existing hypotheses and better understand the mechanisms that lead to and maintain PTSD. The second study uses the same theory and quantitative techniques, but takes advantage of an ongoing longitudinal study in its 20th year. It includes fewer, but similar, tests to the first study and a sample of several thousand adults approximately 60 years old. It includes tests of current PTSD symptom severity, mood and personality tests, as well as health data, to do a truly prospective study of current PTSD symptoms as predicted by measures obtained longitudinally. Additional tests and experiments will be conducted to test specific supporting hypotheses. In particular, we will examine the coherence of narrative of memories of traumatic, very positive, and important events in participants who have or do not have a clinical diagnosis of PTSD. Based on measures of the severity of a traumatic event, the personality of the person experiencing the event, and the properties of the memories that the person has of the event and of other non-traumatic events, we attempt to predict which people will develop posttraumatic stress disorder (PTSD) and how severe their symptoms will be. We do this by trying to understand autobiographical memory for emotional, stressful events. Our quantitative theory, if successful, would help identify risk factors for PTSD and should suggest which properties of traumatic memories therapy should attempt to change
Keywords: Address; Adult; Affect; Affective; Back; base; Clinical; clinical Diagnosis; Cognition; Cognitive; Conflict (Psychology); Couples; Data; Data Collection; Data Set; Diagnosis; Diagnostic; Emotional; Emotions; Equation; Event; Exclusion Criteria; experience; Funding; Future; Grant; Health; Heart; inclusion criteria; Individual Differences; Lead; Literature; Longitudinal Studies; Measures; meetings; Memory; memory process; Military Personnel; Mind; MMPI; Modeling; Moods; novel; Outcome; Participant; Personality; Personality Tests; Persons; Population; Post-Traumatic Stress Disorders; Process; Property; Prospective Studies; Protocols documentation; Psychology; public health relevance; Recording of previous events; Reporting; Research; Research Personnel; research study; response; Risk Factors; Sampling; Scientist; Sensory; Severities; Solid; Spouses; standardize measure; Stressful Event; Structural Models; Subgroup; Symptoms; System; Techniques; Temperament; Testing; theories; Trauma; Veterans; Vietnam; Weight; Work
Relevance: Based on measures of the severity of a traumatic event, the personality of the person experiencing the event, and the properties of the memories that the person has of the event and of other non-traumatic events, we attempt to predict which people will develop posttraumatic stress disorder (PTSD) and how severe their symptoms will be. We do this by trying to understand autobiographical memory for emotional, stressful events. Our quantitative theory, if successful, would help identify risk factors for PTSD and should suggest which properties of traumatic memories therapy should attempt to change
Project start date: 2002-09-01
Project end date: 2015-02-28
Budget start date: 1-MAY-2011
Budget end date: 29-FEB-2012
PFA/PA: PA-09-137
5R01MH066079-07 (2011): $613297
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to C David
2011 US-HUPO CONFERENCE -- PROTEOMICS: NEW DEVELOPMENTS AND GRAND CHALLENGES
C David, Professor
North Carolina State University Raleighcity: Raleigh country: United States (us)
Grant 1R13RR032268-01 from National Center For Research Resources
Abstract: We request partial funding support for operation of the 2011 Annual Meeting of the United States Human Proteome Organization (US-HUPO) entitled "Proteomics New Developments and Grand Challenges", to be held March 20-23, 2011 in Raleigh, North Carolina. This meeting has been and continues to be a vital conference for the highly interdisciplinary scientific field of proteomics directed towards biological and clinical questions. US-HUPO is a unique meeting of scientists because it truly reflects the multiple disciplines, strategies, and technologies for which proteomics encompasses to enable this field to approach and solve sophisticated biomedical problems and provide perspective and accomplishments on how these findings can be translated into the clinic for diagnostic, prognostic and treatment purposes. The field is rich with diverse technological platforms including mass spectrometry, protein microarrays, biosensors, clinical assays, and biomarker discovery and validation. The first meeting of US-HUPO was in 2005 and what has evolved is a program that has provided the scientific foundation that has propelled the field of proteomics forward in rapid fashion. The conference is heavily attended and has always attracted first-rate speakers in this field. The 2011 Annual Meeting will again bring together an outstanding and diverse group of scientists at the forefront of proteomics. Invited speakers in the symposium will explicitly discuss applications relevant to a wide range of diseases including cardiovascular disease, cancer, and infectious diseases. The technological advances that have been made in the recent year are of critical importance to allow scientists to more effectively address biological problems and thus, this will also be a hallmark of the meeting. The topics chosen will educate participants on the latest, most effective technologies and methods, illustrate successful translation of these technologies into the clinic, and highlight new directions and grand challenges for the future of this field. Panel discussions will be held on key topics in order to encourage a robust dialogue between speakers and meeting participants to discuss critical goals for the future in proteomics, outline anticipated obstacles, and brainstorm solutions. This year US- HUPO will introduce a Business Meeting in the program to allow the participants to understand the mission and details of US-HUPO and thus allow for direct feedback from those in attendance to further improve the meeting. The poster sessions will also offer a more informal exchange of scientific ideas and advances. Ample time will be devoted to social venues for attendees to meet each other and establish new contacts and collaborations. Currently, 33% of the invited speakers are either women or members of minority groups and 33% are new investigators (Assistant/Associate Level). Attendance is expected to be 350-450 participants, including 100-150 students/post A docs. Registration is not restricted, and all interested persons may attend. A special effort will be made to recruit minority and industrial participants; the latter should be readily achievable given that Research Triangle Park is only 15 minutes from downtown Raleigh. Participants will present posters on new findings each afternoon. Importantly, the conference provides a forum for young investigators to see the connection between fundamental scientific inquiry and the application of scientific methods to the design of efficacious interventions for human disease. To emphasize this goal, over 20 poster presentations that complement the themes of the meeting will be selected for short oral presentations during the concurrent sessions. Finally, it is important to note that preceding the meeting, US-HUPO offer several Full-Day and Half-Day short courses on contemporary topics in proteomics. PUBLIC HEALTH RELEVANCE Funding is requested to support the 2011 Annual Meeting of the United States Human Proteome Organization (US-HUPO), whose mission is to promote scientific and educational activities to encourage the use of new technologies for analyzing proteins in human tissues and fluids, and model organisms, with the ultimate goal of developing critically needed methods for early diagnosis, prognosis of human diseases and new therapies for treating contemporary health problems that affect millions of people worldwide
Keywords: ing; Address; Affect; Animal Model; base; Biological; Biological Assay; biomarker; Biosensor; Businesses; Cardiovascular Diseases; career; cell growth regulation; Cells; Clinic; Clinical; clinical application; clinical assay development; Coffee; Collaborations; Communicable Diseases; Complement; Country; density; design; Development; Diabetes Mellitus; Diagnostic; Disabled Persons; Discipline; Disease; Early Diagnosis; Educational Activities; Educational workshop; Experimental Designs; Faculty; Feedback; Fostering; Foundations; Funding; Funding Applicant; Future; Goals; graduate student; Growth; handicapping condition; Health; Historically Black Colleges and Universities; Human; human disease; human tissue; improved; innovation; Institution; interest; Intervention; Laboratories; Learning; Liquid substance; Mails; Malignant Neoplasms; Maryland; Mass Spectrum Analysis; medical schools; meetings; member; Methods; Minority; Minority Groups; Minority-Serving Institution; Mission; nervous system disorder; new technology; North Carolina; novel; Obesity; operation; Oral; outcome forecast; Participant; Persons; Postdoctoral Fellow; posters; prognostic; programs; Protein Microchips; Proteins; Proteome; Proteomics; public health relevance; Published Comment; Records; Recruitment Activity; Research; Research Personnel; Scientist; Site; social; Societies; Solutions; South Carolina; Students; symposium; Technology; Thinking, function; Time; Training; Translating; translational medicine; Translations; treatment strategy; Underrepresented Minority; United States; Universities; Validation; Virginia; Woman
Relevance: Funding is requested to support the 2011 Annual Meeting of the United States Human Proteome Organization (US-HUPO), whose mission is to promote scientific and educational activities to encourage the use of new technologies for analyzing proteins in human tissues and fluids, and model organisms, with the ultimate goal of developing critically needed methods for early diagnosis, prognosis of human diseases and new therapies for treating contemporary health problems that affect millions of people worldwide
Project start date: 2011-03-18
Project end date: 2012-02-29
Budget start date: 18-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: PA-10-071
1R13RR032268-01 (2011): $25000
QUINOLONE AND MULTIDRUG RESISTANCE IN STAPHYLOCOCCUS AUREUS
C David, Professor Of Medicine, Physician
Massachusetts General Hospitalcity: Boston country: United States (us)
Grant 5R37AI023988-23 from National Institute Of Allergy And Infectious Diseases
Abstract: We propose to study the regulation of expression of chromosomally encoded multidrug resistance (MDR) efflux pumps and their roles in antimicrobial resistance in Staphylococcus aureus, with a focus on quinolone resistance. In prior work we identified quinolone resistance caused for increased expression of the NorA, B, and C pumps, tetracycline resistance due to the Tet38 pump, (-lactam resistance due to the AbcA pump, and others have identified biocide resistance due to the MepA pump. We have also identified direct transcriptional regulators of pump expression, MgrA and NorG, which interact with each other and have broad effects. There are five Specific Aims. Under Aim 1, we will define the interactions of MgrA and NorG in expression of norA and other genes encoding efflux pumps. We specifically hypothesize that phosphorylation of MgrA alters its interactions with NorG and changes its effects on transcription of pump genes. The work will include measuring expression of norA by Northern hybridization in strains with constructed mutations in HprK kinase, and measurements of promoter binding of phosphorylated and unphosphorylated MgrA. Under Aim 2, we will identify the direct regulators of norB, tet38, and abcA by isolating proteins from cell extracts that bind to immobilized promoter DNA fragments, determining their identity by mass spectroscopy, and generating strains with mutations in and overexpression of the genes so identified. Such strains will be assessed for changes in expression of genes encoding pumps by Northern hybridization and transcriptional profiling. Under Aim 3, we will evaluate the global effects of NorG by transcriptional profiling of strains with mutations in and overexpression of norG. Under Aim 4, we will identify other candidate efflux pumps shown to be over-expressed in microarray analyses of regulatory networks and environmental stresses and define their roles in antibiotic resistance. Specific novel candidate pump genes distinct from those listed have been shown to be overexpressed in sarA, mgrA, and rot global regulatory mutants and under conditions evoking the stringent response or growth in a mouse subcutaneous abscess model. These candidate pump genes will be cloned and the effects of their overexpression on susceptibility to antibiotics and biocides will be assessed in order to add to the complement of known efflux resistance mechanisms. Under Aim 5, we will identify the environmental triggers of increased expression of norB, tet38, and other efflux pump genes identified under Aim 4. We have shown that norB and tet38 are overexpressed in S. aureus abscesses and that knockouts of these genes reduce fitness in the abscess milieu. Thus, we hypothesize that pumps are important for bacterial survival in an abscess in part due to relative protection from antimicrobial peptides, which are present in high concentrations. We will test specifically the role of low iron conditions and high concentrations of antimicrobial peptides as inducers of pump expression by measurement of pump gene RNA levels by Northern blotting, and we will determine the effects of pump overexpression of resistance to antimicrobial peptides in vitro. PUBLIC HEALTH RELEVANCE Antibiotic resistance in common bacterial pathogens such as Staphylococcus aureus is increasing in hospitals and the community. Efflux pumps serve to protect bacteria from adverse environments. Multidrug (MDR) and quinolone resistance conferred by multidrug resistance efflux pumps can also compromise drug utility and affect patient responses to antibiotics. Thus, defining the full complement of MDR efflux pumps in S. aureus and how they are regulated will provide both practical and fundamental information that are important for understanding of staphylococcal fitness to cause disease in diverse environments and for optimizing antibiotic action and use
Keywords: Abscess; Address; Affect; Antibiotic Resistance; Antibiotics; antimicrobial peptide; Antimicrobial Resistance; Bacteria; Bacterial Drug Resistance; Binding (Molecular Function); Biocide; Biological Models; Candidate Disease Gene; Cell Extracts; Cell physiology; Cell Survival; Communities; Community Hospitals; Community-Acquired Infections; Complement; Development; Disease; DNA; efflux pump; Environment; Environmental Risk Factor; Enzymes; Exposure to; fitness; fluoroquinolone resistance; Gene Expression; Genes; Genetic Transcription; Growth; Health; Hospitals; In Vitro; Institution; Iron; knockout gene; Lactams; Mass Spectrum Analysis; Measurement; Measures; member; Methicillin; Modeling; Multi-Drug Resistance; Mus; mutant; Mutation; Northern Blotting; northern hybridization; novel; overexpression; Oxidative Stress; pathogen; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Play; Predisposition; Promotor (Genetics); Protein Binding; Proteins; Pump; quinolone resistance; Regulation; Relative (related person); Reporting; Resistance; resistance mechanism; resistant strain; response; RNA; Role; Signal Transduction; Staphylococcus aureus; Stress; subcutaneous; Testing; Tetracycline Resistance; tool; Work
Relevance: Antibiotic resistance in common bacterial pathogens such as Staphylococcus aureus is increasing in hospitals and the community. Efflux pumps serve to protect bacteria from adverse environments. Multidrug (MDR) and quinolone resistance conferred by multidrug resistance efflux pumps can also compromise drug utility and affect patient responses to antibiotics. Thus, defining the full complement of MDR efflux pumps in S. aureus and how they are regulated will provide both practical and fundamental information that are important for understanding of staphylococcal fitness to cause disease in diverse environments and for optimizing antibiotic action and use
Project start date: 1986-09-01
Project end date: 2013-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R37AI023988-23 (2011): $394268
5R37AI023988-22 (2010): $438075
TRAINING GRANT IN VISION SCIENCE
C David
University Of Rochestercity: Rochester country: United States (us)
Grant 2T32EY007125-21 from National Eye Institute
Abstract: Twenty one faculty of the Center for Visual Science (CVS) at the University of Rochester request renewal of support for a pre-doctoral and postdoctoral training program that emphasizes two broadly defined areas of vision research - research into central visual processing using psychophysical, physiological, and computational approaches and research in physiological optics using advanced optical techniques to study both basic questions about retinal processing and for translational research on eye disease. Training is interdisciplinary, drawing particularly on the unique technical and intellectual resources of the Center. It covers a broad range of basic and clinical problems in vision, but emphasizes approaches that link visual performance to underlying neural mechanisms. We request each year support for six pre-doctoral trainees, who will generally enter the program through Brain and Cognitive Science, Computer Science, Neuroscience, Biomedical Engineering, or the Institute of Optics. Students take core courses plus advanced seminars in visual science, augmented by courses from the department through which they entered the program. They attend regular colloquia, research meetings and the biannual CVS Symposium and Fall Vision Meeting. Concurrently with course work, students complete research projects in CVS preceptor labs we request each year support for one postdoctoral fellow. Postdoctoral training has a heavy emphasis on research. The training grant will be used especially to draw talented scientists from other areas into vision research. We are also requesting stipends for eight summer undergraduate research fellows to participate in an ongoing program that we have developed to introduce students to research in vision science and recruit students into graduate training in visual science. The vision training grant provides interdisciplinary training in vision science for graduate students and post-docs of 21 faculty mentors in the Center for Visual Science at the University of Rochester. It also supports a summer undergraduate research program that attracts students from outside Rochester to spend 10 weeks in the summer working in CVS mentors´ labs and attending lectures on a broad range of topics in vision science
Keywords: Area; bioengineering; bioengineering/biomedical engineering; Biomedical Engineering; Brain; Clinical; cognitive psychology; Cognitive Science; computer science; conference; Encephalon; Encephalons; Eye diseases; eye disorder; Faculty; falls; graduate student; Grant; Institutes; lectures; Lectures; Lectures (PT); Lectures [Publication Type]; Link; meetings; Mentors; Methods and Techniques; Methods, Other; Nervous System, Brain; neural mechanism; neuromechanism; Neurosciences; ophthalmopathy; Optics; Physiologic; Physiological; post-doc; post-doctoral; post-doctoral training; Postdoc; Postdoctoral Fellow; postdoctoral training; pre-doc; pre-doctoral; predoc; predoctoral; Process; programs; Programs (PT); Programs [Publication Type]; psycho-physiological; Psychology, Physiologic; Psychology, Physiological; Psychophysiological; Psychophysiology; public health relevance; R01 Mechanism; R01 Program; recruit; Recruitment Activity; Research; Research Associate; Research Grants; Research Project Grants; Research Projects; Research Projects, R-Series; Research Resources; Resources; Retinal; RPG; Scientist; Sight; Students; symposium; Techniques; Training; Training Programs; translation research enterprise; Translational Research; Translational Research Enterprise; Translational Science; Universities; Vision; Vision research; vision science; visual performance; visual process; visual processing; Work
Relevance: The vision training grant provides interdisciplinary training in vision science for graduate students and post-docs of 21 faculty mentors in the Center for Visual Science at the University of Rochester. It also supports a summer undergraduate research program that attracts students from outside Rochester to spend 10 weeks in the summer working in CVS mentors´ labs and attending lectures on a broad range of topics in vision science
Project start date: 1990-09-30
Project end date: 2015-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-10-036
2T32EY007125-21 (2011): $192760
INTERDISCIPLINARY CARDIOVASCULAR TRAINING PROGRAM
C David
University Of Kentuckycity: Lexington country: United States (us)
Grant 5T32HL072743-08 from National Heart, Lung, And Blood Institute
Abstract: This training program offers pre-doctoral trainees a breadth of exposure and a depth of expertise to acquire the essential aptitudes and tools to thrive in an aggressive cardiovascular research environment. Our specific goals are to(a) provide rigorous state-of-the-art education in basic sciences of the cardiovascular system; (b) provide training in ethical conduct of research; (c) facilitate translational science by providing our trainees with the requisite tools and experience to compete in this arena; and (d) create future "citizens of science" by fostering an environment that promotes advocacy of research with highest ethical standards. We propose to train 5 pre-doctoral fellows and 4 Summer Minority Scholars. Our training faculty, composed of 30 scientists, are all extramurally funded with laboratories well suited to train young scientists, and with excellent training records. The highly collaborative training faculty will implement a structured program covering the areas of cardiac hypertrophy and heart failure, arrhythmogenesis, central nervous control of cardiovascular function and vascular biology with a focus on mechanisms of atherosclerosis, abdominal aortic aneurysms, and thrombosis. This breadth of cardiovascular research opportunities for fellows is supported and enhanced by strong links to the Cardiovascular Research Center and the Gill Heart Institute. A multidisciplinary training faculty represent the combined resources of 11 academic departments in 3 Colleges and 3 Centers, providing both faculty and students a rich environment within which to work and interact, and opportunities for translational research. The curriculum exposes students to essential knowledge ranging from molecules to the integrated physiology of the whole organism with numerous opportunities for in-depth study of focused areas of cardiovascular function. An important feature of our program is the development of new vehicles to train fellows in techniques of translational research. Moreover, our successful minority recruitment program will continue to promote diversity within our training program. Finally, the University of Kentucky strategic plan targets the cardiovascular sciences for focused development, optimizing the environment for the training of superbly-equipped young scientists
Keywords: Cardiovascular system; Training Programs
Project start date: 2003-04-01
Project end date: 2014-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-08-226
5T32HL072743-08 (2011): $105900
SENSORY MECHANISMS AND DISORDERS
C David, Associate Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5T32DC000011-33 from National Institute On Deafness And Other Communication Disorders
Abstract: This training program for predoctoral, postdoctoral, and undergraduate trainees provides an interdisciplinary education and research experience in hearing, balance and chemical senses (HBCS). Predoctoral training is based in one of the 15 academic departments and degree-granting graduate programs with which the 28 training faculty are associated. Doctoral thesis research and postdoctoral research training reside primarily within the laboratories of the mentors. Our affiliated faculty provides outstanding training in each of their corresponding disciplines bioengineering, cellular and molecular biology, genetics, molecular and neurophysiology, developmental biology, and biopsychology of sensory processing. The HBCS program integrates investigators in auditory, vestibular and chemosensory research with trainees from across these disciplines and thereby fosters innovative training opportunities into mechanisms and disorders of hearing, balance, taste and smell. Cross-disciplinary integration is made possible by the training program through a) introductory and advanced courses in sensory systems; b) seminars in hearing, balance and chemical senses with experts from within and outside the University of Michigan; c) student and faculty seminars, journal clubs and research forums; d) exposure to clinical research issues in Otolaryngology and clinical/translational resources available at the University of Michigan Medical School, and d) training in research standards and ethics. Support for 5 predoctoral and 4 postdoctoral trainees is requested. Predoctoral trainees will be selected from the most highly qualified graduate students in the training faculty´s affiliated departments and programs. Interest and motivation for research in sensory systems will be an important criterion. Postdoctoral trainees must have a doctoral degree such as a Ph.D. or M.D. and a strong commitment to sensory biology. Support is also requested to recruit hearing impaired individuals into biomedical research. The deaf are clearly underrepresented in scientific and medical professions. The goal of our Science Mentorship Program (SMP) is to provide these under-represented individuals with direct exposure to mainstream research in the sensory sciences in order to better prepare them for entry into graduate and professional schools. We propose to continue the SMP, begun in 1990, by training 5 deaf undergraduate students per year in summer research internships. RELEVANCE Our primary goal for this training program is to attract promising scientists to the research fields of hearing, balance, taste and smell and to provide them with the mentoring and training that will result in their pursuit of productive research careers in these areas. A better understanding of these areas of sensory neuroscience will provide important insight into many human sensory disorders that greatly affect quality of life
Keywords: Sensory Disorders; sensory mechanism
Project start date: 1983-07-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-06-468
5T32DC000011-33 (2011): $343465
BASIC MICROBIOLOGY AND INFECTIOUS DISEASES
C David, Professor
University Of Floridacity: Gainesville country: United States (us)
Grant 5T32AI007110-29 from National Institute Of Allergy And Infectious Diseases
Abstract: This revised renewal application seeks five years of continued funding for a training program in Basic Microbiology and Infectious Diseases (BMID) to support 7 predoctoral trainees with the aim of producing independent investigators capable of sustaining productive research programs studying molecular mechanisms of infectious disease. This program has been active for 27 years. The program comprises 16 faculty preceptors from 7 departments (Molecular Genetics & Microbiology, Biochemistry & Molecular Biology, Infectious Diseases and Pathology, Oral Biology, Pediatrics, Pathology, Immunology & Laboratory Medicine, and Medicine) within the Colleges of Medicine, Dentistry and Veterinary Medicine in the Health Science Center at the University of Florida. The program faculty include bacteriologists (Brown, Gulig, Morris, Progulske-Fox and Southwick), virology (Bloom, Berns, Byrne, Condit, Flanegan, Goodenow, Moyer, McFadden, and Muzyczka), and mycology (Lewin and Nguyen). The program faculty have expertise in genetics, cell biology, pathogenesis, immunology, epidemiology and molecular biology. The program faculty also includes clinician scientists (Berns, Byrne, Morris and Southwick), thus reinforcing the clinical relevance and application of microbiology and infectious disease. Predoctoral trainees are recruited and initially trained in collaboration with the College of Medicine´s Interdisciplinary Program in biomedical Sciences (IDP). The pool of trainee candidates averages 53 per year, they come from throughout the US, and they average combined verbal and quantitative GRE scores of 1250 and GPAs of 3.5. The IDP provides comprehensive classroom training, an introductory laboratory, laboratory rotations, and advanced course work in specialized disciplines. Subsequent training focuses on independent laboratory research supplemented with program-specific activities stressing communications skills. Predoctoral training requires a total of approximately 5 years. This training program provides a strong interdisciplinary infrastructure for enhancing the training of scientists in the area of infectious disease. This will increase the number of researchers trained to study the molecular mechanisms of the pathogenesis of disease and develop therapies for diseases of humans caused by a wide range of microbial agents
Keywords: Communicable Diseases; Microbiology
Project start date: 1978-07-01
Project end date: 2013-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-06-468
5T32AI007110-29 (2011): $186598
TRAINING IN COMPUTATIONAL NEUROSCIENCE: INTEGRATING EXPERIMENT, THEORY, AND TECHN
C David, Professor
Boston Universitycity: Boston country: United States (us)
Grant 1T90DA032484-01 from National Institute On Drug Abuse
Abstract: This proposal seeks 5 years of NIH support to establish a campus-wide training program in which young scientists, mathematicians, and engineers interested in computational neuroscience will be trained in both theoretical and experimental neuroscience. In addition, they will learn how to "translate" their research ideas from the laboratory to the clinic. This proposal consists of the two required components in RFA-DA-11-005. This first is R90 components that will fund six full-time undergraduate research trainees give them a combination of coursework and hands-on laboratory research experience. The R90 will also fund two predoctoral students. The second component is a full-time Ruth L. Kirschstein National Research Service Award (NRSA) institutional predoctoral training program (T90) that will fund 4 predoctoral students. The goal of this proposal is to create a unique training experience in computational neuroscience in which young scientists, mathematicians, and engineers interested in computational neuroscience will be trained in both theoretical and experimental approaches to studying the brain. In addition, they will learn how to "translate" their research ideas from the laboratory to the clinic. The program will integrate fundamental knowledge, interdisciplinary thinking, and translational skills to solve challenges in the neurosciences, as well as promote a strong community of faculty and students with similar interests. Specific Objectives - Undergraduate Training Program 1. Provide students majoring in the biological sciences with a strong background in the application of mathematical and engineering concepts to neuroscience 2. Provide three of the most accomplished students per year with a 21-month research experience that integrates theoretical and empirical approaches 3. Expose students to the diversity of research careers in computational neuroscience Specific Objectives - Graduate Training Program 4. Provide strong training in experimental neuroscience to students with engineering and mathematics degrees 5. Provide three of the most accomplished students per year with a 24-month fellowship to develop research projects integrating theoretical and empirical approaches 6. Provide career guidance and training in grant writing Specific Objectives - All Programs 7. Foster faculty and student networking across departments and colleges 8. Expose all students to the translational challenges in neuroscience 9. Encourage and provide support for all trainees to attend local and national conferences and workshops The purpose of this program is to train a new generation of neuroscientists who will combine experimental and theoretical techniques to increase our understanding of the brain, to transition their discoveries from the lab bench to the clinic, and to invent new technologies to restore lost brain function
Keywords: Biological Sciences; Brain; career; Clinic; college; Communities; computational neuroscience; Educational workshop; Engineering; experience; Faculty; Fellowship; Fostering; Funding; Goals; Grant; Institutional National Research Service Award; interest; Knowledge; Laboratories; Laboratory Research; Learning; Mathematics; Neurosciences; pre-doctoral; programs; Research; Research Project Grants; research study; Scientist; skills; Students; symposium; theories; Thinking, function; Time; Training; Training Programs; Translating; United States National Institutes of Health; Writing
Relevance: The purpose of this program is to train a new generation of neuroscientists who will combine experimental and theoretical techniques to increase our understanding of the brain, to transition their discoveries from the lab bench to the clinic, and to invent new technologies to restore lost brain function
Project start date: 2011-08-15
Project end date: 2016-07-31
Budget start date: 15-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: RFA-DA-11-005
1T90DA032484-01 (2011): $165226
COMPUTATIONAL MODELING OF INDIVIDUAL HEALTH BEHAVIOR
C David, Associate Research Scientist
Columbia University Health Sciencescity: New York country: United States (us)
Grant 1R21HD067570-01 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: This project develops a computational model of individual health behavior. Computational models allow for understanding the explicit psychological mechanisms that underlie behavior. There is a high need for this because, 1) current work in health behavior lacks and understanding of explicit processes, 2) a computational model can mesh with higher and lower level computational models (such as agent-based models, dynamic social network models, and computational neuroscience), 3) aggregate data of health behavior do not allow for making direct inferences about individual level psychological processes. Aims We propose to build a novel theoretical model of health behavior that combines 1) the psychological, intra-individual processes, 2) the social, inter-individual processes, and 3) the interaction between the two as a complex system. Furthermore, we propose to evaluate this theoretical model against extant epidemiological and psychological data. Key Features of the Proposed Work (1) Computational Architecture We will implement the theoretical model as a neural network. This is the first attempt to do so in health behavior with respect to both the individual-level and the social dynamics. This will allow for interfacing with current and future insights into health behavior that come from neurophysiological mechanisms and is highly compatible with other decision-based models such as neuroeconomics and social cognitive neuroscience as well as social network theory and social epidemiological constructs. (2) Study Design We build a model of the Theory of Reasoned Action (a prominent health behavior change theory) in reference to adolescent sexual initiation behavior. Then, we compare the model behavior to extant empirical work that was collected and designed to test the causal structural model of the Theory of Reasoned Action in reference to adolescent sexual initiation behavior. Finally, we extend the neural network model into a social dynamic process model (with multiple neural networks) that is constrained in its structure by extant social network data. (3) Recommendations for Policy Resistant Behaviors. Individual health behaviors are policy resistant because the underlying mechanisms are difficult to understand without developing explicit computational models. This is compounded when individual level behavior and social dynamics are interdependent. Therefore, policy efforts towards prevention of socially-bound individual-level health behaviors may be under-informed by current methodologies. The proposed work is well suited to elucidating this complex process. This project proposes a computational model of individual health behavior that will lend insight into the related explicit psychological processes. Furthermore, by embedding this model into a social context, this work provides a computational account of the interdependence of social structure and individual health behavior
Keywords: Accounting; Address; Adolescent; Adolescent Youth; Aggregated Data; Aggregation, Data; Architecture; base; Behavior; behavioral/social science; Binding; Binding (Molecular Function); Biological Neural Networks; Chronic Disease; chronic disease/disorder; chronic disorder; Chronic Illness; Cognitive; cognitive neuroscience; Complex; computational framework; computational modeling; computational models; computational neuroscience; computational simulation; computer based models; computer framework; Computer Simulation; computerized modeling; Computerized Models; computerized simulation; Connectionist Models; Data; Data Aggregation; Data Set; Dataset; design; designing; Engineering / Architecture; Epidemiology; Future; Goals; Health; Health behavior; Health behavior change; Health Status; in silico; Individual; Influentials; insight; interest; juvenile; juvenile human; Leadership; Level of Health; Mathematical Model Simulation; Mathematical Models and Simulations; Measures; meetings; Method LOINC Axis 6; Methodology; Methods; Modeling; Models, Computer; Models, Theoretic; Molecular Interaction; Mortality; Mortality Vital Statistics; National Institutes of Health; National Institutes of Health (U.S.); network models; neural network; neural network (computer simulation of nervous system); Neural Network Models; Neural Network Simulation; Neural Networks (Computer); neuroeconomics; neurophysiology; NIH; novel; Perceptrons; Policies; Prevention; Process; psychologic; psychological; Public Health; public health medicine (field); public health relevance; Recommendation; Research Design; Resistance; resistant; response; Science of neurophysiology; Simulation, Computer based; social; Social Behavior; social climate; social context; Social Environment; social model; Social Network; sociobehavior; sociobehavioral; socioenvironment; Structural Models; Structure; study design; Study Type; success; Sum; System; System, LOINC Axis 4; Testing; Theoretical model; theories; United States National Institutes of Health; virtual simulation; Work
Relevance: This project proposes a computational model of individual health behavior that will lend insight into the related explicit psychological processes. Furthermore, by embedding this model into a social context, this work provides a computational account of the interdependence of social structure and individual health behavior
Project start date: 2011-01-01
Project end date: 2012-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PAR-08-213
1R21HD067570-01 (2011): $172571
NEW KIND OF QUALITY MANAGEMENT FOR X-RAY & NMR MODELS
C David, Professor
Duke Universitycity: Durham country: United States (us)
Grant 5R01GM073930-06 from National Institute Of General Medical Sciences
Abstract: This laboratory is improving quality management for experimental structures of biological molecules - using all-atom contact analysis (including the hydrogens) and updated geometrical and torsion-angle criteria to guide procedures for validating and correcting local problems in 3D structures of proteins and RNAs. Progress in the previous grant period yielded widespread acceptance of these new techniques, producing an observable improvement in quality measures across all new structures in the worldwide Protein Data Bank. There is now a need for further fundamental research to underpin the correctness of individual methodological details and extend its applicability to new classes of structures. A recent breakthrough was recognition of an error-producing systematic local ambiguity possible in one type of NMR data. These now can be analyzed to avoid faulty ensemble models. For assessment of template-based modeling in the CASP8 prediction experiment, measures were developed that go beyond the C1 backbone to assess the full predicted models, many of which are now accurate enough that such criteria are appropriate. A very important expansion would be to enable improvement of structural accuracy at the lower resolutions typical for the large molecular complexes whose structures are the most significant for biological and medical research. This will depend on analysis of the patterns of systematic distortion in low- resolution electron density, and modeling strategies that are not misled by those distortions. The relevance of this project for NIGMS is to increase the impact of a very large and important segment of the funded research, leading across-the-board to better biological understanding and better prospects for demanding applications such as drug design, arising from better knowledge of the 3D molecular conformations, their dynamics and chemistry, and their detailed interactions with ligand molecules. The science behind our all-atom contact and MolProbity techniques has resulted in an effective 3D "spell-checker" for macromolecular crystal structures, using the underlying science and context sensitivity to recognize and correct systematic errors, but doing no harm analogous to an overzealous spell-checker changing "CASP" to "gasp". Over the past 4-year grant period, this system was adopted widely enough to produce an observable improvement in quality measures across new depositions to the worldwide Protein Data Bank; this improved accuracy is especially crucial for detail-sensitive biomedical research such as drug design. This grant proposes fundamental research to enhance that underlying science and extend its benefits to other "languages" of structure such as NMR methodology, homology modeling, the increasingly important RNAs, and the lower-resolution structures characteristic of the most biologically and medically important large molecular complexes
Keywords: Adopted; Advisory Committees; base; Bioinformatics; Biological; biological research; Biomedical Research; Burial; CASP8 gene; Characteristics; Chemistry; Complement component C1s; Complex; Computer Simulation; Computer software; Coupling; Data; Data Analyses; Data Set; Databases; density; Deposition; Disease; Disulfides; Drug Design; electron density; Ensure; Evaluation; Family; fundamental research; Funding; Goals; Grant; Homology Modeling; Hydrogen; Hydrogen Bonding; improved; Individual; Knowledge; Laboratories; Language; Learning; Libraries; Ligands; Manuals; Measurement; Measures; Medical; Medical Research; Membrane Proteins; Methodology; Modeling; Molecular; Molecular Conformation; National Institute of General Medical Sciences; Noise; Pattern; Positioning Attribute; Procedures; Proteins; public health relevance; Quality Control; quantum; Recommendation; Research; research study; Residual state; Resolution; RNA; Roentgen Rays; Science; Shapes; Signal Transduction; Solutions; Specificity; spelling; Structure; success; System; Techniques; Testing; three dimensional structure; Torsion (malposition); trend; Update; Validation; Vertebral column
Relevance: Relevance: The science behind our all-atom contact and MolProbity techniques has resulted in an effective 3D "spell-checker" for macromolecular crystal structures, using the underlying science and context sensitivity to recognize and correct systematic errors, but doing no harm analogous to an overzealous spell-checker changing "CASP" to "gasp". Over the past 4-year grant period, this system was adopted widely enough to produce an observable improvement in quality measures across new depositions to the worldwide Protein Data Bank; this improved accuracy is especially crucial for detail-sensitive biomedical research such as drug design. This grant proposes fundamental research to enhance that underlying science and extend its benefits to other "languages" of structure such as NMR methodology, homology modeling, the increasingly important RNAs, and the lower-resolution structures characteristic of the most biologically and medically important large molecular complexes
Project start date: 2005-05-01
Project end date: 2014-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R01GM073930-06 (2011): $285850
Sponsored Links Excellgen http://Excellgen.com
MIDCAREER INVESTIGATOR AWARD IN GERIATRIC DEPRESSION
C David, Professor
Duke Universitycity: Durham country: United States (us)
Grant 5K24MH070027-08 from National Institute Of Mental Health
Abstract: This is a competing renewal application for a K24 Career Award in Patient-Oriented Research. The candidate, Dr. David Steffens, is Professor of Psychiatry and Medicine at Duke University Medical Center, where he serves as the Head of the Division of Geriatric Psychiatry and Director of an NIMH-sponsored T32 Research Training Program. Dr. Steffens has established a record of scholarship in the area of geriatric depression, and he serves as Principal Investigator on two large NIMH-funded grants, an R01 focusing on longitudinal geriatric depression outcomes and on the Recruitment Core of a Conte Neuroscience Center studying cerebrovascular disease in late-life depression. He is the previous recipient of a Clinical Geriatric Mental Health Academic Award (K07). Dr. Steffens has mentored individuals at all levels, including undergraduates, graduate students, medical students, pre- and post-doctoral research fellows, psychiatry residents, geriatric psychiatry fellows, and junior faculty. These experiences make the candidate well qualified for this K24 Award. Through this Award, the candidate will expand his research by focusing on genes related to folate metabolism in late life depression. Using his funded research as a source for teaching, the candidate will be well positioned to mentor pre-doctoral and post-doctoral fellows as well as junior faculty. Under the Award, the candidate will spend at least 50% of his time conducting patient-oriented research and mentoring. There is a lack of well-trained junior investigators interested in late-life mental health research. With the aging of the population, better understanding of mental illness in older Americans is essential. Support of individuals such as Dr. Steffens who have an interest and ability to train the next generation of geriatric mental health researchers will help address an important and growing public health need
Keywords: Academic Medical Centers; Address; advanced age; Aged 65 and Over; Aging; Alleles; Allelomorphs; Amentia; American; Ammon Horn; amyloid beta plaque; Amyloid Plaques; amyloid-b plaque; Apo-E; ApoE; APOE [{C0003595}]; Apolipoprotein E; Area; Award; Blood Vessels; Brain; brain control; Brain scan; Brain Vascular Disorders; career; cerebrovascular; Cerebrovascular Disease; Cerebrovascular Disorders; Clinical; Cognitive; Cognitive decline; Cognitive Disturbance; cognitive dysfunction; Cognitive function abnormal; Cognitive Impairment; cognitive loss; cognitively impaired; cored plaque; Cornu Ammonis; Data; Dementia; density; depressed; Depressed mood; Depression; Development; diffuse plaque; Disturbance in cognition; Educational process of instructing; Elderly; Elderly depression; elderly patient; Elderly, over 65; elders; Encephalon; Encephalons; experience; Faculty; Folate Metabolism; folic acid metabolism; Folic Acid Metabolosm; frontal cortex; frontal lobe; functional status; Funding; Genes; Genetic; Genetic Polymorphism; geriatric; geriatric depression; geriatric mental health; Geriatric Psychiatry; geriatric psychology; geropsychiatry; geropsychology; geropsychopharmacology; graduate student; Grant; Head; Health; hippocampal; Hippocampus; Hippocampus (Brain); Impaired cognition; Incidence; Individual; interest; Intracranial Vascular Disorders; Investigators; K24 Award; late life; late life depression; later life; long term depression; Long-Term Depression (Neurophysiology); Long-Term Depression (Physiology); Long-Term Synaptic Depression; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Medical Students; Medicine; Mental Depression; Mental disorders; Mental Health; Mental health disorders; Mental Hygiene; mental illness; Mentors; Mid-Career Clinical Scientist Award (K24); mild cognitive disorder; mild cognitive impairment; mild neurocognitive disorder; mind control; Moods; Morphology; Mortality; Mortality Vital Statistics; MR Imaging; MR Tomography; MRI; National Institute of Mental Health; National Institute of Mental Health (U.S.); Nervous System, Brain; Neuritic Plaques; neurofibrillary degeneration; neurofibrillary lesion; neurofibrillary pathology; Neurofibrillary Tangles; neuroimaging; neuropsychological; Neurosciences; next generation; NIMH; NMR Imaging; NMR Tomography; Nuclear Magnetic Resonance Imaging; older adult; older patient; older person; Outcome; Pathology; patient oriented research; patient oriented study; Patients; polymorphism; Polymorphism (Genetics); Polymorphism, Genetic; Population; Position; Positioning Attribute; post-doc; post-doctoral; Postdoc; Postdoctoral Fellow; pre-doc; pre-doctoral; predoc; predoctoral; Principal Investigator; professor; Psychiatric Disease; Psychiatric Disorder; Psychiatry; Psychiatry for older adults; Psychiatry for older people; Psychiatry for seniors; Psychiatry for the elderly; Psychogeriatrics; psychological disorder; Psychological Health; Public Health; public health medicine (field); Qualifying; receptor; Receptor Protein; Research; Research Associate; Research Personnel; Research Training; Researchers; Risk; Role; sadness; Scholarship; Science of Medicine; Senescence; senescent; Senile Plaques; senior citizen; social; social role; Social support; social support network; Source; tangle; Teaching; Time; Training; Training Programs; United States National Institute of Mental Health; University Medical Centers; Unspecified Mental Disorder; vascular; Vascular Diseases, Intracranial; White Matter Disease; Zeugmatography
Project start date: 2004-01-15
Project end date: 2013-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-04-107
5K24MH070027-08 (2011): $182247
EXPLOITING DEEP OCEAN BIOLOGY FOR BIOMEDICAL DISCOVERY
C David, Assoc Professor
University Of Rhode Islandcity: Kingston country: United States (us)
Grant 1R15AI093158-01 from National Institute Of Allergy And Infectious Diseases
Abstract: This AREA application seeks to establish a new collaboration among three investigators at the University of Rhode Island with complementary expertise in marine microbial natural products chemistry, deep ocean microbiology, and antibiotics research. This collaboration will capitalize upon expeditions of the Integrated Ocean Drilling Program (IODP) to provide access to the seafloor of the world ocean. Our proposal seeks to leverage the millions of dollars of federal funds that support IODP expeditions by isolating novel microorganisms from remote, deep ocean environments for drug discovery. The initial focus for these studies will be on diverse bacteria cultivated from sediment cores retrieved within the South Pacific Gyre, an enormous mid-ocean zone that has yet to be accessed by drug discovery investigations. AIM 1 will create a novel collection of genetically diverse bacteria isolated from ocean sediments acquired at abyssal (>2000 m) depths. The microbes will be isolated using methods tailored to life adapted to low nutrient and high-pressure environments. Natural products chemistry (AIM 2) will then link the biosynthetic capabilities of these organisms with pharmacological evaluation of their secondary metabolites. Antibiotic testing will be conducted on pure microbial metabolites and semi-purified fractions from culture supernatants. The focus of this testing (AIM 3) will be growth inhibition of both ATCC and clinical strains of multiple drug resistant Staphylococcus aureus, Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Thus, this project will focus on finding antibiotics against the most problematic clinical pathogens. Pure molecules will be quantitatively tested for bacterial growth inhibition and reduction of biofilm formation using proven and cutting edge methods. For example, compounds that prevent biofilm formation will be tested in an intravascular catheter model. These tests will determine if antibiotic agents can prevent biofilms from forming in catheters, a problematic source of infections in hospitals. All compounds will be additionally tested for cytotoxicity and sufficient quantities will be submitted to the NIH Molecular Libraries Small Molecule Repository for more comprehensive biomedical evaluation. The proposed collaboration will enhance the competitiveness of health-related research at the University of Rhode Island and will promote cross-disciplinary training of both undergraduate and graduate students in sciences related to drug discovery. Human Health Relevance The long-term goal of the project is the discovery of new antimicrobial agents useful in the treatment of drug-resistant bacterial infections. Our ability to treat infectious disease is increasingly compromised by the emergence of drug-resistant strains of pathogenic bacteria. For example, more than 60% of staph infections in intensive care units are resistant to at least one medicine commonly used to treat these infections. Antibiotic drug discovery is not keeping pace with rising resistance. This project will extend our search for new antibiotics to include novel molecules produced by microbes from the most remote deep ocean environments, a highly promising but mostly unknown resource. This project will investigate previously inaccessible microbial biodiversity in the deep ocean as novel resources for biomedical discovery. A specific project goal is the discovery of potent new antibiotics to combat drug resistant pathogens
Keywords: 2-dimensional; Acinetobacter baumannii; Actinobacteria; Actinobacteria class; Actinomyces; Actinomycetes; anti-microbial agent; anti-microbial drug; Antibiotic Agents; Antibiotic Drugs; Antibiotics; antimicrobial agent; antimicrobial drug; Assay; Attention; Bacteria; bacterial disease; Bacterial Infections; Bioassay; Biodiversity; biofilm; Biologic Assays; Biological; Biological Assay; Biological Diversity; Biological Factors; Biology; biomedical resource; Catheters; Chemical Fractionation; Chromatography, High Performance Liquid; Chromatography, High Pressure Liquid; Chromatography, High Speed Liquid; Clinical; Collaborations; Collection; combat; Communicable Diseases; cytotoxicity test; drug discovery; Drug resistance; Drug Resistance, Multiple; drug resistant; Drug Resistant, Multiple; Drug-sensitive; Drugs, Investigational; E coli; Environment; Escherichia coli; Evaluation; Expeditions; experiment; experimental research; experimental study; Factor, Biologic; FRACN; Fractionation; Fractionation Radiotherapy; Funding; Generalized Growth; Goals; graduate student; Gram-Positive Bacteria, High G+C; Growth; Health; High Pressure Liquid Chromatography; HOSP; Hospitals; HPLC; Human; Human, General; Infection; Infectious Disease Pathway; Infectious Diseases; Infectious Diseases and Manifestations; Infectious Disorder; Intensive Care Units; Intermediary Metabolism; Investigation; Investigational Drugs; Investigational New Drugs; Investigators; K. pneumoniae; Klebsiella pneumonia bacterium; Klebsiella pneumoniae; Libraries; Life; Link; living system; Location; Man (Taxonomy); Man, Modern; Marines; Measures; Medical Device; Medicine; Metabolic Processes; Metabolism; METBL; meter; Methods; Methods and Techniques; Methods, Other; Microbe; microbial; Microbial Biofilms; Microbiology; microorganism; Microorganisms, General; Miscellaneous Antibiotic; Modeling; Molecular Bank; Multi-Drug Resistance; multi-drug resistant; Multidrug Resistance; multidrug resistant; National Institutes of Health; National Institutes of Health (U.S.); Natural Products; Natural Products Chemistry; next generation; NIH; novel; Nutrient; Oceans; ontogeny; Organism; P. aeruginosa; P.aeruginosa; pathogen; pathogenic bacteria; preclinical evaluation; Pressure; pressure; Pressure- physical agent; prevent; preventing; Process; programs; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Pseudomonas aeruginosa; Pseudomonas pyocyanea; public health relevance; repository; Research; Research Personnel; Research Resources; research study; Researchers; Resistance; resistance to Drug; Resistance to Multi-drug; Resistance to Multidrug; Resistance to Multiple Drug; resistant; resistant strain; resistant to Drug; Resistant to multi-drug; Resistant to multidrug; Resistant to Multiple Drug; Resources; Rhode Island; S. aureus; S.aureus; Science; Science of Medicine; Science of Microbiology; Sea Water; Seawater; small molecule; Source; Staphylococcus aureus; Structure; tandem mass spectrometry; Techniques; Testing; Tissue Growth; Training; two-dimensional; United States National Institutes of Health; Universities; Work
Relevance: This project will investigate previously inaccessible microbial biodiversity in the deep ocean as novel resources for biomedical discovery. A specific project goal is the discovery of potent new antibiotics to combat drug resistant pathogens
Project start date: 2010-12-15
Project end date: 2013-11-30
Budget start date: 15-DEC-2010
Budget end date: 30-NOV-2013
PFA/PA: PA-10-070
1R15AI093158-01 (2011): $418299
INTRAVENOUS MAGNESIUM FOR SICKLE CELL VASOOCCLUSIVE CRISIS
C David, Professor
Medical College Of Wisconsincity: Milwaukee country: United States (us)
Grant 5R01HD062347-02 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: There are over 18,000 hospitalizations and 75,000 hospitalization days annually for children suffering vaso-occlusive crises secondary to sickle cell disease. The vast majority of these hospitalizations are for pain crisis, making pain one of the most significant morbidities for children with sickle cell disease. The acute treatment for these pain crises has changed little over the past three decades, mainly relying on intravenous fluids, opioids and non-steroidals. More recently, there has been a greater recognition of the role that nitric oxide plays in the pathogenesis of pain crises, and inhaled nitric oxide is being studied as a possible treatment. We have recently tested an alternative approach, intravenous magnesium, that produces vaso- dilation through both endothelium-dependent nitric oxide mechanisms, as well as direct action on the underlying vascular smooth muscle. The safety profile, ease of administration, and low cost of magnesium make its potential as a sickle cell therapy particularly exciting. In this application, we utilize the Pediatric Emergency Care Applied Research Network to develop a four-center collaboration between pediatric emergency medicine and pediatric sickle cell centers to test this novel therapy through a double-blind, randomized, placebo controlled trial assessing the impact of the addition of intravenous magnesium to standard therapy for sickle cell pain crisis. The primary clinical outcome is the decrease in length of hospital stay for pediatric sickle cell pain crisis, with a secondary clinical outcome measuring the effect of intravenous magnesium on the use of opioid pain medication during the hospitalization. In addition to the clinical outcomes, we will gain valuable insight into the pathophysiology of sickle cell crisis through the measurement of hemolysis, nitric oxide pathway metabolites, and markers of cellular injury and inflammation. At the conclusion of this study, we have the potential to improve the care of children with sickle cell disease using a low cost, low risk treatment. In the United States alone, there are over 18,000 hospitalizations and 75,000 hospitalization days annually for children suffering vasoocclusive pain episodes secondary to sickle cell disease; the vast majority of these children are African-American. With this application, we aim to decrease the pain children experience with these crises, thus shortening hospitalizations and decreasing the cost associated with caring for children with this painful disease
Keywords: 0-11 years old; 18 year old; Absence of pain sensation; Absence of sensibility to pain; Accident and Emergency department; Actions of Nitric Oxide in the Heart; Active Follow-up; Acute; Acute Pain; Adverse event; Adverse Experience; African American; Afro American; Afroamerican; analgesia; Analgesic Agents; Analgesic Drugs; Analgesic Preparation; Analgesics; Anodynes; Antinociceptive Agents; Antinociceptive Drugs; Applied Research; Applied Science; Asthma; Attenuated; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; black American; Black or African American; Black Populations; Blinded; Blood Coagulation Factor IV; Blood Plasma; Blood Pressure, Low; Bronchial Asthma; BSF-2; BSF2; BSF2 (B cell stimulating factor 2); Ca++ element; Calcium; CD106; CD106 Antigens; cell damage; cell injury; Cell Therapy; cell-based therapy; Cells; Cellular injury; Child; Child Care; Child Youth; Childhood; children; Children (0-21); Clinic; Clinical; Coagulation Factor IV; Collaborations; cost; cytokine; DIF; Differentiation Factor, B-Cell; Disease; disease/disorder; Disorder; Dose; Double-Blind Method; double-blind placebo controlled trial; Double-Blind Study; Double-Blinded; double-masked controlled study; double-masked controlled trial; Double-Masked Method; Double-Masked Study; drepanocyte; drug/agent; Drugs; Dysfunction; effective intervention; eighteen year old; Emergency Care; Emergency Department; Emergency Medicine; Emergency room; Endogenous Nitrate Vasodilator; endothelial cell derived relaxing factor; Endothelial Cells; Endothelium; Endothelium-Derived Relaxing Factor; enroll; Enrollment; Esthesia; Event; experience; Factor IV; Feels no pain; follow-up; Functional disorder; Gamma interferon; Hb SS disease; HbSS disease; Hemoglobin; Hemoglobin S Disease; Hemoglobin sickle cell disease; Hemoglobin sickle cell disorder; Hemolysis; Hepatocyte-Stimulating Factor; HOSP; hospital days; hospital length of stay; hospital stay; Hospitalization; Hospitals; Hour; HPGF; Human, Child; Hybridoma Growth Factor; Hypotension; IFN-beta 2; IFN-g; IFN-Gamma; IFNB2; IFNG; IL-6; IL6 Protein; improved; in vivo; INCAM-110; Individual; Inducible Cell Adhesion Molecule 110; Inflammation; Inflammatory; Inflammatory Response; INFLM; Infusion; Infusion procedures; inhaled nitric oxide; Injury; innovate; innovation; innovative; iNO; Inpatients; insight; Institution; interferon beta 2; Interferon Gamma; Interferon gamma (human lymphocyte protein moiety reduced); Interferon Type II; Interferon, Immune; Interferon-gamma; Interleukin 6 (Interferon, Beta 2); Interleukin-6; Intervention; intervention effect; Intervention Strategies; interventional strategy; Intravenous; Intravenous Fluid; IV Fluid; Length of Stay; lFN-Gamma; Lipopolysaccharides; LPS; Magnesium; Magnesium Deficiency; Magnesium SO4; Magnesium Sulfate; Measurement; Measures; Medication; Mg element; MGI-2; Monitor; Mononitrogen Monoxide; Morbidity; Morbidity - disease rate; Muscle, Smooth, Vascular; Myeloid Differentiation-Inducing Protein; new approaches; Nitric Oxide; Nitric Oxide Pathway; Nitric Oxide, Endothelium-Derived; Nitrites; Nitrogen Monoxide; Nitrogen oxide; Nitrogen Protoxide; No sensitivity to pain; novel; novel approaches; novel strategies; novel strategy; Number of Days in Hospital; Opioid; Outcome; Outcome Measure; Pain; Painful; Pathogenesis; pathophysiology; Patients; PBO; pediatric; Pharmaceutic Preparations; Pharmaceutical Preparations; Phone; Physicians; Physiopathology; Placebo Control; Placebos; Plasma; Plasmacytoma Growth Factor; Play; Production; public health relevance; Puericulture; randomisation; randomization; Randomized; randomized placebo controlled study; randomized placebo controlled trial; randomly assigned; Research; response; Reticulocyte Count; Reticulocyte count (procedure); Reticulocyte Number; Reticuloendothelial System, Serum, Plasma; Risk; Role; Safety; Secondary to; Selectins; Sensation; Serum, Plasma; sham therapy; Sham Treatment; Sickle Cell; Sickle Cell Anemia; sickle cell crisis; sickle cell disease; sickle disease; sickle erythrocyte; sickle RBC; sickle red blood cell; sicklemia; social role; Study Subject; Sulfuric acid magnesium salt (1[{..}]1); Telephone; Testing; Thalassemia; Therapy, Cell; TNF; TNF A; TNF gene; TNFSF2; translational study; Tumor Necrosis Factor Gene; United States; Vascular Cell Adhesion Molecule; Vascular Cell Adhesion Molecule-1; Vascular Hypotensive Disorder; vaso-occlusive pain; Vasodilatation; Vasodilating Agent; Vasodilation; Vasodilator Agents; Vasodilator Drugs; Vasodilators; Vasorelaxation; VCAM; VCAM-1; youngster
Relevance: Relevance In the United States alone, there are over 18,000 hospitalizations and 75,000 hospitalization days annually for children suffering vasoocclusive pain episodes secondary to sickle cell disease; the vast majority of these children are African-American. With this proposal, we aim to decrease the pain children experience with these crises, thus shortening hospitalizations and decreasing the cost associated with caring for children with this painful disease
Project start date: 2010-04-09
Project end date: 2014-02-28
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: PAR-08-261
5R01HD062347-02 (2011): $508674
1R01HD062347-01 (2010): $431519
C David, Chair
Wake Forest University Health Sciencescity: Winston-salem country: United States (us)
Grant 268200900048C-5-0-1 from National Heart, Lung, And Blood Institute
Abstract: The Systolic Blood Pressure Intervention Trial (SPRINT) is a 2-arm, multicenter, randomized clinical trial designed to test whether a treatment program aimed at reducing systolic blood pressure (SBP) to a lower goal than currently recommended will reduce cardiovascular disease (CVD) risk. About 9250 participants with SBP greater than or equal to 130 mm Hg and at least one additional CVD risk factor will be recruited at approximately 80 clinics within 5 clinical center networks (CCNs) over a 2-year period, and will be followed for 4-6 years. Approximately 4300 participants will have chronic kidney disease (CKD), and about 3250 will be aged 75 or older. The primary outcome is the first occurrence of a myocardial infarction (MI), acute coronary syndrome (ACS), stroke, heart failure (HF), or CVD death. Secondary outcomes include all-cause mortality, decline in renal function or development of end stage renal disease (ESRD), dementia, decline in cognitive function, and small vessel cerebral ischemic disease
Keywords: African American; Age-associated memory impairment; Alzheimer`s Disease; Asian Americans; Blood Pressure; blood pressure regulation; brain volume; Cardiovascular Diseases; cardiovascular disorder prevention; cardiovascular disorder risk; Chronic Kidney Failure; Clinical; Clinical Trials; Cognition; cognitive function; Congenital neurologic anomalies; cost effectiveness; Dementia; Diabetes Mellitus; Diagnosis; DNA; Enrollment; Epidemiology; Event; Genes; genome wide association study; Goals; Health; high risk; Hispanics; Hypertension; Hypotension; Image; Impaired cognition; Incidence; Individual; Intervention; Intervention Trial; Investigation; Kidney Diseases; Magnetic Resonance Imaging; member; Memory; Mind; Minority Groups; Morbidity - disease rate; Mortality Vital Statistics; Native Americans; Neuraxis; Participant; Pathway interactions; Patients; Persons; Polycystic Kidney Diseases; Population; premature; Quality of life; Randomized Controlled Clinical Trials; Recruitment Activity; Relative (related person); Risk; Risk Factors; Smoke; Staging; stroke; Subgroup; systolic hypertension; Testing; treatment strategy; United States National Institutes of Health; Variant; Vascular Dementia; Woman
268200900048C-5-0-1 (0000): $8511177
LUNG DISEASE IN CHINESE TEXTILE WORKERS
C David, Professor
Harvard University (sch Of Public Hlth)city: Boston country: United States (us)
Grant 5R01OH002421-18 from National Institute For Occupational Safety And Health
Abstract: The Shanghai Textile Worker study is a competing continuation of R01 OH 02421. This proposal is designed to address unanswered questions regarding the respiratory health of workers chronically exposed to organic dust and endotoxin. Exposure to gram-negative bacterial endotoxin has been described in laboratory studies as producing acute respiratory symptoms and lung function change. To date, no other prospective epidemiologic study has addressed the relative contributions of cotton dust and endotoxin in producing both acute and chronic respiratory effects of workers. Although the study to date has elucidated new aspects of dust and endotoxin-related pulmonary responses, significant questions remain unanswered. In AIM 1, we will model changes in pulmonary function over 25 years for each subject (stage 1) and the association of these declines with dust and endotoxin (stage II). In AIM 2, we will examine the long-term effects of removal by retirement from exposure on respiratory health status. Finally, we have added an innovative AIM 3 to assess gene-environment interactions for acute and chronic pulmonary responses to exposure. The study population (a closed cohort) that has been followed since 1981 is unusually well-suited for epidemiologic study due to low turnover; very low smoking prevalence among women workers; reliable baseline data; a suitable comparison group studied in identical fashion; excellent cooperation among industry officials, union and the collaborative research team; access to subjects who have retired or left the industry in disability; and cost-efficiency. The population includes 447 cotton textile and 472 silk textile workers first surveyed in 1981. Follow-up surveys were conducted in 1986,1992,1996, and 2001 with excellent participation. The proposed study is unique because exposure estimates for both dust and endotoxin over a 25-year period allow assessment of exposure response relationships for both dust and endotoxin for the full study interval. This cohort represents the largest prospective study of a working population exposed to vegetable dust and endotoxin. Results of this work are relevant to disease control in a wide variety of occupational settings, including textiles, grain processing, wood processing, animal confinement, sewage treatment, biotechnology, and clean-up of environmental disasters such as Hurricanes Katrina and Rita
Project start date: 1995-09-30
Project end date: 2011-07-30
Budget start date: 31-AUG-2009
Budget end date: 30-JUL-2011
5R01OH002421-18 (2009): $317054
C David, Chief
Tufts University Bostoncity: Boston country: United States (us)
Abstract: The responsibility of the Animal Model Core (AMC) is to provide the individual projects with expert assistance with animal model experimentation. The AMC will provide oversight of the management and treatment of transgenic and wildtype mice for tumorigenesis studies. It will provide and keep current a central repository of data related to the animals. It will be responsible for tumor detection and monitoring, necropsy, and tissue collection and distribution to the Program investigators. The AMC will oversee shipping tissues to our consultant/collaborator and External Advisory Board member Dr. Robert Cardiff of the U.C. Davis Center for Comparative Medicine. The AMC will provide uniform tissue samples and extracts to investigators for their biochemical and molecular studies. These functions will assure consistency of the animal tissues used in the three component projects and permit direct comparisons of the results of a wide variety of studies on the same tissues. These procedures promote efficient use of tissues and animals, reducing the overall numbers of animals needed. Drs. Sonenshein, Seldin, and Sherr have worked closely over the past 10 years on collaboratively designed and implemented experiments and found this strategy to be highly productive and efficient. Dr. Seldin, with his considerable experience producing transgenic mice, has been a resource in the design and execution of all mouse studies. In the previous grant period, Dr. Adrianne Rogers was Leader of the Core. Her efforts focused upon the rat models, and her leadership was invaluable. However, rat studies are not part of the renewal application, and Dr. Rogers (who is retiring this month) will serve as an informal consultant and collaborator but not as Core co-Leader. Specific Accomplishments The centralized animal core has performed multiple common tasks that would be wasteful if carried out by the three individual projects instead of the Core. These tasks, which are crucial to all three projects, include 1) developing DMBA treatment conditions for mouse mammary tumor formation, 2) treatment of mice with DMBA and preparing mouse tissue samples for histologic and molecular analyses, 3) necropsy of mice and extraction of mammary tissue RNA and protein and distributing them to the laboratories of the project leaders, 4) caring for and monitoring mice before and during carcinogenesis studies, 5) assisting with development and breeding of 5 transgenic mouse lines [MMTVc- rel (Romieu-Mourez et al., 2003), MMTV-SR-kB-a (Demicco et al., 2005), MMTV-c-rel x MMTV-CK2 bitransgenics (Eddy et al., 2005), LEF-GFP, and MMTV-AhR)], 6) centralizing preparation of tail DMA and genotyping for all transgenic lines, 7) providing mice at timed stages of pregnancy for study, 8) establishing and maintaining an accessible database on mouse treatment, health, and necropsy and molecular results, 9) performing animal MRI to monitor tumor growth and metastases. These tasks are being carried out by animal and laboratory assistants employed by the program. They require a considerable level of expertise, supervision and training, which will continue to be effectively provided in the Program Project by Drs. Seldin, Xiao, and Yang. Duplication of these resources under the auspices of individual RO1s would have required many more animals, more technical support, and would not have the advantage of uniformity of techniques and protocols that has allowed reliable comparative studies. Thus, on financial and logistical grounds there is considerable value added of the AMC to the Program Project
Keywords: 9, 10-Dimethyl-1, 2-benzanthracene; Amendment; Animal Model; animal tissue; Animals; Anthracenes; Autopsy; Biochemical; Breeding; carcinogenesis; Carcinogens; Caring; Cause of Death; comparative; Comparative Study; Core Facility; Databases; design; Detection; Development; Diet; Dimensions; DNA; Drug or chemical Tissue Distribution; Evaluation; experience; feeding; Flow Cytometry; Genes; Genotype; Grant; Health; Histologic; Human Resources; IACUC; Image; in vivo; Individual; interest; Laboratories; Laboratory Animal Science; Laboratory Assistant; Leadership; Magnetic Resonance Imaging; Maintenance; Mammary gland; Mammary Neoplasms; Measurement; Medicine; member; Modeling; Molecular; Monitor; Mouse Mammary Tumor Virus; mouse model; Mus; Neoplasm Metastasis; NOD/SCID mouse; Nuclear Protein; Palpation; Pregnancy; Preparation; Procedures; programs; Proteins; Protocols documentation; Rattus; Reporting; Research Personnel; Research Project Grants; research study; Resources; RNA; Schedule; Shipping; Ships; Signal Pathway; Site; Staging; Supervision; Tail; Techniques; Time; Tissue Banks; Tissue Extracts; tissue processing; Tissue Sample; Tissues; Training; Transgenic Mice; Transgenic Organisms; tumor; tumor growth; tumorigenesis; United States National Institutes of Health; Weight; Work; Yang
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5P01ES011624-10_9002 (2011): $204781
7P01ES011624-08_9002 (2009): $286481
NETWORKS OF HETEROSEXUAL RISK AND HIV
C David
Indiana Univ-purdue Univ At Indianapoliscity: Indianapolis country: United States (us)
Grant 5R01HD055826-04 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: The purpose of the proposed research is to study the critical pathway for heterosexual transmission of HIV within serodiscordant intimate relationships. The proposed research will expand on the AIDS Risk Reduction Model (ARRM), which focuses on the person´s self protection motivation in the labeling of risk behaviors as problematic, the person´s intention to reduce risk, and the enactment of risk reduction behaviors. The expansion will include the person´s motivation to protect the partner and the motivation to preserve the relationship. Participants in the primary sample will include 200 dyads, consisting of 200 HIV positive (HIV+) persons and their heterosexual HIV negative (HIV-) partners. Study participants will be recruited from HIV care sites and from HIV testing sites. Regression analyses will provide a formal test of the three forms of the ARRM separately and then will test a combined model. A second element in the proposed study is to test the feasibility of recruiting multiple partner "HIV gatekeepers" (HIV- persons who have both HIV+ and HIV- sex partners). HIV gatekeepers are the critical route by which HIV can be transmitted into the general uninfected population. The project will recruit 35 gatekeeper triads (gatekeeper/HIV+/HIV-) to develop procedures for studying this complete critical pathway by which HIV will enter into the general population. This study seeks to identify the motivations, perceptions, and attitudes of both partners in critical HIV discordant relationships. Plausible interventions to reduce sexual risk need to tap into both self-interested and partner-oriented motivations. The proposed study is a necessary prelude to improving such interventions. The purpose of the proposed research is to study the critical pathway for heterosexual transmission of HIV from HIV positive persons to their HIV negative sexual partners and thus to other HIV negative persons in the general population
Keywords: Acquired Immunodeficiency Syndrome; Address; Area; Attitude; base; Behavior; Belief; Biological Preservation; Caring; Critical Pathways; Data; Future; Gatekeeping; General Population; Heterosexuals; HIV; HIV Seropositivity; Human immunodeficiency virus test; improved; indexing; Indium; innovation; Intention; interest; Intervention; Label; Lead; Measures; Modeling; Motivation; Multiple Partners; Participant; Pathway interactions; Pattern; Perception; Persons; Phase; Population; Prevention; Probability; Procedures; Recruitment Activity; Regression Analysis; Research; Risk; Risk Behaviors; Risk Reduction; Risk Reduction Behavior; Role; Route; Sample Size; Sampling; sex; Sex Behavior; sex risk; Sexual Partners; sexual relationship; Site; Testing; transmission process; Triad Acrylic Resin; Unsafe Sex
Project start date: 2008-04-09
Project end date: 2013-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R01HD055826-04 (2011): $304960
MATHEMATICAL DEVELOPMENT IN LEARNING DIASBLED CHILDREN
C David, Professor
University Of Missouri-columbiacity: Columbia country: United States (us)
Grant 5R37HD045914-09 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: The proposed research will provide a 5-year longitudinal study of the development of arithmetic-procedural competencies and number estimation skills in children with a learning disability in mathematics (MD) and normal peers. It is well established that during the solving of simple arithmetic problems (e.g., 6+7) MD children 1) rely on developmentally immature strategies, such as finger counting; 2) frequently commit counting errors; 3) use immature counting procedures [e.g., they count both addends rather than stating the cardinal value of one addend and counting-on a number of times equal to the value of the other addend]; 4) and, have difficulties retrieving basic facts from long-term memory. The focus of our currently funded research is to identify the basic cognitive systems, such as working memory, that underlie these arithmetic deficits. We have found, for instance, a strong relation between working memory and MD children´s reliance on finger counting and counting errors, and a relation between their use of immature counting procedures and knowledge of counting concepts. In other words, MD children have a lower working memory capacity than their normal peers, and this group difference in working memory explains part of the group differences in use of finger counting and counting errors. Group differences in knowledge of counting principles, in contrast, is unrelated to use of finger counting or counting errors, but explains part of the group difference in the type of procedure used during counting. The proposed research will provide the first longitudinal assessment of these relations between MD children´s arithmetic deficits and underlying cognitive systems, and will expand the assessments to include more complex arithmetic problems than have been used in most previous studies. The proposed research will also be the first to assess MD children´s ability to use spatial representations (i.e., a mental number line) to make number estimations, and assess how the form of the representation changes with formal schooling. The goals are to document the developmental progression of arithmetic and number estimation competencies in MD children, and to identify - based on the theoretical rationale described in the Background and Significance Section - the cognitive systems (e.g., working memory) that underlie MD children´s developmental delays and deficits in these competencies
Keywords: base; Child; Cognitive; cognitive system; Commit; Complex; Development; Developmental Delay Disorders; Fingers; Funding; Goals; Knowledge; Learning; Learning Disabilities; long term memory; Longitudinal Studies; Mathematics; peer; Peer Group; Procedures; Psyche structure; Reliance; Research; Schools; Short-Term Memory; skills; Study Section; Time
Project start date: 2008-08-01
Project end date: 2013-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: RFA-HD-02-031
5R37HD045914-09 (2011): $400363
Sponsored Links Excellgen http://Excellgen.com
INTERNET INITIATION OF TYPE 2 DIABETES IN KANSAS (THE I-KAN STUDY)
C David, Director Ku Diabetes Institute
University Of Kansas Medical Centercity: Kansas City country: United States (us)
Grant 1R34DK089444-01A1 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The proposed project will test in a limited number of rural and semi-rural sites in the state of Kansas an innovative model of synchronous ("live") Internet initiation and intensification of once- daily basal insulin glargine in type 2 diabetic patients that can be deployed statewide in a subsequent larger study (R18). The study´s specific aims are to 1) develop a synchronous ("live") interactive Internet-administered course designed to teach groups of type 2 diabetic patients to safely administer basal insulin without significant support from their usual source of diabetic management and to self- adjust the dose to achieve a HbA1c d 7.0% using a treat-to-target algorithm; and 2) to assess for the Internet patients selected clinical and psychometric outcomes. These will include HbA1c, frequency and severity of hypoglycemia, psychological resistance to insulin treatment, diabetes quality of life, and treatment satisfaction. The study builds upon the findings of the Treat-to-Target and INITIATE trials, as well as on successful Internet interventions for weight management, and both lays the conceptual foundation and gathers the expertise to successfully apply for the R18, which will have as primary aims addressing of delays to insulin therapy documented in the DAWN study and cost- effectiveness analysis of the Internet intervention. Aim 1 represents development of a "proof of concept" model of the innovation that can form the basis for the R18. Aim 2 will allow us to estimate the effect size needed for power calculations for the R18 designed to identify statistically significant parameters of effectiveness of and treatment satisfaction with Internet-initiation and intensification as compared to practice-based initiation and to estimate the potential for statewide deployment of the innovation, as well as its potential for reducing critical delays to insulin treatment. The pilot hopes to show that Internet teaching of basal insulin therapy is comparable to traditional insulin management with respect to safety and effectiveness as measured against expected (published) results for frequency of hypoglycemia and percent of patients reaching target. Psychometric outcomes are exploratory - and hypothesis generating with respect to the subsequent R18 application. The proposed pilot project will test the safety and effectiveness of a synchronous ("live"), interactive Internet intervention for initiating Type 2 diabetic patients on once-daily basal insulin using a treat-to-target algorithm and, to our knowledge, is the first trial designed to conduct group insulin initiation and intensification in a synchronous and highly interactive Internet environment. Initiating insulin is a particularly time-consuming process for time- and resource-constrained primary care providers and, in a largely rural state such as Kansas, patients often have to drive 60 miles to see a diabetes educator - or 300 miles to see a diabetes specialist. Thus, the proposed project addresses critical access barriers to insulin therapy and has the potential for reducing complications associated with the disease, as well as lessening cost burden to patient, provider, and the State
Keywords: Address; Algorithms; Antidiabetic Drugs; arm; basal insulin; base; Beta Cell; Clinical; Clinical Trials Design; Combined Modality Therapy; Complications of Diabetes Mellitus; cost; Cost Effectiveness Analysis; design; Development; diabetes control; diabetes educator; diabetes management; Diabetes Mellitus; Diabetic Angiopathies; diabetic patient; Diet; diet and exercise; Dietitian; Disease; Dose; Educational process of instructing; Effectiveness; Environment; Evaluation; Failure (biologic function); Focus Groups; Foundations; Frequencies (time pattern); glycemic control; Glycosylated hemoglobin A; Goals; Guidelines; high risk; Hyperglycemia; Hypoglycemia; Incidence; innovation; Insulin; Insulin, Glargine, Human; Internet; Intervention; Kansas; Life; Life Style; Measures; Metformin; Methods; Modeling; Modification; Non-Insulin-Dependent Diabetes Mellitus; Oral; Outcome; Outpatients; Patients; Persons; Physicians; Pilot Projects; Prevention; Primary Health Care; Process; Provider; psychologic; Psychometrics; Publishing; Quality of life; Research Infrastructure; Resistance; Resources; Risk; Rural; Safety; safety testing; satisfaction; Severities; Site; Societies; Source; Specialist; Techniques; Telemedicine; Testing; Time; Treatment Effectiveness; Weight
Relevance: The proposed pilot project will test the safety and effectiveness of a synchronous ("live"), interactive Internet intervention for initiating Type 2 diabetic patients on once-daily basal insulin using a treat-to-target algorithm and, to our knowledge, is the first trial designed to conduct group insulin initiation and intensification in a synchronous and highly interactive Internet environment. Initiating insulin is a particularly time-consuming process for time- and resource-constrained primary care providers and, in a largely rural state such as Kansas, patients often have to drive 60 miles to see a diabetes educator - or 300 miles to see a diabetes specialist. Thus, the proposed project addresses critical access barriers to insulin therapy and has the potential for reducing complications associated with the disease, as well as lessening cost burden to patient, provider, and the State
Project start date: 2011-08-01
Project end date: 2013-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PAR-09-177
1R34DK089444-01A1 (2011): $225000
NA/K PUMP CURRENT IN ISOLATED HEART CELLS
C David, Professor
Rockefeller Universitycity: New York country: United States (us)
Grant 5R01HL036783-24 from National Heart, Lung, And Blood Institute
Abstract: The Na/K pump generates the transmembrane electrochemical gradients of Na and K ions that underlie electrical signaling and secondary coupled transport, and is the receptor for digoxin, the widely prescribed cardiotonic steroid that specifically inhibits the Na/K pump. Inherited Na/K pump mutations are now linked to rapid-onset dystonia-parkinsonism and familial hemiplegic migraines. Our long term goal remains to understand in detail how the Na/K pump works, i.e. what the ion translocation pathways and associated gates look like, and how their orchestrated interaction transports first 3 Na and then 2 K ions in opposite directions across the cell membrane. We view the Na/K pump as a specialized ion channel with cytoplasmic and extracellular gates whose movements are tightly coupled so that both gates are never normally open at the same time (unlike the gates of ion channels). Accordingly, we investigate the Na/K pump by applying powerful electrophysiological methods that have proven successful in learning how ion channels work. Thus, the stationary current that results from the unequal transport of Na and K ions sensitively assays turnover rate during steady cycling, and charge relaxations following voltage jumps monitor conformational transitions that rate limit certain partial reactions. Together, these signals have shed light on the molecular mechanism of ion transport by the Na/K pump. Now, to further investigate the ion transport mechanism, we combine these recording methods with three new tools (a) homology models of the Na/K pump alpha subunit based on recent high-resolution crystal structures of key conformations of the related SR Ca pump; (b) site-specific mutagenesis based on those structural models, and expression in Xenopus oocytes, of ouabain-resistant mutant Xenopus Na/K pumps, some bearing novel cysteine residues introduced to test their accessibility to small sulfhydryl-specific reagents; (c) the marine toxin, palytoxin, which disrupts the coupling between the Na/K pump´s two gates, transforming it into an ion channel gated by the pump´s physiological ligands, Na and K ions and nucleotides. The specific aims are to use these tools (1) to determine the location, structure, and physico-chemical characteristics of the ion-translocation pathway (or pathways) traversed by the transported Na and K ions, (2) to determine the location and structure of the Na/K pump´s two principal gates, and (3) to examine the mechanisms controlling opening and closing of the gates
Keywords: Acocantherin; Acolongifloroside K; Assay; ATP phosphohydrolase (Na+ K+ transporting); Axon; base; Binding Sites; Bioassay; Biologic Assays; Biological Assay; biological signal transduction; body movement; Card-20(22)-enolide, 3-((6-deoxy-alpha-L-mannopyranosyl)oxy)-1, 5, 11, 14, 19-pentahydroxy-, (1beta, 3beta, 5beta, 11alpha)-; Cardiac Glycosides; Cardiac Myocytes; Cardiocyte; cardiomyocyte; Cardiotonic Steroids; Cavia; Cell Communication and Signaling; Cell membrane; Cell Signaling; Cells; Characteristics; Charge; Chemicals; Combining Site; conformation; conformational conversion; conformational state; conformational transition; Core Protein; Coupled; Coupling; Cysteine; Cytoplasmic Membrane; digoxin receptor; Dystonia 12; Embryo; Embryonic; experiment; experimental research; experimental study; extracellular; Familial Hemiplegic Migraine; Funding; G-Strophanthin; Gated Ion Channel; gene product; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Goals; Grant; Guinea Pigs; Half-Cystine; heart cell; Heart myocyte; Hereditary; Homology Modeling; Human; Human, General; Inherited; Intracellular Communication and Signaling; Ion Channel; Ion Channel Gating; Ion Channel Gatings; Ion Pumps; Ion Transport; Ionic Channels; Ions; kidney cell; L-Cysteine; Learning; Life; Ligands; Light; Link; Location; Mammals, Guinea Pigs; Man (Taxonomy); Man, Modern; marine biotoxin; Marine Toxins; Measurement; Measures; Membrane; Membrane Channels; Membrane Potentials; membrane structure; Methods; millisecond; Molecular; Molecular Configuration; Molecular Conformation; Molecular Stereochemistry; Monitor; Movement; Msec; Muscle Cells; Muscle Cells, Cardiac; Muscle Cells, Heart; Muscle Cells, Mature; Mutagenesis, Site-Directed; mutant; Mutation; Myocytes; Myocytes, Cardiac; Na(+)-K(+)-Exchanging ATPase; Na(+)-K(+)-Transporting ATPase; Na+ K+ ATPase; novel; Nucleotides; Oocytes; Ouabain; Ovocytes; palytoxin; pathway; Pathway interactions; Photoradiation; Physiologic; Physiological; Plasma Membrane; plasmalemma; Potassium Pump; Proteins; Pump; Rapid onset Dystonia Parkinsonism; Reaction; Reactive Site; Reagent; reagent testing; Relaxation; Renal Cell; research study; Resistance; resistant; Resolution; Resting Potentials; Side; Signal Transduction; Signal Transduction Systems; Signaling; Site-Directed Mutagenesis; Site-Specific Mutagenesis; sodium potassium exchanging ATPase; Sodium Pump; Sodium, Potassium Adenosine Triphosphatase; Sodium, Potassium Adenosinetriphosphatase; Sodium, Potassium ATPase; Sodium-Potassium Pump; Solutions; Squid; stoichiometry; Structural Models; Structure; System; System, LOINC Axis 4; Targeted DNA Modification; Targeted Modification; Testing; Time; tool; Transmembrane Potentials; Transport Reaction; V (voltage); Ventricular; voltage; voltage clamp; Work; Xenopus; Xenopus oocyte
Project start date: 1987-04-01
Project end date: 2012-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
5R01HL036783-24 (2011): $338000
TRAINING PROGRAM IN ENVIRONMENTAL EPIDEMIOLOGY
C David, Professor
Harvard University (sch Of Public Hlth)city: Boston country: United States (us)
Grant 5T32ES007069-32 from National Institute Of Environmental Health Sciences
Abstract: The mission of the Training Program in Environmental Epidemiology is to prepare a cadre of outstanding researchers in environmental epidemiology through a program of rigorous training and research methodology. This program is currently in its 29th year and is the established cornerstone of support for students working in area of environmental epidemiology at the Harvard School of Public Health. To date the investigators have graduated 177 professionals who conduct research, teach, and consult in environmental epidemiology and related disciplines, with 28 supported since the last competitive submission. The track in environmental molecular epidemiology, which was developed to provide trainees with comprehensive exposure to the application of molecular genetics techniques to environmental epidemiologic research, is now established and flourishing with trainees and new faculty. Training for both of these tracks is offered at the pre- and postdoctoral levels. Pre-doctoral students in the environmental track take courses in epidemiology, exposure analysis, exposure biology, biostatistics, occupational health, toxicology, and biomarkers. Additional research credits are obtained on the methodology of epidemiologic research through tutorials on current problems in epidemiology, and from the completion of a doctoral thesis of substance. In addition to course offerings, the track in environmental molecular epidemiology offers trainees additional courses in molecular biology and genetics, and the opportunity to select from four laboratories dedicated to research in molecular epidemiology with emphasis upon gene- environment interactions. The pre-doctoral training period usually lasts between 3 to 5 years, but varies depending on the students´ preparation. The first 2 years are devoted primarily to course work. Most didactic teaching is shared by the Departments of Epidemiology and Environmental Health at the School of Public Health, but also includes a large host of affiliates working within the Harvard Medical Area. Postdoctoral trainees are exposed to a wide variety of interdisciplinary and integrated intellectual offerings, including didactic instruction, seminars, professional colloquia, meetings, and academic collaboration. Significant research usually begins for the postdoctoral fellow in his/her second year and varies in duration depending on the scope of work. The program has been updated according to the NIEHS NOT-ES-06-007, with programmatic focus on priority areas and exposures. This program will continue a long history of excellence in training successful researchers in the field of environmental epidemiology at Harvard University. Relevance The Training Program in Environmental Epidemiology produces a continuing group of outstanding researchers who assess the role of environmental exposures in disease risk. This education involves state-of-the-art training in quantitative, biological and physical sciences. These young scientists go on to become leaders in the field, and work to identify, to prevent and control environmental risks
Keywords: Environmental Epidemiology; Training Programs
Project start date: 1978-07-01
Project end date: 2015-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5T32ES007069-32 (2011): $536713
MECHANISM OF ANESTHETIC PRECONDITIONING
C David, Professor And Chairman
Medical College Of Wisconsincity: Milwaukee country: United States (us)
Abstract: The long-term objective of this work is the continued analysis of mechanisms involved in the cardioprotective actions of volatile anesthetics such as isoflurane. Cardioprotection produced by these drugs is well documented across diverse species including rodents, large animals and humans, and mimics ischemic preconditioning in that a prior exposure to the volatile agent continues to be protective after the anesthetic has been eliminated, a phenomenon we termed "anesthetic preconditioning" (ARC). Project I will extend key findings of the previous funding cycle to investigate the global hypothesis that administration of volatile anesthetics such as isoflurane causes a cascade of events including activation of the hypoxia inducible factor la-vascular endothelial growth factor-nitric oxide (HIF1a-VEGF-NO) axis leading to ARC. Specific Aim I will test hypotheses related to how isoflurane regulates myocardial concentrations of HIF1a including actions on intracellular kinases, reactive oxygen species and/or the chaperone protein heat shock protein 90 (HSP90). Enhanced synthesis versus reduced ubiquination mechanisms elicited by isoflurane will be examined. Specific Aim II will test hypotheses related to the contribution of VEGF as an intermediate cardioprotective protein in ARC. Whether VEGF is a mediator of alterations in sarcKATp channel sensitivity and mitochondrial permeability transition by isoflurane will be explored. The importance of vascular endothelium in the protection of cardiomyocytes against hypoxia+reoxygenation injury by isoflurane will be established. Specific Aim III will test hypotheses related to the role and mechanism of action of NO in ARC. The NO synthase (NOS) isoform(s) involved in ARC will be delineated. The effect of NOS inhibition on isoflurane-induced changes in mitochondrial function, mitochondrial proteome, and NO feedback on HIF1a will be determined. NO feedback on HIF1a will be examined as the basis for the memory of ARC. A combination of in vivo rat and mouse models of cardioprotection and in vitro endothelial cell and cardiomyocyte cultures will be used to address the Specific Aims. Molecular and biochemical analyses related to the Specific Aims will be conducted with support from the Molecular and Biochemical and Proteomics Cores. The actions of reactive oxygen species and NO on mitochondrial function and effects of HSP90, an intracellular protein chaperone on the cardioprotection elicited by isoflurane will be studied in collaboration with investigators from Project II and III, respectively. Lay Cardiovascular disease is a significant problem in our society, and it is important to define new therapeutic strategies, including optimal delivery of anesthesia to patients with coronary artery disease. Protection against ischemia and reperfusion injury by drugs including the volatile anesthetic isoflurane is a complex process involving multiple intracellular mediators which will be defined by the proposed research
Keywords: Address; Anesthesia procedures; Anesthetics; Animals; Attention; base; Binding (Molecular Function); Biochemical; Bioenergetics; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Death; cell type; Collaborations; Communication; Complex; Coronary Arteriosclerosis; Coronary Occlusions; Coupled; Data; Dependence; Electron Transport; Endothelial Cells; Enzymes; Event; Exposure to; Feedback; Funding; Growth Factor; Heat-Shock Proteins 90; Human; Hypoxia; Hypoxia Inducible Factor; In Vitro; in vivo; Injury; Investigation; Ischemic Preconditioning; Isoflurane; Measurement; Mediating; Mediator of activation protein; Membrane Potentials; Memory; Mitochondria; mitochondrial membrane; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Chaperones; mouse model; Myocardial; Myocardial Ischemia; Nitric Oxide; Nitric Oxide Synthase; novel therapeutics; Outer Mitochondrial Membrane; Oxygen measurement, partial pressure, arterial; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; preconditioning; Process; Production; Protein Isoforms; Protein Kinase C; Proteins; Proteome; Proteomics; Rattus; Reactive Oxygen Species; Receptor Protein-Tyrosine Kinases; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Rodent; Role; Signal Transduction; Societies; Structure; Testing; Ubiquitination; Vascular Endothelial Growth Factors; Vascular Endothelium; Work
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5P01GM066730-09_0004 (2011): $460119
B CELL SUBSETS AS ANTIGEN-PRESENTING CELLS IN PERIPHERAL SELF-TOLERANCE
C David, Professor
Oregon Health And Science Universitycity: Portland country: United States (us)
Grant 5R01AI070934-05 from National Institute Of Allergy And Infectious Diseases
Abstract: The long-range goal of this research is to identify the significant antigen presenting cells (APC) that induce peripheral tolerance to self antigens, with a focus on weakly autoreactive B cell subsets. B cells are particularly efficient APC for antigens bound to their antigen receptors, so self-reactive B cells may present self-antigens more efficiently than conventional tolerizing APC in the thymus and periphery. To avoid positive feedback in a vicious cycle of mutual activation by pathogenic T and B cells, it may be necessary for autoreactive B cells to induce helper T cell tolerance to those self-antigens that they recognize and present efficiently, before those T cells are activated by infections. It is known that B cell subsets differ substantially from one another in their ability to recruit T cell help and their propensity to secrete autoantibodies, but they have not been compared with regard to their ability to induce tolerance in naive CD4 T cells. Three subsets of self-reactive B cells may be particularly important as tolerogenic APC for CD4 T cells. One subset is the short-lived, anergic, immature transitional B cells that are retained in T cell areas and fail to enter the longlived B cell compartments because their antigen receptors are engaged by self-antigens. Another is the self-renewing marginal zone B cells that are selected into this special B cell subset by self antigens, and are poised for a rapid antibody response to blood-borne pathogens. The third is the self-renewing B-1 B cells that are seeded to the periphery in early development, are selected and sustained by self-antigen reactivity, and produce germline-encoded, natural and T-independent antibodies that protect against bacterial infections. The objective of this project is to determine for the first time the intrinsic efficiency of antigen presentation and tolerance induction by B cell subsets in their natural locations in the steady state in healthy lymphoid organs, using a unique transgenic animal model in which antigen presentation can be limited to B cells of certain subsets. The proposed experiments will also test whether animals deficient in particular B cell subsets are deficient in CD4 T cell tolerance to self-antigens presented by those B cells. Relevance The failure of self-tolerance underlies autoimmune disease. This application investigates the mechanisms that maintain self-tolerance while allowing a vigorous response to infections. Understanding mechanisms of immunological tolerance may lead to new interventions for prevention or cure of autoimmune diseases, such as lupus erythematosus, rheumatoid arthritis, and diabetes. New methods to induce immunological tolerance will also have important applications in organ and tissue transplantation, gene therapy, and treatment of chronic infections
Keywords: Adjuvant; Animal Model; Animals; Antibodies; Antibody Formation; antigen binding; Antigen Presentation; Antigen Receptors; Antigen-Presenting Cells; Antigens; Area; Autoantibodies; Autoantigens; Autoimmune Diseases; autoreactive B cell; B-Lymphocyte Subsets; B-Lymphocytes; Back; Bacterial Infections; Blood-Borne Pathogens; CD4 Positive T Lymphocytes; Cell division; cell type; Cells; Chronic; cytokine; Dendritic Cells; Development; Diabetes Mellitus; Failure (biologic function); Feedback; Flow Cytometry; Frequencies (time pattern); gene therapy; Goals; Helper-Inducer T-Lymphocyte; Histology; Immune system; Immunoglobulins; In Vitro; in vivo; Infection; Inflammation; intercellular cell adhesion molecule; Knock-out; Label; Lead; Life; Location; Lupus Erythematosus; Lymphoid; Measures; Methods; Mus; Organ; Organ Transplantation; Peptide/MHC Complex; Peripheral; peripheral tolerance; Play; Population; Preventive Intervention; Problem Solving; Production; programs; Property; Recruitment Activity; Research; Research Personnel; research study; response; Rest; Rheumatoid Arthritis; Role; Self Tolerance; self-renewal; T-Cell Activation; T-Lymphocyte; Testing; Thymus Gland; Time; Tissue Survival; Tissue Transplantation; Transgenic Animals; Transgenic Organisms
Project start date: 2007-03-01
Project end date: 2012-02-29
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
5R01AI070934-05 (2011): $336518
C David, Professor
Dana-farber Cancer Institutecity: Boston country: United States (us)
Abstract: The investigators assembled in the DF/HCC Lung Cancer SPORE have a substantial record in mentorship and development of junior faculty members in lung cancer translations! research that is described in this program. The goal of the Career Development Program Program (COP) is to continue to build on this record and expand on the formal process for the identification, selection, funding, and mentoring individuals pursuing a career in th6 basic biologic sciences and applied sciences related to lung cancer. We will set aside $50,000 per year for the Career Development Awards from SPORE funds. The DF/HCC SPORE has an extensive track record of using institutional funds to support our CDP. This will be supplemented with an additional $200,000 per year in institutional support as we have in the past. Two to 3 individuals will be awarded each year for as much as two years of funding. The second year of funding will be dependent on making sufficient progress on review by the CDP. The award will facilitate the research and development of independence of basic biological science, translational science, and applied science within the DF/HCC Lung Cancer SPORE program. Thus, candidates will be fellows, postdoctoral fellows, and junior faculty within the different training programs across the Harvard campus. It is our goal to continue to attract, mentor, and assure the success of the CDA recipients. Success in this CDA will be defined as the development of physician scientists in training to their independence as investigators
Keywords: Anatomy; anticancer research; Applied Research; Appointment; Area; Award; base; Biological; Biological Sciences; biomarker; Cancer Center; Cancer Center Planning Grant; Cancer stem cell; career; career development; Clinical; clinical care; Clinical Investigator; Clinical Research; Clinical Trials; Commit; Dana-Farber Cancer Institute; Development; Direct Costs; Discipline; Ensure; Equilibrium; experience; Facilities and Administrative Costs; Faculty; Funding; Goals; Individual; Institution; instructor; interest; Investments; K-Series Research Career Programs; Laboratories; Laboratory Scientists; Leadership; Malignant neoplasm of lung; Malignant Neoplasms; Medical Oncology; Medicine; member; Mentors; Mentorship; Minority; Molecular Epidemiology; molecular pathology; mouse model; multidisciplinary; Operative Surgical Procedures; Outcome; Pathology; Patient Care; Patients; Physicians; Policy Research; Postdoctoral Fellow; pressure; Principal Investigator; Process; professor; programs; public health medicine (field); Qualifying; Radiation Oncology; Radiobiology; Records; Research; research and development; Research Personnel; response; Science; Scientist; Secure; Signal Transduction; success; Talents; Techniques; Thoracic Surgical Procedures; Time; Training; Training Programs; transcription factor; Transgenic Mice; Translational Research; Translations; Woman
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5P50CA090578-09_0012 (2011): $136559
BARRETT´S AND ESOPHAGEAL ADENOCARCINOMA GENETIC SUSCEPTIBILITY STUDY (BEAGESS)
C David, Program Head And Professor
Fred Hutchinson Cancer Research Centercity: Seattle country: United States (us)
Grant 5R01CA136725-03 from National Cancer Institute
Abstract: The incidence of esophageal adenocarcinoma (EA), a rapidly fatal disease, has increased faster than any other cancer in the US over the last three decades - over 500 percent. Gastroesophageal reflux and obesity have been found to be key modifiable risk factors for the development of EA and its main precursor, Barrett´s esophagus (BE). However, while reflux appears to be crucial to the neoplastic process, only about 10 - 15 percent of individuals with long-standing reflux symptoms develop BE in their lifetimes; among those who do, most do not progress to EA. Similarly, the mechanisms by which obesity increases risk of EA are not known. Thus, there must be other cofactors modulating the reflux-related chronic inflammatory effects on the esophageal epithelium and the local and systemic consequences of being overweight, that largely determine risk. Many of these cofactors are likely to be genetically mediated, and while family, twin and candidate gene studies support this notion, no genes have been established yet as playing a causal role. Here, we propose a large-scale genome-wide association study which takes advantage of the extensive data collected by investigators in the Barrett´s and Esophageal Adenocarcinoma Consortium (BEACON) in 18 epidemiologic studies, representing the vast majority of the well-designed largely population-based studies of these diseases in the world. The overall goal of our research is to evaluate the influence of genetic susceptibility on risk of EA and BE. The primary aim is to identify tagSNPs most strongly associated with risk of BE and EA. In secondary aims we will evaluate the extent to which the most significant associations vary according to key environmental and host risk factors for these conditions, including gender, obesity and cigarette smoking. We propose a single phase approach over three years involving 7,500 participants, all of whom have been previously interviewed regarding major environmental and host risk factors and have donated blood specimens. The Illumina Infinium Human 610-Quad Chip will be used to genotype approximately 1,500 cases of EA, 3,000 cases of BE and 3,000 population controls. Additional sources of samples and data have been identified to provide replication studies (funding to be requested separately.) The resources of BEACON, together with recent advances in genomic technology and analytic methods, present a unique and cost-effective opportunity to a) study the influence of genetic and environmental factors in the etiology of these important diseases, b) aid in the identification of key biological pathways in their pathogenesis, and c) help target persons at highest risk so that screening, prevention and surveillance efforts can be directed most effectively. The incidence of esophageal adenocarcinoma, a rapidly fatal disease, has increased more than six-fold over the past 30 years. By conducting a large-scale genome-wide association study using pooled data and DNA from 18 epidemiologic studies, we propose to evaluate the influence of genetic susceptibility on risk of this cancer and its main precancerous condition, Barrett´s esophagus, and determine the extent to which susceptibility factors vary according to key environmental and host risk factors for these conditions. These results will aid in the identification of biological pathways important in the etiology of this cancer, and help target persons at highest risk so that screening, prevention and surveillance efforts can be directed most effectively
Keywords: abdominal pressure; Apoptosis; Barrett Esophagus; Barrett`s Adenocarcinoma; Biological; Blood specimen; Cancer Etiology; cancer risk; Candidate Disease Gene; Chronic; cigarette smoking; cofactor; Complex; cost; cost effective; Data; design; Development; Disease; DNA; DNA Damage; DNA Repair; Environmental Risk Factor; Epidemic; Epidemiologic Studies; Epithelium; Esophageal; Esophageal Adenocarcinoma; Etiology; Family; Female; Funding; Gastroesophageal reflux disease; Gender; Genes; Genetic; Genetic Predisposition to Disease; genetic risk factor; Genome; genome wide association study; Genomics; Genotype; Goals; Gonadal Steroid Hormones; Health; high risk; Human; Incidence; Individual; Inflammation; Inflammatory; Insulin Resistance; Interview; Knowledge; Light; male; Malignant Neoplasms; Mediating; Meta-Analysis; Metabolic; Methods; model development; Modeling; modifiable risk; Neoplastic Processes; Obesity; Overweight; Oxidative Stress; Participant; Pathogenesis; Pathway interactions; Pattern; Persons; Phase; Play; population based; Population Control; Precancerous Conditions; Predisposition; Prevalence; Prevention; Process; Reflux; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Sampling; Screening procedure; Severities; Source; Stimulation of Cell Proliferation; Symptoms; Syndrome; Technology; Telomere Maintenance; Telomere Shortening; Twin Multiple Birth; Variant; Variation (Genetics)
Relevance: The incidence of esophageal adenocarcinoma, a rapidly fatal disease, has increased more than six-fold over the past 30 years. By conducting a large-scale genome-wide association study using pooled data and DNA from 18 epidemiologic studies, we propose to evaluate the influence of genetic susceptibility on risk of this cancer and its main precancerous condition, Barrett´s esophagus, and determine the extent to which susceptibility factors vary according to key environmental and host risk factors for these conditions. These results will aid in the identification of biological pathways important in the etiology of this cancer, and help target persons at highest risk so that screening, prevention and surveillance efforts can be directed most effectively
Project start date: 2009-09-21
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-07-070
5R01CA136725-03 (2011): $1230812
GENETICS OF BRAIN STRUCTURE AND FUNCTION
C David, Associate Professor
Yale Universitycity: New Haven country: United States (us)
Grant 5R01MH078143-06 from National Institute Of Mental Health
Abstract: The goal of this project is to identify quantitative trait loci associated with variation in brain structure and function. The ultimate promise of this research is the discovery of genes that predispose to brain disorders and mental illnesses. We believe that the analysis of genetic influences on brain structure and function in randomly sampled extended pedigrees will provide significant clues regarding the genes that are involved in both normal and pathological brain function. The focus of the project is on the genetic dissection of quantitative endophenotypes that more directly index the underlying biological basis of brain function than do discrete disease states themselves. To this end, we will perform neuroimaging and conduct neuropsychological examinations on Mexican American individuals who have been part of our ongoing genetic research studies for the past 15 years. All participants were previously genotyped and our plan is to utilize existing genome scan and genome-wide quantitative transcriptomic data for correlation with neuroanatomic and neurocognitive variables. Our specific aims are to 1) perform high quality brain magnetic resonance imaging and neuropsychological examinations on 1,000 Mexican Americans who are members of approximately 30 large extended families, 2) assess the quantitative genetic architecture of brain-related phenotypes by estimating their heritabilities and their genetic correlations, 3) classify specific brain morphological variables and quantitative leukocyte-derived gene expression measures as endophenotypes related to brain function, 4) localize QTLs influencing variation in the quantitative brain-related phenotypes by performing linkage-based genome scanning using the variance component method, 5) refine the position of localized QTLs and identify positional candidate loci using an objective prioritization strategy that jointly utilizes in silico bioinformatics, genetic, and transcriptional data, and 6) identify the most likely functional variations within the two best positional candidate genes. This project involves coordinated R01 applications from Dr. John Blangero, Southwest Foundation for Biomedical Research, and Drs. David Glahn and Peter Fox, University of Texas Health Science Center at San Antonio. If funded, our data and biomaterials will be incorporated into the NIMH Human Genetics Initiative making them available to qualified researchers in the wider scientific community. Relevance to agency mission Brain-related mental diseases are a major public health burden whose biology is still largely unknown. By identifying genes involved in brain function and structure, we will provide novel biological candidates for the determinants of such diseases and thus improve potential for intervention
Keywords: addiction; Affect; affection; Anatomy; Anxiety Disorders; Architecture; Attention deficit hyperactivity disorder; Autistic Disorder; base; Base of the Brain; Biocompatible Materials; Bioinformatics; Biological; Biology; Biomedical Research; Brain; Brain Diseases; Brain imaging; Candidate Disease Gene; Chromosome Mapping; Communities; Complex; Computer Simulation; cost effective; Data; Data Correlations; Dementia; Development; Diabetes Mellitus; Disease; disorder risk; Dissection; DNA Resequencing; Economic Burden; endophenotype; Epilepsy; Evaluation; Exhibits; Extended Family; Family; Foundations; Foxes; Funding; Future; gene discovery; Gene Expression; Genes; Genetic; genetic analysis; Genetic Determinism; genetic pedigree; Genetic Research; genetic resource; Genome Scan; genome-wide; genome-wide linkage; Genomics; Genotype; Goals; Health Sciences; Heart Diseases; Heritability; Human; Human Genetics; improved; in vivo; indexing; Individual; Individual Differences; Intervention; Joints; Lead; Leukocytes; Link; Magnetic Resonance Imaging; Measurable; Measurement; Measures; member; Mental disorders; Methods; Mexican Americans; Mission; Modeling; Molecular Analysis; Mood Disorders; Morbidity - disease rate; Mortality Vital Statistics; National Institute of Mental Health (U.S.); Neurocognitive; neuroimaging; Neurologic; neuropsychological; Neurosciences; Noise; novel; novel diagnostics; Nucleotides; Osteoporosis; Participant; Pathology; Phenotype; Positioning Attribute; Procedures; programs; Psyche structure; public health medicine (field); Qualifying; Quantitative Genetics; Quantitative Trait Loci; Relative (related person); Research; Research Design; Research Personnel; research study; Resource Sharing; Resources; Reverse Transcriptase Polymerase Chain Reaction; Risk; Sampling; Schizophrenia; sharing data; Short Tandem Repeat Polymorphism; Signal Transduction; Single Nucleotide Polymorphism; Source; Structure; Susceptibility Gene; Testing; Texas; Therapeutic; trait; transcriptomics; Uncertainty; Universities; Variant
Project start date: 2006-08-01
Project end date: 2012-07-31
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2012
PFA/PA: PA-01-123
5R01MH078143-06 (2010): $272714
BAYESIAN COMPUTATIONS IN HUMAN 3D VISUAL PERCEPTION
C David
University Of Rochestercity: Rochester country: United States (us)
Grant 5R01EY017939-05 from National Eye Institute
Abstract: The goal of the proposed research is to understand how the human visual system resolves the inherent geometric ambiguities associated with most visual cues to depth. The brain can resolve cue ambiguity in two ways, (1) by applying prior knowledge of ecological constraints on those variables (e.g. that figures tend to be symmetric) and (2) by cooperatively using the information from other sensory cues to disambiguate their values. The first two principal aims focus on the first part of the problem. They are shaped by the observation that much of the statistical structure that makes monocular cues to depth informative is categorical in nature - motions are rigid or not, figures are symmetric or not, textures are homogeneous or not, etc.. We will study how the visual system combines information from multiple cues to disambiguate which of the several possible prior constraints to use when interpreting a cue. Casting the problem within a Bayesian framework provides a formal system for modeling robust cue integration, which allows the visual system to effectively deal with large conflicts between sensory cues. We will perform experiments to test the Bayesian model against other models of robust cue integration. The model also provides a framework for characterizing how the brain adapts its internal models of the prior statistics that make monocular cues informative. We will study how human observers use the information obtained by combining multiple cues to adapt these internal models and how this impacts how they integrate cues to estimate surface orientation and shape. The final principal aim tests whether and how the brain uses non-visual information (haptic / kinesthetic) derived from active movement and exploration of objects to disambiguate scene properties on which visual cues depend. The research will focus on three monocular visual cues about surface orientation and shape- figure shape, texture and motion - and how the brain combines these cues with stereoscopic cues. The psychophysics is motivated by and will be coupled with computational modeling of ideal Bayesian models for visual cue integration, learning and multi-modal cue integration. The results of the proposed research will elucidate the types of statistical inferences that are built into the neural computations underlying visual depth perception and define the limits of these computations. This will ultimately direct and constrain future studies of the neural mechanisms underlying vision
Keywords: Behavior; Biological Models; Brain; Code; Computer Simulation; Conflict (Psychology); Coupled; Cues; Data; Depth Perception; Future; Goals; grasp; haptics; Human; Image; improved; Judgment; Knowledge; Lead; Learning; Measures; Modality; Modeling; monocular; Motion; Movement; Nature; neuromechanism; object shape; optic flow; Perception; Problem Solving; Process; programs; Property; Psychophysics; Psychophysiology; relating to nervous system; Research; research study; Retinal; Scheme; Sensory; Shapes; Signal Transduction; Source; Statistical Models; statistics; stereoscopic; Structure; Surface; Testing; Texture; theories; Uncertainty; Vision; Visual; visual feedback; visual information; Visual Perception; Visual system structure
Project start date: 2007-08-01
Project end date: 2012-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5R01EY017939-05 (2011): $295680
INSTITUTIONAL TRAINING GRANT IN THE GENOMIC SCIENCES
C David, Kellett Prof. Of Chem. & Gen.
University Of Wisconsin Madisoncity: Madison country: United States (us)
Grant 5T32HG002760-09 from National Human Genome Research Institute
Abstract: The Genomic Sciences Training Program (GSTP) is helping to produce the new generation of genomic scientists with strengths spanning multiple disciplines. The primary motivation for the research training opportunities proposed here is predicated on the rapidly growing set of significant biological and genetics-based questions that can now be addressed given the wealth of genomic data elucidated by new technologies that generate and interpret increasingly complex data sets. The new genomic approaches to biological investigation demand scientists who are knowledgeable and skilled across several fields in effective ways that potentiate new insights or inventions. Accordingly, the development of new tools for the creation and interpretation of large-scale experimental efforts is what GSTP has focused on by the didactical interweaving of investigative approaches drawn from multiple fields (biology, genetics, physical sciences, engineering, computer science, and statistics) that were individually contoured for complementing a trainee´s core disciplinary focus, yet built upon achievement and knowledge within the genomic sciences. Given the incredibly rich scientific and engineering span of the University of Wisconsin, GSTP was able to recruit outstanding trainees who greatly advanced mass spectroscopy, microarray technology, bio-devices, and created new applications exploiting these advantages for cutting-edge investigation into proteomics, transcription, metabolomics, and genome biology. These groundbreaking developments have propelled many trainees and trainers to become "magnets" for significant collaborations reaching across departments, centers, and other training programs. We propose that for the renewal of this program that we continue this focus with added emphasis on programmatic evaluation of GSTP and increased embracement of URM trainees. We request funding for training on a yearly basis 10 predoctoral (1-3 yrs), 4 postdoctoral (1-3 yrs), and 2 short-term (0.25 yr) trainees; we will seek trainees with recent undergraduate and graduate degrees. Modern medical practice is increasingly relying on the fruits of genomic research for new diagnostics, drugs, and other therapies. We propose to train scientists who will be developing the systems that will enable greater use of genomic information for biomedical researchers and the general public
Keywords: Genomics; Grant; Science; Training
Project start date: 2003-07-01
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-06-468
5T32HG002760-09 (2011): $678994
Sponsored Links Excellgen http://Excellgen.com
PUBLIC POLICY AND THE DEMAND FOR LONG-TERM CARE INSURANCE
C David, Assistant Professor Of Health Policy
Harvard University (medical School)city: Boston country: United States (us)
Grant 1R01AG041109-01 from Office Of The Director, National Institutes Of Health
Abstract: The financing of long-term care is an increasingly important issue for the elderly and our population as a whole. We propose to use two novel databases to study the demand for long-term care insurance (LTCi) and to consider the potential role of governmental policy moving forward. These data include multiple waves of detailed survey information on buyers and non-buyers of LTCi policies and longitudinal enrollment and utilization data from the state Long-Term Care Partnership Program, a public-private partnership between states and insurance companies designed to reduce Medicaid spending by delaying or eliminating the need for some people to rely on Medicaid for long-term care services. Relative to previous research, we will have much more detailed information on individuals´ attitudes and opinions about long-term care, family caregiving, and related government policies; the primary reasons for purchase/non-purchase of LTCi; and demographics factors relevant to purchase decisions, including asset and income levels. For LTCi buyers, these detailed survey data are linked to information on level of policies that were purchased. Thus, our first two research aims are to analyze the effect of individual factors, such as demographic traits and attitudes about the intertwined roles of family caregiving, Medicaid, and private insurance, and state-level factors, such as Medicaid eligibility policies, tax incentives, and the presence of a Partnership Program, on 1) the purchase of LTCi and 2) the level of LTCi policy that was purchased. Both of these analyses will use person-level survey data merged with state-level policy factors to model the effect of individual and state traits on LTCi purchase. The analyses will exploit the longitudinal nature of the survey data (surveys were conducted in 1990, 1995, 2000, 2005, and 2010) to account for unobserved, time invariant state characteristics that may be correlated with both LTCi purchase and state policy features (e.g., tax incentives for LTCi). Understanding the key determinants of individuals´ decision to purchase LTCi can help shape relevant government policies and marketing campaigns, including product targeting for the Community Living Assistance and Supportive Services (CLASS) program. The third aim of our project is i) to describe the early experience of state Long- Term Care Partnership Programs in terms of the number and type of policies sold and the claims experience of enrollees and ii) to simulate the potential effect of these programs on future Medicaid long-term care spending. To accomplish these aims, we will use detailed information on policies, policyholders, and claimants available from all state LTC Partnership Programs merged with information from the 2010 LTCi buyers survey (e.g., the asset/income levels of purchasers of Partnership policies) and long-term care utilization data from similar individuals in the Health and Retirement Survey. Evaluating the early experience of state Partnership programs can help shape expectations for the program going forward, particularly around its ability to impact Medicaid spending. To date, private long-term care insurance has played a minimal role in financing long-term care in the United States; instead, out of pocket payments and public financing through state Medicaid programs have played primary roles, leaving individuals, families, and state governments vulnerable to the potentially catastrophic costs of long-term services and supports. We propose to use two key databases to study the factors influencing the demand for long-term care insurance and the role of government policy moving forward, including multiple waves of survey data from buyers and non-buyers of LTCi policies and longitudinal enrollment and utilization data from the Long-Term Care Partnership Program, a public-private partnership between states and insurance companies designed to reduce Medicaid spending by delaying or eliminating the need for some people to rely on Medicaid for long-term care services. By shedding light on key factors that influence the demand for insurance and the early experience of the LTC Partnership program, our analyses will offer key insights for policymakers as they implement and refine the government´s approach to financing long- term care in the future
Keywords: Accounting; Acute; Age; Attitude; care systems; caregiving; Caring; Characteristics; Charge; community living; cost; Data; Databases; Demographic Factors; design; Disability Insurance; early experience; Elderly; Eligibility Determination; Enrollment; expectation; experience; Family; Future; Government; Government Financing; Growth; Health; Incentives; Income; Individual; insight; Insurance; Laws; Lead; Left; Light; Link; Long-Term Care; Long-Term Care Insurance; Marketing; Medicaid; Medical; Medicare; meetings; Modeling; Myopia; Nature; novel; Participant; Patients; payment; Persons; Play; Policies; Population; Program Sustainability; programs; Public Policy; public-private partnership; Relative (related person); Research; Research Infrastructure; Research Personnel; Resort; Retirement; Risk; Role; safety net; Services; Shapes; Simulate; Source; State Government; Structure; success; Supportive assistance; Surveys; Taxes; Time; trait; Uncertainty; United States
Relevance: To date, private long-term care insurance has played a minimal role in financing long-term care in the United States; instead, out of pocket payments and public financing through state Medicaid programs have played primary roles, leaving individuals, families, and state governments vulnerable to the potentially catastrophic costs of long-term services and supports. We propose to use two key databases to study the factors influencing the demand for long-term care insurance and the role of government policy moving forward, including multiple waves of survey data from buyers and non-buyers of LTCi policies and longitudinal enrollment and utilization data from the Long-Term Care Partnership Program, a public-private partnership between states and insurance companies designed to reduce Medicaid spending by delaying or eliminating the need for some people to rely on Medicaid for long-term care services. By shedding light on key factors that influence the demand for insurance and the early experience of the LTC Partnership program, our analyses will offer key insights for policymakers as they implement and refine the government´s approach to financing long- term care in the future
Project start date: 2011-09-15
Project end date: 2013-08-31
Budget start date: 15-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-RM-11-002
1R01AG041109-01 (2011): $327545
MECHANISMS OF MUSCLE MICROCIRCULATORY DYSFUNCTION IN HEART FAILURE
C David, Assoc Professor
Kansas State Universitycity: Manhattan country: United States (us)
Grant 1R15HL108328-01 from National Heart, Lung, And Blood Institute
Abstract: The exercise intolerance of chronic heart failure (CHF) has a substantial skeletal muscle component. Repeated contractions of skeletal muscle require precise matching of O2 delivery (QO2) - to-O2 utilization (VO2). However, CHF impairs capillary hemodynamics thereby lowering the QO2/VO2 ratio and microvascular O2 pressure and compromising blood-myocyte O2 flux. Our unique intravital microscopy model (rat spinotrapezius - a muscle amenable to exercise training) facilitates direct observation of muscle microcirculation and high temporal fidelity-determination of blood-myocyte O2 flux using phosphorescence quenching during contractions. Building on the observation that CHF decreases muscle nitric oxide (NO) bioavailability and acute increases of NO restore QO2-to-VO2 matching in CHF this proposal will test the global hypothesis that multiple strategies designed to increase NO bioavailability either directly (exercise training, increased tetrahydrobiopterin (BH4, via sepiapterin)) or via modulation of reactive O2 species ( ROS, reduced O2O-, via apocynin, Gp91 ds-tat, and Tempol; reduced OHO- via deferoxamine) will improve capillary hemodynamics and blood-myocyte O2 flux. Recognizing the inflammatory component of CHF, we will investigate whether microvascular deficits in CHF can be ameliorated by reduction of inflammatory mediators IL-12 (using anakinra, IL-12 receptor antagonist) and TNF1 (using pentoxifylline). Significant strengths of this proposal include 1. Pentoxifylline, which lowers circulating TNF-1, has proven efficacy in human CHF whereas TNF-1 blockers etanercept (recombinant TNF receptor) and infliximab (monoclonal TNF-1 antibody), for example, may worsen the condition. We will test the hypothesis that pentoxifylline improves capillary hemodynamics during contractions and assess the role of NO in this process. 2. Involvement of undergraduate and graduate students in meritorious cutting-edge scientific research, and 3. Avoiding the technical impossibility of making precise micron-level [NO] measurements in contracting muscle by determining quantitatively the extent to which NO bioavailability actually facilitates capillary hemodynamics. This will be accomplished using conditions of NOS blockade (L-NAME) and exogenous NO application (sodium nitroprusside and/or NONOate) under each experimental condition. It is anticipated that these investigations will establish a sentinel role for NO in facilitating the capillary hemodynamics and blood-myocyte O2 flux response to muscle contractions in health and reveal that deficits in NO bioavailability in CHF - evoked by dysfunction at multiple steps in the NO production pathway including BH4-induced NOS uncoupling and ROS- mediated NO destruction - are causative to CHF-induced dysfunction. The proposed studies will provide novel and important data addressing the mechanisms of muscle capillary hemodynamic dysfunction in CHF and assess the mechanistic bases for the efficacy of pentoxifylline in treating CHF patients whilst fulfilling the AREA award mandate to integrate authentic research with undergraduate/graduate student education. The exercise intolerance of patients suffering from chronic heart failure (CHF) is based substantially in skeletal muscle and, irrespective of left-ventricular function per se, results from a mismatching of oxygen delivery to oxygen demands in contracting muscles. Recent evidence indicates that this mismatching is the consequence of impaired capillary blood flow secondary to decreased nitric oxide bioavailability. This proposal assesses the efficacy of strategies to increase nitric oxide bioavailability to improve capillary hemodynamics, oxygen delivery/utilization matching and muscle function in CHF. One key aspect is determination of the mechanistic bases for the efficacy of pentoxifylline to treat CHF patients. Under these auspices and the AREA Award mission this proposal integrates meritorious science with opportunities for development of undergraduate and graduate student scientists
Keywords: 2, 2, 6, 6-tetramethyl-4-piperidinol-N-oxyl; acetovanillone; Acute; Address; American; anakinra; Antibodies; Arginine; Atrophic; Award; base; Biological Availability; Blood; Blood capillaries; Blood flow; Blood Vessels; capillary; Chronic; Clinical Trials; Contracts; Coronary; cytokine; Data; Deferoxamine; design; Development; Disodium Salt Nitroprusside; Educational aspects; Etanercept; Exercise; Exercise Tolerance; Fiber; Functional disorder; graduate student; Health; Heart failure; hemodynamics; Human; human NOS3 protein; improved; Inflammation Mediators; Inflammatory; infliximab; interest; Interleukin-12; Interleukins; intravital microscopy; Investigation; Kinetics; Left Ventricular Ejection Fraction; Left Ventricular Function; Ligation; Literature; Measurement; Measures; Mediating; Microcirculation; Mission; Modeling; Monoclonal Antibodies; Muscle; Muscle Cells; Muscle Contraction; Muscle function; Myocardial Infarction; NADPH Oxidase; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Pathway; novel; outcome forecast; Oxygen; Pathology; Pathway interactions; Patients; Pentoxifylline; Peptides; phosphorescence; Preparation; pressure; prevent; Process; Production; public health relevance; Pump; Quality of life; Rattus; receptor; Recombinants; Research; response; Rest; Role; Science; Scientist; Secondary to; Sentinel; sepiapterin; Skeletal muscle structure; Testing; tetrahydrobiopterin; Therapeutic; TNF gene; Training; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors
Relevance: Relevance: The exercise intolerance of patients suffering from chronic heart failure (CHF) is based substantially in skeletal muscle and, irrespective of left-ventricular function per se, results from a mismatching of oxygen delivery to oxygen demands in contracting muscles. Recent evidence indicates that this mismatching is the consequence of impaired capillary blood flow secondary to decreased nitric oxide bioavailability. This proposal assesses the efficacy of strategies to increase nitric oxide bioavailability to improve capillary hemodynamics, oxygen delivery/utilization matching and muscle function in CHF. One key aspect is determination of the mechanistic bases for the efficacy of pentoxifylline to treat CHF patients. Under these auspices and the AREA Award mission this proposal integrates meritorious science with opportunities for development of undergraduate and graduate student scientists
Project start date: 2011-04-01
Project end date: 2014-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-10-070
1R15HL108328-01 (2011): $365546
METAL EXPOSURE AND CHILDREN?S PRESCHOOL NEURODEVELOPMENT
C David, Professor Of Neurology
Children´s Hospital Bostoncity: Boston country: United States (us)
Grant 5R01ES016283-04 from National Institute Of Environmental Health Sciences
Abstract: The developing central nervous system is particularly vulnerable to environmental toxicants such as heavy metals. While lead (Pb) poisoning has been extensively studied, the neurotoxicities and dose-effect relationships associated with other heavy metals, such as arsenic (As) and manganese (Mn), are poorly understood. Data are even more limited on the effects of joint exposures to these metals, even though this exposure scenario more accurately reflects the real world situation. In this project we will build upon an ongoing birth cohort study of 750 mothers and their children at a former hard rock mining community, the Tar Creek, OK, Superfund mega-site. To date, children have been followed to age 2 years, involving the collection of extensive Pb, Mn, and As biomarker data (blood, hair, nails), providing a record of lifetime (including prenatal) exposures to these metals. In the proposed project, assessments will be conducted when children are 5.5 years of age. At that time, Mn and Pb will be measured in blood; Mn, As, and selenium (Se) in hair; and As and Se in nails. The neurodevelopmental assessment will include tests of intelligence, memory, visual- motor/spatial abilities, executive functions, and behavior. Data analyses will model the associations between neurodevelopment and individual metals and between neurodevelopment and joint exposures to metals. Another goal is to determine if genetic susceptibility factors modify the associations between metal exposures and neurodevelopment, focusing on genetic variations in 4 pathways chosen to reflect metal metabolism or synaptic plasticity iron metabolism (HFE, transferrin, DMT-1), cholesterol metabolism (apolipoprotein E), neurotransmitter metabolism (dopamine transporter, dopamine D4 receptor, norepinephrine transporter, monoamine oxidase, catechol O-methyltransferase, NMDA receptor, 5-HT1A receptor), and methylation metabolism (methylenetetrahydrofolate reductase, GST- M1, T1, P1, omega, purine nucleoside phosphorylase, cytosolic serine hydroxymethyltransferase). This prospective study will provide the most comprehensive data to date on the potential neurodevelopmental correlates of Mn and As exposures, and on the potential interactions among Pb, Mn, and As exposures. This prospective study of children from birth will provide the most comprehensive data available on the potential adverse effects on neurodevelopment of exposure to the heavy metals arsenic and manganese. The effects of exposures to combinations of metals, including lead, is also a major focus. This more closely mirrors "real world" exposures, which invariably involve a mixture of compounds rather than a single compound
Keywords: 2 year old; Adverse effects; Age-Years; Apolipoprotein E; Arsenic; Behavior; biomarker; Birth; Blood; Catechol O-Methyltransferase; Child; Cholesterol Homeostasis; cohort; Cohort Studies; Collection; Communities; Data; Data Analyses; dopamine D4 receptor; dopamine transporter; Dose; executive function; Exposure to; Genetic Predisposition to Disease; Glycine Hydroxymethyltransferase; Goals; Hair; Heavy Metals; Individual; Intelligence; Intelligence Tests; iron metabolism; Joints; Lead; lead exposure; Lead Poisoning; Manganese; Measures; Memory; Metabolism; Metal exposure; metal metabolism; Metals; Methylation; Methylenetetrahydrofolate reductase (NADPH); Mining; Modeling; Monoamine Oxidase; Mothers; N-Methyl-D-Aspartate Receptors; Nail plate; Neuraxis; neurodevelopment; Neurodevelopmental Deficit; neurotoxicity; neurotransmitter metabolism; noradrenaline transporter; Nursery Schools; Oklahoma; Participant; Pathway interactions; population based; postnatal; Pregnancy; prenatal; prenatal exposure; Prospective Studies; Purine-Nucleoside Phosphorylase; Receptor, Serotonin, 5-HT1A; Research Infrastructure; Resources; Selenium; Site; Superfund; superfund site; Synaptic plasticity; Tars; Time; Toxic Environmental Substances; Transferrin; Variant; Variation (Genetics); visual motor; Work
Project start date: 2008-06-01
Project end date: 2013-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R01ES016283-04 (2011): $431913
INSIGHTS ON GLAUCOMA FROM ANALYSIS OF THE CIGTS DATA
C David, Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 1R21EY020912-01A1 from National Eye Institute
Abstract: The Collaborative Initial Glaucoma Treatment Study (CIGTS), a National Eye Institute supported multicenter clinical trial, provided unique insights to how newly diagnosed open-angle glaucoma (OAG) should be treated, whether by initial surgical or medical intervention. Even so, much clinically-relevant and important information to glaucoma and its treatment remains to be evaluated in the extensive CIGTS data resource. Conduct of the proposed data analyses described in this grant application will provide unique, cost-effective opportunities to investigate additional research questions that are directly relevant to the management and care of patients who have open-angle glaucoma. We propose to conduct extensive analyses that address the following four specific aims (1) Develop a predictive model that provides a ranking of factors that influence improvement in visual field (VF) during treatment of OAG. (2) Describe the natural history of open-angle glaucoma (OAG) development in initially un-treated fellow eyes, and develop a predictive model for the onset of OAG in such eyes. (3) Investigate VF defects documented in the CIGTS, including their location, cluster number, and extent at baseline, response to IOP reduction and elevation, and the association of baseline VF defect characteristics with the probability of progressive VF loss. (4) Compare alternate methods to define and analyze progressive loss of visual field - pointwise linear regression, mixed linear regression, "event-based" methods, and trajectory analysis - with regard to the outcomes they yield (risk factors, estimates of VF progression). The Collaborative Initial Glaucoma Treatment Study, a National Eye Institute supported multicenter clinical trial, provided unique insights to how newly diagnosed glaucoma should be treated, whether by initial surgical or medical intervention. Conduct of the proposed data analyses described in this grant application will expand our ability to provide evidence-based direction to the management and care of patients diagnosed with glaucoma. In addition, these analyses will inform future studies of how best to evaluate progression of visual field loss in glaucoma, which is the most important outcome to monitor in studies of glaucoma treatment
Keywords: Address; African; Aftercare; Age; Applications Grants; base; Characteristics; Clinical Trials; clinically relevant; Comorbidity; cost effective; Data; Data Analyses; Development; Diabetes Mellitus; Diagnosis; Event; evidence base; Eye; Family; Future; Glaucoma; Incidence; insight; Intervention; Linear Regressions; Location; Medical; Methods; Monitor; Morphologic artifacts; National Eye Institute; Natural History; Newly Diagnosed; Open-Angle Glaucoma; Operative Surgical Procedures; Outcome; Patient Care Management; Patients; Physiologic Intraocular Pressure; predictive modeling; Probability; Race; Recording of previous events; Reporting; Research; Resources; response; Risk Factors; Role; Scotoma; Time; Variant; Vision; Visual Fields
Relevance: The Collaborative Initial Glaucoma Treatment Study, a National Eye Institute supported multicenter clinical trial, provided unique insights to how newly diagnosed glaucoma should be treated, whether by initial surgical or medical intervention. Conduct of the proposed data analyses described in this grant application will expand our ability to provide evidence-based direction to the management and care of patients diagnosed with glaucoma. In addition, these analyses will inform future studies of how best to evaluate progression of visual field loss in glaucoma, which is the most important outcome to monitor in studies of glaucoma treatment
Project start date: 2011-07-01
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PAR-09-252
1R21EY020912-01A1 (2011): $233250
CHRONIC NICOTINE EFFECTS ON RECEPTOR SUBTYPES
C David, Professor
George Washington Universitycity: Washington country: United States (us)
Grant 5R01DA015767-07 from National Institute On Drug Abuse
Abstract: The CNS effects of nicotine are mediated by multiple subtypes of neuronal nicotinic cholinergic receptors (nAChRs). The effects of nicotine after chronic administration differ from those after acute administration, and nicotine effects also vary at different stages of development. Our previous work characterized the effects of chronic nicotine on expression and function of different subtypes of nAChRs. Knowledge of the shifting expression pattern of these receptors during nicotine use is critical for understanding cholinergic neurophysiology as well as nicotine pharmacology. Chronic nicotine is associated with dependence, changes in gene expression and behavior, and altered neural development. This latter effect is of critical importance given the widespread exposure to nicotine that occurs during periods of critical neural development, particularly due to prenatal exposure from mothers who smoke or use NRT products, and adolescents who are beginning to experiment with tobacco. Prenatal nicotine exposure can have profound effects upon subsequent development and behavior of offspring. Adolescent exposure to nicotine is associated with higher rates of adult dependence, both to nicotine and to other drugs of abuse. Thus these represent uniquely vulnerable periods for nicotine exposure. The overarching goal of the present proposal is to compare the effects of chronic nicotine exposure at three critical ages prenatal, adolescence and adult. We will employ rat models to study the overlapping effects of chronic nicotine exposure on nAChR expression and function, neuronal morphology and gene expression; we will focus on receptors, genes and brain regions associated with nicotine dependence. In particular, we will examine for persistent effects of nicotine exposure on these parameters. These studies will test the general hypothesis that nicotine´s effects on these parameters differ at different developmental stages of exposure. In particular, Aim 4 will test the hypothesis that prenatal nicotine exposure inhibits the response of adolescents to subsequent nicotine challenge, increasing the number of cigarettes smoked and thus the likelihood of subsequent dependence. For each of the following Specific Aims, we will test for both the short-term and persistent effects of chronic nicotine exposure on expression (using autoradiography and immunoprecipitation) and function (using rubidium efflux and neurotransmitter release) of nAChR subtypes, alteration of neuronal morphology (measuring dendritic length and spine density), and changes in global gene expression (using microarrays and rtPCR) in brain regions associated with nicotine dependence. Differential developmental effects will be determined by comparison across aims. SPECIFIC AIMS 1. Determine the immediate and the persistent direct effects of prenatal chronic nicotine exposure. 2. Determine the immediate and the persistent direct effects of adolescent chronic nicotine exposure. 3. Determine the immediate and the persistent direct effects of adult nicotine exposure. 4. Determine the persistent indirect effects of prenatal nicotine exposure by determining how prenatal nicotine exposure alters the ability of the adolescent to respond to a new nicotine exposure This work will address hypotheses critical for understanding how chronic exposure to nicotine, such as occurs in tobacco smokers and NRT users, can alter receptor expression and function, neuronal structure, and gene expression. The work will measure nicotine´s effects on these parameters caused by prenatal exposure in rats, and compare them to those effects from exposure during adolescence and adulthood. These studies should help to better understand the unique age-specific effects underlying vulnerability to nicotine´s effects at these younger ages
Keywords: Acute; Address; Adolescence; Adolescent; Adult; Age; Animals; Antibodies; Autoradiography; Behavior; Biological Assay; Birth; Brain; Brain region; Candidate Disease Gene; cholinergic; Cholinergic Receptors; Chronic; Cigarette; critical period; density; Dependence; desensitization; Development; Drug Addiction; drug of abuse; Exposure to; fetal tobacco exposure; functional status; Gene Expression; Goals; Health; Immunoprecipitation; in utero; Individual; Knowledge; Length; mature animal; Measures; Mediating; Methods; Microarray Analysis; Modeling; Morphology; Mothers; neurochemistry; neurodevelopment; Neurons; neurophysiology; neurotransmitter release; Neurotransmitters; Nicotine; Nicotine Dependence; offspring; Pattern; Pharmacology; Phenotype; postnatal; Pregnancy; pregnant; prenatal; prenatal exposure; Preparation; Quantitative Autoradiography; Rattus; receptor; receptor expression; receptor function; Receptor Gene; Regimen; Regulation; Research Design; research study; response; Rubidium; Saline; Smoke; Smoker; Staging; Structure; Testing; Tobacco; Vertebral column; Work
Relevance: This work will address hypotheses critical for understanding how chronic exposure to nicotine, such as occurs in tobacco smokers and NRT users, can alter receptor expression and function, neuronal structure, and gene expression. The work will measure nicotine´s effects on these parameters caused by prenatal exposure in rats, and compare them to those effects from exposure during adolescence and adulthood. These studies should help to better understand the unique age-specific effects underlying vulnerability to nicotine´s effects at these younger ages
Project start date: 2002-12-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01DA015767-07 (2011): $338146
NEW PHYSICAL METHODOLOGIES FOR GENOMIC ANALYSIS
C David, Kellett Prof. Of Chem. & Gen.
University Of Wisconsin Madisoncity: Madison country: United States (us)
Grant 5R01HG000225-15 from National Human Genome Research Institute
Abstract: The broad, long term objectives of this proposal are to develop a high-throughput platform for single molecule analysis capable of acquiring large datasets for human genomic analysis commensurate with next generation sequencing. The research proposed aims to integrate robust devices for genome analysis with equally robust biochemical and detection schemes. This high-throughput system, "Nanocoding," will feature disposable devices offering "effective" nanoscale geometries within disposable devices sufficiently small for the presentation of large elongated genomic DNA molecules, for the advancement of whole genome studies as a means for analysis of populations and cancer genomes. The research plan proposes to create disposable silastic devices with nanoconfinement capabilities that closely parallel those found in sub-100 nm devices requiring traditional lithographic approaches. A new single molecule labeling scheme has been shown to introduce fluorochome label at specific sites on genomic DNAs - and offers distinct advantages for robust detection and integration within a system for genome analysis. The aims focus on presentation, decoration and visualization of single genomic DNA molecules, and potentiate a nanoslit device based on physical modification of large single DNA molecules. The Research Plan describes new developments enabling the Nanocoding system to complete a high-resolution scan in 1-7 days (projected) allowing comprehensive discovery of structural variation within a human genome. This analysis capacity will be extended through software developments for melding and complementing the short comings of next generation sequencing platforms, thus allowing more comprehensive discernment of structural polymorphisms and aberrations. Integration of experimental studies with computational and simulation approaches as well as associated bioinformatic approaches lend promise to make Nanocoding robust and applicable to genome-wide analysis across human populations and cancer samples. A new single molecule platform, Nanocoding, will be developed for cost-effective analysis of human populations for pinpointing genetic differences. Successful development and wide use of Nanocoding will identify a broad range of genetic differences that will span from entire chromosomes to regions smaller than a gene. These advances will foster large-scale human population studies that will power new drug discoveries, diagnostics, and perhaps, meaningful personal genomic profiles
Keywords: Algorithms; Bacterial Genome; base; Biochemical; Bioinformatics; cancer genome; Chromosomes; Complement; computer infrastructure; Computer Simulation; Computer software; cost effective; Cost Effectiveness Analysis; Data; Data Set; density; design; Detection; Development; Device Designs; Devices; Diagnostic; DNA; DNA Markers; DNA Restriction Enzymes; drug discovery; empowered; Ensure; Enzymes; Explosion; Fluorescence Resonance Energy Transfer; Fluorochrome; Fostering; Genes; Genetic; Genetic Polymorphism; Genome; genome-wide analysis; Genomics; Human; Human Genome; human population study; Image; Image Analysis; Imagery; Individual; Ionic Strengths; Label; Link; lithography; Malignant Neoplasms; Maps; Measurement; Methodology; Modification; Molecular; Names; nanoscale; next generation; Nucleotides; Optics; Physical Map of the Human Genome; physical mapping; Plant Genome; Population; Population Analysis; public health relevance; Publishing; Research; research study; Resolution; Sampling; scaffold; Scanning; Scheme; Series; Silastic; simulation; single molecule; Site; software development; Solutions; System; Techniques; tool; Translations; Variant; vertebrate genome; Visualization software; Work; YOYO-1
Relevance: A new single molecule platform, Nanocoding, will be developed for cost-effective analysis of human populations for pinpointing genetic differences. Successful development and wide use of Nanocoding will identify a broad range of genetic differences that will span from entire chromosomes to regions smaller than a gene. These advances will foster large-scale human population studies that will power new drug discoveries, diagnostics, and perhaps, meaningful personal genomic profiles
Project start date: 1991-01-01
Project end date: 2012-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01HG000225-15 (2011): $574635
GENOMIC STUDIES MAMMALIAN Y CHROMOSOMES
C David, Member/professor
Whitehead Institute For Biomedical Rescity: Cambridge country: United States (us)
Grant 3R01HG000257-21S1 from National Human Genome Research Institute
Abstract: The aims of this 5-year project are to (1) initiate and complete the sequencing of the Y chromosomes of five species - rhesus macaque, marmoset, rat, bull, and opossum, and (2) complete the sequencing of the chicken W chromosome (currently ~10% sequenced). NHGRI has approved the targeting of these five Y chromosomes and the chicken W chromosome for full-scale sequencing. The new Y chromosomes will be added to our queue of three current sex chromosome sequencing projects, the mouse Y and the chicken Z and W, which are in various stages of completion. Our goal is to complete the sequence and annotation of all 8 chromosomes by the end of the next 5-year funding period. During the last 18 years, genomic studies have revealed that Y chromosomes are biologically richer and medically more important than anyone would have predicted. These genomic studies recently culminated in the finished and annotated sequences of the human and chimpanzee Y chromosomes, which are, to date, the only sex-specific chromosomes to have been sequenced from any species, vertebrate or invertebrate, plant or animal. Knowledge of the human Y chromosome sequence has allowed researchers to identify and characterize recurrent Y deletions, which have emerged as the most common of the known causes of infertility in men. Comparative sequencing in chimpanzee has shed light on the functional importance of genes on the human Y chromosome. We suspect that the sex-specific chromosomes of six of NHGRI´s high-priority sequencing targets - rhesus, marmoset, rat, bull, opossum, and chicken - will also prove to be of great biomedical interest. The sequences of the new Y chromosomes will offer insight into the human Y chromosome´s role in health and disease and will provide essential infrastructure for elucidating mammalian and human germ cell development and sperm production. The chicken W chromosome will be the first female-specific chromosome to be sequenced from any species. We anticipate that the sequence of the W chromosome will inform our understanding of human biology by offering insights into female fertility, oogenesis, and sex determination. In recent decades, genomic studies in human, chimpanzee, and mouse have revealed that Y chromosomes are biologically richer and medically more important than anyone would have predicted. The Y chromosome sequences of five new species - rhesus macaque, marmoset, rat, bull, and opossum - will likely prove to be of great biomedical interest as well, offering insights into the human Y chromosome´s role in health and disease and providing the essential infrastructure for elucidating mammalian and human germ cell development and sperm production. The chicken W chromosome, as the female counterpart of the mammalian Y, will inform our understanding of human biology by offering insights into female fertility, oogenesis, and sex determination
Keywords: Animal Experimentation; Animal Model; Animals; autosome; Biological; Birds; Bos taurus; Callithrix; Callithrix jacchus jacchus; Chickens; Chromosomes; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 8; Chromosomes, Human, Y; Collaborations; college; comparative; Complementary DNA; Defect; Development; Didelphidae; Disease; Ensure; expectation; Female; Fertility; Funding; Genes; Genetic; Genome; genome sequencing; Genomics; Germ Cells; Goals; Grant; Health; Human; Human Biology; human male; Infertility; insight; interest; Invertebrates; Knowledge; Laboratories; Length; Light; Link; Macaca mulatta; male; Male Infertility; Malignant Neoplasms; Mammals; Maps; Medical; Medicine; member; men; Monodelphis Domestica; Morphology; Mus; National Human Genome Research Institute; Oogenesis; Pan Genus; Paper; Pattern; Plants; Play; Process; Production; public health relevance; Rattus; Rattus norvegicus; Recurrence; Reproduction; reproductive function; Research Infrastructure; Research Personnel; response; Rest; Role; Sequence Analysis; sex; Sex Chromosomes; sex determination; Shotguns; sperm cell; Spermatogenesis; Staging; Structure; System; Transcript; Turner`s Syndrome; Universities; Validation; Vertebrates; Washington; Whole-Genome Shotgun Sequencing; Work; X Chromosome; Y Chromosome
Relevance: In recent decades, genomic studies in human, chimpanzee, and mouse have revealed that Y chromosomes are biologically richer and medically more important than anyone would have predicted. The Y chromosome sequences of five new species - rhesus macaque, marmoset, rat, bull, and opossum - will likely prove to be of great biomedical interest as well, offering insights into the human Y chromosome´s role in health and disease and providing the essential infrastructure for elucidating mammalian and human germ cell development and sperm production. The chicken W chromosome, as the female counterpart of the mammalian Y, will inform our understanding of human biology by offering insights into female fertility, oogenesis, and sex determination
Project start date: 1991-01-01
Project end date: 2014-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
3R01HG000257-21S1 (2011): $450000
5R01HG000257-21 (2011): $1073820
LONGTERM TREATMENT EFFECTS ON JUVENILE JUSTICE GIRLS´ DEPRESSION AND SUICIDE RISK
C David, Assistant Professor
Oregon Social Learning Center, Inc.city: Eugene country: United States (us)
Grant 5R03MH091611-02 from National Institute Of Mental Health
Abstract: The aims of the proposed project address gaps in the evidence base concerning interventions with girls in the juvenile justice system (JJS). All aims focus on the extent to which a delinquency-focused intervention disrupts depressive symptoms and suicide risk trajectories in young adulthood for these high-risk females. Participants are 164 women who were involved in the JJS as adolescents. The women initially participated at ages 13-17 in a randomized controlled trial to test the effectiveness of Multidimensional Treatment Foster Care (MTFC, Chamberlain, 2003) versus treatment as usual (TAU) at reducing delinquency and drug abuse. Delinquency, depressive symptoms, and suicidal thoughts were measured four times across the original 2-year follow-up period. A study is currently underway (R01 DA024672 February 2009-December 2012) in which in- person and telephone assessments of these women will be conducted across multiple 6-month intervals in young adulthood (18-28 years). The aims of this R01, however, do not address the course of depressive symptoms or suicide risk among these high-risk women. In the present application, we capitalize on rich existing longitudinal data and the active assessment phase in the R01 study to propose a new focus on the effects of MTFC on these problems. Specifically, we propose to 1) conduct a lifetime assessment of the number and timing of suicide attempts; and 2) augment R01 assessments planned at 6-month intervals to include self-reported suicidal thoughts and behaviors. Two of these assessments will occur prior to the proposed study, and will be supported with limited internal resources; we request funding for three additional measurement occasions (at 6-month intervals), for a total of five assessments in young adulthood. Using existing and proposed data collection, we will pursue three aims that estimate MTFC effects on depressive symptoms and suicide risk in young adulthood, and specify three key mechanisms of indirect effects. In Aim 1, we will use latent growth modeling to characterize the course of depressive symptoms across 9 time points in adolescence and young adulthood, and then to test intervention effects; girls randomly assigned to MTFC are expected to show decreases in depressive symptoms over time relative to girls assigned to TAU. Aim 2 tests whether changes in three domains already demonstrated to be impacted by MTFC (Chamberlain et al., 2007; Leve et al., 2007) mediate effects of the intervention on changes in depressive symptoms; specifically, MTFC is expected to reduce depressive symptoms through early adulthood via decreased delinquency and teenage pregnancy/child-bearing, and educational attainment. Aim 3 tests the effects of MTFC on suicide attempts and whether such effects are mediated by intervention-related reductions in delinquency and depressive symptoms. Findings will suggest directions for development and augmentation of interventions for JJS girls. Thus, the proposed study answers calls for innovative approaches to reaching high risk youth who do not benefit from existing depression prevention paradigms (Avenevoli et al., 2006). Adolescent girls with serious conduct problems are at high risk for depression and suicide. Yet, effective treatments for these problems in this group are lacking. We examine whether a delinquency-focused intervention for girls in the juvenile justice system will reduce depressive symptoms and rates of suicide attempt into young adulthood via changes in delinquency, teen pregnancy rates, and educational attainment
Keywords: Accounting; Address; Adolescence; Adolescent; Age; boys; Child; community setting; Data; Data Collection; Depression and Suicide; depressive symptoms; Development; Developmental Process; deviant; Drug abuse; effective therapy; Effectiveness; emerging adult; evidence base; Feeling suicidal; Female; Female Adolescents; follow-up; foster care; Funding; girls; Growth; high risk; High Risk Woman; innovation; Intercept; Intervention; intervention effect; intervention program; Interview; Justice; juvenile justice system; Measurement; Measures; Mediating; Mediation; Mental Depression; Modeling; National Institute of Mental Health (U.S.); Parents; Participant; Pathway interactions; Patient Self-Report; peer; Persons; Phase; Population; Pregnancy; Pregnancy in Adolescence; Pregnancy Rate; prevent; Prevention; Probability; programs; Psychopathology; psychosocial; public health relevance; Randomized; Randomized Controlled Trials; Recording of previous events; Recurrence; Relative (related person); Research Project Grants; Resources; Risk; Sampling; Schools; Specific qualifier value; suicidal behavior; suicidal risk; Suicide attempt; Telephone; Testing; Time; To specify; treatment as usual; treatment effect; United States National Institutes of Health; Woman; young adult; Youth
Relevance: Adolescent girls with serious conduct problems are at high risk for depression and suicide. Yet, effective treatments for these problems in this group are lacking. We examine whether a delinquency-focused intervention for girls in the juvenile justice system will reduce depressive symptoms and rates of suicide attempt into young adulthood via changes in delinquency, teen pregnancy rates, and educational attainment
Project start date: 2010-07-06
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-09-163
5R03MH091611-02 (2011): $69597
INFLUENCE OF PSYCHOSIS ON BRAIN-BEHAVIOR ENDOPHENOTYPES FOR BIPOLAR DISORDER
C David, Associate Professor
Yale Universitycity: New Haven country: United States (us)
Grant 5R01MH080912-04 from National Institute Of Mental Health
Abstract: The aims in this study will (1) develop candidate neurocognitive and neuroimaging endophenotypes for bipolar I disorder (BPI), (2) examine the association of history of psychosis and these brain-behavior markers in BPI patients, and (3) determine if markers are sensitive to liability for psychosis. Thus, the project has two overlapping goals the development of candidate endophenotypes for BPI broadly and the identification of candidate endophenotypes for psychosis. The ultimate promise of this research is to develop markers that will characterize the biological mechanisms of BPI and facilitate the discovery of genes that predispose the illness. We believe that a comprehensive assessment of neuropsychological functioning and brain structure and function in sibling pairs discordant for bipolar disorder and stratified for psychosis history is a strategically strong first step towards reaching these goals. To this end, we will perform anatomic and functional neuroimaging and conduct neuropsychological examinations on 130 euthymic patients with BPI (65 with history of psychosis), 130 of their unaffected same-sex siblings and 65 unrelated comparison subjects. Markers found to be aberrant in both affected individuals (regardless of history of psychosis) and in their unaffected relatives will be considered candidate endophenotypes for BPI (Aim 1). Neuropsychological and neuroimaging measures that distinguish between BPI patients with and without history of psychosis (Aim 2) and their siblings (Aim 3) will be considered potential endophenotypes for psychosis. Bipolar I disorder represents a significant economic burden and is associated with substantial morbidity and mortality rates. Although it is well established that BPI is substantially heritable, the molecular genetic basis for this illness remains elusive, potentially because of illness complexity, heterogeneity of disease expression, and comorbidity with other disorders that may distort clinical presentation. In the face of evidence that genes predisposing to BPI may be transmitted without expression of the clinical phenotype, interest has arisen in developing endophenotypes for the illness, indicators of processes mediating between genotype and phenotype. Given the high rates of psychosis in BPI and that history of psychosis may alter brain structure and function, we believe that elucidating neurocognitive and neuroimaging endophenotypes for the disorder must account for the potential impact of hallucinations and delusions on these markers. This research will established biomarkers that could improve the identification and treatment of BPI patients and, potentially, patients with psychotic disorders, independent of their formal diagnosis. Bipolar I disorder is a major public health burden whose biology is still largely unknown. Through the development of brain-behavior markers sensitive to genetic liability for bipolar disorder, the proposed research should significantly aid the discovery of genes that predispose the illness and facilitate the identification of the biological determinants of bipolar disorder. This, in turn, should lead to improved characterization and treatment of bipolar disorder
Keywords: abuse of substances; Accounting; Adoption; Affect; affection; Affective Disorders, Psychotic; Affective Psychosis, Bipolar; Amygdala; Amygdaloid Body; amygdaloid nuclear complex; Amygdaloid Nucleus; Amygdaloid structure; Anatomic; Anatomical Sciences; anatomy; Anatomy; Anterior; Antipsychotic Agents; Antipsychotic Drugs; Antipsychotics; base; Biological; Biology; biomarker; bipolar affective disorder; Bipolar Disorder; Brain; brain behavior; candidate identification; Causality; Characteristics; Clinical; clinical phenotype; Comorbidity; Data; Defect; Delusions; density; Development; Diagnosis; Diagnostic; Disease; disease causation; disease etiology; Disease remission; disease/disorder; disease/disorder etiology; Disorder; disorder etiology; drug/agent; Drugs; Dysfunction; Economic Burden; Emotional; Emotions; Encephalon; Encephalons; endophenotype; Etiology; Evaluation; Family; First Degree Relative; fMRI; Functional disorder; Functional Magnetic Resonance Imaging; gene discovery; Genes; Genetic; genetic pedigree; Genotype; Goals; gray matter; Hallucinations; Health; heavy metal lead; heavy metal Pb; Heterogeneity; History; improved; Individual; interest; IQ Deficit; Lateral; Lead; Link; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Magnetic Resonance Imaging, Functional; Major Tranquilizers; Manias; Manic; manic depressive disorder; manic depressive illness; Manic State; Measures; Mediating; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Medication; Memory; Memory, Immediate; Memory, Short-Term; Memory, Shortterm; millimeter; Molecular Genetic; Molecular Genetics; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; MR Imaging; MR Tomography; MRI; MRI, Functional; Nervous; Nervous System; Nervous system structure; Nervous System, Brain; neural; Neurocognition; Neurocognitive; Neurocognitive Deficit; neuroimaging; Neuroleptic Agents; Neuroleptic Drugs; Neuroleptics; Neurologic Body System; Neurologic Organ System; neurophysiology; neuropsychological; NMR Imaging; NMR Tomography; NRVS-SYS; Nuclear Magnetic Resonance Imaging; Participant; pathophysiology; Patients; Pb element; Pedigree; pedigree structure; Performance; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Physiopathology; predisposing gene; Predisposition gene; proband; Process; Psychoses; Psychoses, Affective; Psychosis, Manic-Depressive; psychosocial; Psychotic Affective Disorders; Psychotic Disorders; Public Health; public health medicine (field); QTL; Quantitative Trait Loci; Recording of previous events; recruit; Recruitment Activity; relating to nervous system; Relative; Relative (related person); Remission; Research; Resolution; Risk; RMSN; Science of Anatomy; Science of neurophysiology; sex; Short-Term Memory; Siblings; Structure; substance abuse; Substance abuse problem; substantia grisea; Susceptibility Gene; Symptoms; Testing; Tranquilizing Agents, Major; treatment response; Twin Multiple Birth; Twins; Ventral Striatum; Work; working memory; Zeugmatography
Project start date: 2008-05-01
Project end date: 2013-01-31
Budget start date: 11-MAR-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-070
5R01MH080912-04 (2011): $488451
Sponsored Links Excellgen http://Excellgen.com
SINGLE MOLECULE FIBER ARRAYS FOR THE DETECTION OF LOW ABUNDANCE PROTEINS
C David, Vice President, Research
Twin Lights Bioscience, Inc.city: Cambridge country: United States (us)
Grant 5R44CA133987-04 from National Cancer Institute
Abstract: The aim of this project is to develop a new technology that can be used to detect very low concentrations (femtomolar and below) of proteins that are diagnostic for cancer. Presently, early diagnosis of cancer is limited by the fact that the limits of detections (LOD) of available technologies, such as ELISA, are higher than the circulating concentrations of low abundance proteins that could indicate the onset of disease. This program would broaden and strengthen the use a novel fiber optic array single molecule detection technology for extremely high sensitivity measurement of cancer markers. This technology is digital in nature, i.e., individual molecules are quantified by their presence ("on" signal) or their absence ("off" signal). By focusing detection at the single molecule level, dramatic improvements in sensitivity are achieved for proteins. Phase I of this project demonstrated that single molecule detection makes it possible to detect concentrations of proteins at levels a thousand times lower than ELISA. Using single molecule detection, prostate specific antigen (PSA) was detected in serum at concentrations less than 1 femtomolar; current immunoanalyzers have an LOD of about 3 picomolar for PSA. The Phase II project has three specific aims that would build on these proof-of-principal experiments to broaden and strengthen the use of the technique for detection of cancer protein markers, and to move the technology closer to commercialization for use by medical researchers and clinicians. First, the ultra-sensitive PSA assay will be used to detect the marker in human clinical samples, specifically to measure the levels of PSA in prostate cancer patients who have undergone radical prostatectomy. Current technologies cannot detect PSA in these samples; this technology could enable the early detection of the return of PSA in serum, which would indicate residual disease. Second, the technology will be expanded to cover more classes of proteins, such as fusion proteins and post-translational modifications, to enable its broader implementation. Third, methods will be developed to measure panels of proteins at low concentrations using small sample volumes. These panels would enable the diagnosis of difficulty to detect diseases, such as ovarian cancer, with greater sensitivity and specificity. The long term objective of this research is to establish a new standard in high sensitivity detection of biological molecules (proteins, peptides, RNA, cells) using instrumentation that would be widely employed in both academic and clinical laboratories. Such an innovation would enable researchers to detect cancer markers at unprecedented levels for early diagnostic applications, and would facilitate the discovery of new low abundance cancer markers. This long term goal satisfies several aspects of the mission of the NIH, in particular, to develop innovative research strategies towards improving the diagnosis, prevention and cure of human diseases. The early diagnosis of cancer is determined by the ability of the clinical oncologist to detect the disease. Quanterix is proposing to develop a technology that would enable clinicians to detect very low concentrations of proteins in blood and, therefore, enable the early diagnosis of disease. This technology has the potential to help medical researchers and doctors to identify and detect many more early cancer diagnostic markers and improve outcomes for patients
Keywords: Area; base; Biological; Biological Assay; Biological Models; biomarker; Blood; Cancer Detection; cancer diagnosis; Cancer Diagnostics; Cancer Patient; Cells; Chimeric Proteins; Clinical; commercialization; Complex; Computer software; Detection; Diagnosis; Diagnostic; digital; Disease; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Fiber; Fiber Optics; Goals; Human; human disease; Immunoassay; improved; Individual; innovation; instrument; instrumentation; Laboratories; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Malignant Neoplasms; Measurement; Measures; Medical; meetings; Methods; Mission; Molecular; Nature; new technology; next generation; novel; Oncologist; Onset of illness; Operative Surgical Procedures; Outcome; Patients; Peptides; Phase; Post-Translational Protein Processing; Prevention; programs; Prostate specific antigen measurement; Prostate-Specific Antigen; protein complex; protein profiling; Proteins; prototype; Radical Prostatectomy; Reading; Reagent; Reproducibility; Research; Research Personnel; research study; Residual Tumors; RNA; Sampling; Sensitivity and Specificity; Serum; Signal Transduction; single molecule; small molecule; Techniques; Technology; Time; TimeLine; Translating; United States National Institutes of Health
Project start date: 2008-08-01
Project end date: 2013-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: RFA-CA-08-011
5R44CA133987-04 (2011): $743891
2R44CA133987-03 (2010): $749935
IMAGING AND FUNCTION OF THE IMMUNOLOGICAL SYNAPSE
C David, Professor
Oregon Health And Science Universitycity: Portland country: United States (us)
Grant 5R01AI050823-09 from National Institute Of Allergy And Infectious Diseases
Abstract: T lymphocytes recognize antigen as small peptides bound to MHC molecules on the surface of antigen presenting cells (APC). In addition to the T cell antigen receptor and peptide-loaded MHC, dozens of other cell surface molecules play necessary or modulating roles in determining the outcome of the T cell/APC interaction. Antigen recognition is accompanied by large-scale, cytoskeleton-dependent rearrangements of these molecules to form an organized contact interface between the T cell and the APC termed the "immunological synapse". Many laboratories are investigating the ways in which the synapse may provide or regulate the signals necessary for full T cell activation. In this grant application, the focus is on the role of the immunological synapse in the delivery of effector functions from CD4 T cells to APC, using FasL (CD178) and CD40L (CD154) as prototypes of membrane-bound effector cytokines. Since most interactions in vivo may be too short to allow for de novo synthesis of effector cytokines, the proposed experiments examine the possibility that preformed, intracellular stores of FasL and CD40L play important roles in T cell/APC interactions. CD40L was first identified as the mediator of cell contact-dependent CD4 T cell help for B cells, and has since been shown to be a potent activator of macrophages for killing of intracellular pathogens of dendritic cells for priming effector functions and memory in CD4 and CD8 T cells. FasL is a principal mediator of contact-dependent killing by CD4 and CD8 T cells, and regulates T cell responses through T cell suicide or fratricide during activation-induced cell death. Using a combination of state-of-the-art microscopy and functional assays in vitro and in vivo, this proposal will test the hypothesis that pre-formed CD40L and FasL are stored in secretory lysosomes in most primed CD4 effector and memory T cells, are delivered rapidly through the immunological synapse to B cells and other APC in transient antigen-specific interactions, and have important functional consequences distinct from those of newly synthesized CD40L and FasL. It will also investigate structural difference between synapses formed by type 1 and type 2 helper T cells, and test the hypothesis that the function of the ring of adhesion molecules in the mature immunological synapse formed by CD4 T cells is to ensure antigen-specific delivery of effector molecules to the APC and prevent delivery to surrounding bystander cells. T lymphocytes recognize antigen only on the surface of other cells, called antigen presenting cells (APC), and exert their effects by secreting potent cytokines and other effector molecules. The goal of this application is to understand how various kinds of CD4 T cells deliver effector cytokines to APC. The application is focused on FasL (CD178) and CD40L (CD154), key membrane-bound cytokines which control the adaptive immune response in health and disease. The proposed experiments will contribute to a basic understanding of the regulation CD4 T cell effector functions, which in turn will have public health-related applications in transplantation, autoimmunity, allergy, cancer immunotherapy, and control of infectious diseases
Keywords: accessory cell; Adhesion Molecule; Adhesions; Affect; Allergy; Antigen-Presenting Cells; Antigens; APC; Applications Grants; APT1LG1; ATGN; Atrophic Arthritis; Autoimmune Diseases; autoimmune disorder; Autoimmune Status; Autoimmunity; Avidity; B blood cells; B-Cells; B-Lymphocytes; balance; balance function; Binding; Binding (Molecular Function); biological signal transduction; Bursa-Dependent Lymphocytes; Bursa-Equivalent Lymphocyte; cancer immunotherapy; CD154; CD178; CD4 Antigen (P55); CD4 Antigens; CD4 lymphocyte; CD4 Molecule; CD4 Positive T Lymphocytes; CD4 Protein; CD4 T cells; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CD40L; CD40LG; CD54 (ICAM 1); CD54 Antigens; CD8; CD8B; CD8B1; CD8B1 gene; CD95L; Cell Adhesion Molecules; cell adhesion protein; Cell Communication; Cell Communication and Signaling; Cell Death; Cell Interaction; Cell Signaling; cell suicide; Cell surface; Cell Surface Antigens; Cell-Mediated Lympholytic Cells; Cell-to-Cell Interaction; Cells; Cells, CD4; Cellular Matrix; cellular suicide; Characteristics; Chronic; Communicable Diseases; CTL; cytokine; Cytolytic T-Cell; Cytoskeletal System; Cytoskeleton; Cytotoxic T Cell; Cytotoxic T-Lymphocytes; Dendritic Cells; DIF; Disease; disease/disorder; Disorder; DNA Sequence Rearrangement; Ensure; Equilibrium; experience; experiment; experimental research; experimental study; Eye; Eyeball; Family; FASL; gene product; Gene Transcription; Genetic Transcription; Glycoprotein ICAM 1 (human clone pHRVr1 deblocked protein moiety reduced); Goals; Grant Proposals; Grants, Applications; Health; Helper Cells; helper T cell; helper T lymphocyte marker; Helper T-Cells; Helper-Inducer T-Lymphocyte; host response; Hypersensitivity; ICAM-1; Image; imaging; Immune response; Immuno-Chemotherapy; Immunochemotherapy; immunogen; Immunologic Accessory Cells; immunological synapse; immunoresponse; Immunotherapy, Cancer, General; in vitro Assay; in vivo; Inducer Cells; Infectious Disease Pathway; Infectious Diseases; Infectious Diseases and Manifestations; Infectious Disorder; Inflammatory; Inflammatory Arthritis; Inflammatory Bowel Diseases; Inflammatory Bowel Disorder; Inflammatory Intestinal Disease; Inflammatory Intestinal Disorder; insular sclerosis; Intercellular adhesion molecule 1; Intracellular Communication and Signaling; intracellular skeleton; Killings; Knock-out; Knockout; Laboratories; Licensing; Lupus; Lysosomes; LYT3; macrophage; Major Histocompatibility Complex Receptor; Mediating; Mediator; Mediator of Activation; Mediator of activation protein; member; Membrane; membrane structure; Memory; memory CD4 T cell; memory CD4 T lymphocyte; memory T lymphocyte; Messenger RNA; MHC Receptor; Microscopy; Molecular Interaction; Monocytes / Macrophages / APC; mRNA; MS (Multiple Sclerosis); Multiple Sclerosis; necrocytosis; OKT4 antigen; Outcome; pathogen; Pattern; Peptides; Play; prevent; preventing; Property; Property, LOINC Axis 2; Proteins; prototype; Public Health; public health medicine (field); public health relevance; Rearrangement; Receptors, Antigen, T-Cell; Receptors, CD4; Receptors, Surface CD4; Regulation; research study; response; Rheumatoid Arthritis; RNA Expression; RNA, Messenger; Role; Sclerosis, Disseminated; Secretory Granules; Secretory Vesicles; self recognition (immune); Shapes; Signal Transduction; Signal Transduction Systems; Signaling; site targeted delivery; social role; Structure; Surface; Surface Antigens; Surface Markers, Immunologic; Surface Markers, Immunological; Synapses; Synaptic; T cell response; T memory cell; T-Cell Activation; T-Cell Antigen T4/Leu3; T-Cell Receptor; T-Cell Subsets; T-Cell Surface Antigen T4/Leu-3; T-Cells; T-Cells, Helper-Inducer; T-Lymphocyte; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Helper; T-Lymphocytes, Inducer; T4 Cells; T4 Lymphocytes; T4 molecule; targeted delivery; Testing; Th-2 Cell; Th2 Cells; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; Time; TNF; TNF A; TNF gene; TNFSF2; TNFSF5; TNFSF5 gene; TNFSF6; TNFSF6 gene; Transcription; Transcription, Genetic; transplant; Transplantation; TRAP Gene; Tumor Necrosis Factor Gene; two-photon; Type 2 Helper Cell; Veiled Cells; VESCL; Vesicle
Project start date: 2001-12-01
Project end date: 2013-02-28
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: PA-07-070
5R01AI050823-09 (2011): $271582
MOLECULAR AND GENETIC ANALYSIS OF LUNG CANCER SURVIVAL
C David, Professor
Harvard University (sch Of Public Hlth)city: Boston country: United States (us)
Grant 5R01CA092824-09 from National Cancer Institute
Abstract: Survival outcomes for lung cancer, the leading cause of cancer-related mortality in the United States, remain poor. Improving lung cancer survival requires a multi-pronged approach, including smoking cessation and better elucidation of gene-environment interactions in risk, identification of new promising drug targets, as well as identification of potential prognostic and predictive markers that optimize treatment for patients. Our molecular epidemiology group has investigated the role of candidate germline polymorphisms and survival in lung cancer since the 2002 initiation of this study, and we have made significant contributions to understanding genetic and other markers of NSCLC survival. In this competing renewal, we will employ high- density genome-wide genotyping and epidemiologic approaches to identify better prognostic and predictive genetic markers of NSCLC survival. The ultimate goal of identifying such markers is to find ways to select the best treatment course for each individual patient. While the candidate approach has the strength of being based in biologic hypotheses, there are limitations to such an approach. A new approach is to use genome wide scans that capitalize on advances in high-throughput technology and in completion of projects such as the HapMap project, to allow for assessment of the human genome. In this renewal, we will take advantage of the large collection of clinical, epidemiologic and over 3,000 biospecimens and clinical data from the parent project begun in 1992. For gene discovery, we will use the new Illumina 610 Quad platform for a genome-wide approach to genotyping of SNPs. Once we have identified high priority SNPs, we will seek to replicate these findings in our larger case-cohort, as well as in separate external validation sets from 4 collaborating centers. Although our primary endpoint will be overall survival (OS), we will also assess disease-free survival (DFS) and progression- free survival (PFS), where appropriate. In Phase 1, we will use the new Illumina 610 Quad (610,000 SNP´s and 60,000 Copy Number Variants) among 1000 lung cancer cases in the parent study, to identify the most promising SNPs that show evidence of association with lung cancer survival. In Phase 2, the top 3,000 SNPs will be selected from this discovery phase for further validation/replication in the remainder of patients. Then, in Phase III, we will assess the top 100 SNP´s (50 each for early and late stages) in 3 external case cohorts with a minimum of 5 year follow-up information MD Anderson, U. of Toronto, Mayo Clinic. To extend our findings to another case-cohort of different ethnicity, and maximize the capture of relevant SNP´s, we will perform Phase 2 (2 Golden Gate 1536 SNP arrays) and Phase 3 (top 100 SNP´s; 50 for early and 50 for late stage) in a Chinese case cohort in Nanjing, China. Finally, we will conduct exploratory functional assays to assess variants effects on gene expression in the final set of replicated candidates. This will be the largest and most complete genetic analysis of NSCLC to date, and will move the field significantly towards to goal of more effective, personalized therapy for NSCLC patients. Survival outcomes for lung cancer, the leading cause of cancer-related mortality in the United States, remain poor, and genetic determinants of survival are not well-defined. The proposed molecular epidemiologic study will employ genome- wide scanning approaches, with multiple replicates, to identify better prognostic and predictive genetic markers of NSCLC survival. The ultimate goal of identifying such markers is to find ways to select the best treatment course for each individual
Keywords: Age; base; Bioinformatics; Biological Assay; Biological Process; Cancer Etiology; Cancer Patient; Caucasians; Caucasoid Race; chemotherapy; China; Chinese People; Clinic; Clinical; Clinical Data; cohort; Cohort Analysis; Collection; Copy Number Polymorphism; Data; density; Disease; Disease-Free Survival; Drug Delivery Systems; Drug or chemical Tissue Distribution; Epidemiologic Studies; Epidemiology; Ethnicity aspects; Evaluation; Excision; follow-up; Gender; gene discovery; gene environment interaction; Gene Expression; Genes; genetic analysis; Genetic Determinism; genetic epidemiology; Genetic Markers; Genetic Polymorphism; Genome; genome wide association study; genome-wide; Genotype; Goals; Health; high throughput technology; Histology; Human Genome; improved; Individual; Introns; Location; Malignant neoplasm of lung; Malignant Neoplasms; Modeling; Molecular; Molecular Analysis; Molecular Epidemiology; Mortality Vital Statistics; Non-Small-Cell Lung Carcinoma; novel strategies; Operative Surgical Procedures; Other Genetics; Outcome; parent project; Parents; Pathogenesis; Patients; Phase; Population; Predictive Factor; Predisposition; Principal Investigator; prognostic; Prognostic Factor; Prognostic Marker; Progression-Free Survivals; Promoter Regions (Genetics); protein aminoacid sequence; protein function; Radiosurgery; Relative (related person); Risk; Role; Screening procedure; Single Nucleotide Polymorphism; Smoking; smoking cessation; Staging; Testing; Time; United States; Validation; Variant
Relevance: Survival outcomes for lung cancer, the leading cause of cancer-related mortality in the United States, remain poor, and genetic determinants of survival are not well-defined. The proposed molecular epidemiologic study will employ genome- wide scanning approaches, with multiple replicates, to identify better prognostic and predictive genetic markers of NSCLC survival. The ultimate goal of identifying such markers is to find ways to select the best treatment course for each individual
Project start date: 2001-07-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01CA092824-09 (2011): $566437
TOWARD A COMPLETE GENETIC DESCRIPTION OF THE YEAST ACTIN CYTOSKELETON
C David
Upstate Medical Universitycity: Syracuse country: United States (us)
Grant 5R01GM074992-04 from National Institute Of General Medical Sciences
Abstract: S. cerevsiae has served as a proving ground for new genomics technologies, application of these technologies and the development of the bioinformatics tools required to analyze these datasets. In addition, focused biological investigations by a large research community has resulted detailed understandings of how individual genes contribute to basic cellular functions. We propose to harness the genetic power of yeast to unify existing knowledge with the functions of the actin cytoskeleton, a major integrator of cellular systems. Actin filaments are constructed of a single protein but diversity in actin function is mediated by a large battery of accessory proteins. Investigations on the yeast actin cytoskeleton have led to the development of powerful tools and reagents to study how interactions with the actin cytoskeleton contribute to its regulation and utilization by cellular systems, but many of these tools and reagents have not been utilized to their fullest extent to realize a complete picture of the yeast actin cytoskeleton or the cellular systems it affects. Notable among these reagents is a large collection of mutants in the single essential actin gene ACT1 that were specifically designed to disrupt protein-protein interactions. We propose to use these reagents and the power of yeast genetics and genomics to uncover a complete or at least nearly complete genetic of those genes that impact, or whose functions are impacted by, the actin cytoskeleton. Complex haploinsufficiency screens will be performed with a null allele of actin against the entire ordered array of yeast gene knock-outs to try and uncover genes sensitive to reductions in actin stoichiometry. This sub- network of genes will then be retested against the large collection of mutant actin alleles to determine which of the genetic interactions can be attributed to reductions in subsets of actin functions. To complete the "actin interactome", this analysis will be complemented by synthetic lethal screening with the set of viable actin alanine scan mutants. All interactions will be correlated back to the loss or reduction in specific subsets of actin functions as defined by the actin mutants. To bring further coherence to the data, genes of the actin interactome will also be examined for genetic interactions with the genes for all known actin-binding proteins. Analysis of this highly integrated data set will be used to arrange both the actin alleles and their interacting genes into groups that we hypothesize will reflect shared defects such as the loss of binding between actin and specific actin binding proteins. Bayesian data integration with other datasets will be used for function prediction and to uncover novel relationships between gene sets and cluster analysis will be used to correlate these patterns back to the structure of actin. Visualization of the network will be facilitated by the development of a three-dimensional version of the network display tool Osprey that will connect nodes of the network back to the structure of actin. All data and data analysis resulting from this proposal will be maintained in a free access, Web-based format within the Toronto GRID database, the SGD, and PIXIE.Princeton.edu
Keywords: Actin-Binding Protein; Actins; Affect; Alanine; Alleles; Back; base; Binding (Molecular Function); Binding Sites; Biochemical; Bioinformatics; Biological; Biological Process; Categories; Cell physiology; Cells; Cluster Analysis; Collection; Communities; Complement; Complex; computer based statistical methods; Cytoskeletal Filaments; Cytoskeleton; Data; Data Analyses; data integration; data mining; Data Set; Databases; Defect; design; Development; Diploidy; Essential Genes; Eukaryotic Cell; functional group; Gene Deletion; gene function; Genes; Genetic; genetic analysis; Genetic Screening; Genetic Structures; Genome; genome database; Genomics; Growth; Hereditary Disease; Housing; human disease; Human Genetics; Imagery; Individual; insight; interest; Investigation; Knock-out; Knowledge; Link; loss of function mutation; Malignant Neoplasms; Maps; Mediating; Methods; Microfilaments; Modeling; mutant; Nature; novel; Online Systems; Organism; Other Genetics; Pattern; Phenocopy; Phenotype; Prevalence; programs; protein protein interaction; Proteins; Reagent; Regulation; Research; Research Personnel; Saccharomyces; Saccharomyces cerevisiae; Scanning; Screening procedure; Site; spatial relationship; stoichiometry; Structure; Surface; System; Systems Biology; Technology; technology development; Testing; three dimensional structure; tool; web-accessible; yeast genetics; Yeasts
Project start date: 2007-02-01
Project end date: 2012-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2012
5R01GM074992-04 (2010): $370640
CHARACTERIZATION OF A NOVEL INVASION-RELATED GENE IN GLIOBLASTOMA
C David, Assist Professor
Durham Va Medical Centercity: Durham country: United States (us)
Abstract: Project Summary Glioblastoma multiforme, the most malignant grade of glioma, represents up to 30% of all primary brain tumors in veterans. Although advances in surgical techniques have allowed removal of up to 99% of the visible tumor; the tumor always recurs due to aggressive tumor cell growth beyond the primary tumor focus or margin. The understanding of the molecular events that underly the dispersion of the cells of these tumors would have enormous clinical potential and impact on this universally fatal disease. Recently, using a state-of-the-art technologies, e.g. digital karyotyping, we mapped the genomic landscape of primary GBM tumors at a high resolution and identified the isolated loss of expression of the Adherens Junctional Associated Protein 1 (AJAP1) gene, located on chromosome 1p36.32, as a frequent molecular event in GBMs. Our goal in this proposal is to explore the clinical implications of the loss of expression of AJAP1 in a large set of GBM primary tumors, to gain insights into the mechanisms underlying its loss, to understand its role in tumor cell dispersion, and to explore the mechanisms by which it modulates tumor cell migratory activity. The rationale for these studies derive from the following observations 1) AJAP1 is located in a hotspot region on chromosome 1p36.3 that is frequently lost in GBM, 2) AJAP1 encodes for a key transmembrane protein involved in formation of a protein complex that plays an important role in cell-cell and cell-extracellular matrix interactions, 3) in preliminary studies, we demonstrated loss of AJAP1 expression in up to 25% of primary GBM tumors, 4) using several GBM cell lines, we provided preliminary evidence that hypermethylation may be an important mechanism underlying the loss of AJAP1 expression in GBM cells, 5) we observed a significant correlation between AJAP1 loss and poor survival in GBM patients, and 6) our preliminary data showed that loss of AJAP1 expression increases tumor cell migration, and its reconstituion decreases tumor cell invasiveness. Based on these critical observations, we hypothesize that AJAP1 functions as a novel dispersion-associated cell membrane protein in GBM cells and that loss or downregulation of its expression increases the migratory potential of these tumor cells and contributes to the aggressive clinical behavior of GBM. Specific aim #1 will characterize mechanisms of loss of AJAP1 expression in a large number of primary GBMs with linked clinical data. Specific aim #2 will characterize the modulation of AJAP1 expression on the migratory activity of GBM cells in vitro and in vivo. Specific aim #3 will characterize the molecular mechanism(s) underlying the effects of AJAP1 loss on tumor cell migration in GBM. We believe that the results of these studies will facilitate the development of molecular-based therapies that target mechanisms of tumor cell migration in GBM and could provide novel adjunctive therapeutic modalities to surgery. Over the past decade, more than 150,000 veterans were diagnosed with a brain tumor. The most common primary brain tumor was GBM. GBM patients die within about 1 year, even with the most aggressive medical care known to mankind. Any therapeutic breakthrough will restore years of human life and decrease millions of dollars in healthcare expenditures. Molecular-based, gene pathway specific cancer therapies are becoming an increasing reality and will be necessary for curing GBM. We have identified a potential novel dispersion-related gene for GBM that plays a critical role in the high migratory and invasive nature of GBM tumor cells
Project start date: 2011-07-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: RFA-BX-10-001
1I01BX000974-01 (2011): $0
DIRECT INTEGRATION OF CORTICAL ELECTRODES BY CONDUCTING POLYMERS DEPOSITED IN-VIV
C David, Professor And Chair
University Of Delawarecity: Newark country: United States (us)
Grant 5R01EB010892-02 from National Institute Of Biomedical Imaging And Bioengineering
Abstract: Project Summary / - Perhaps the most important problem limiting the performance and utility of electronic biomedical devices that are implanted in tissue is the reactive response near the electrode that limits performance over extended periods of time. In the cortex, this is known to involve the activation of microglia and astrocytes, and the associated die-off of target cells (neurons) in a region of ~100 microns proximal to the probe surface. Strategies to overcome this problem have included the use of anti-inflammatory agents and neurotrophic factors. However, it is not clear that inflammatory agents will work over the long term. Attracting the neurons to the electrode is also a strategy that may not work well, since the inorganic electrode surface represents an interface between the hard metallic or semiconducting engineered device and the much softer organic tissue, and is thus inevitably a mechanically unstable environment that is dangerous for cell viability. It would therefore be useful if there were some alternative means to create nanoscale, electronically active filaments that were an extension of the metal electrodes, providing an efficient means of communication across the reactive scar and out into the surrounding tissue. Here we propose a method that may accomplish this by the direct, in- vivo polymerization of conducting polymers such as poly(3,4-ethylenedioxythiophene) (PEDOT). PEDOT is a conjugated polymer that is effective at facilitating charge transport between metallic electrodes and ionically conductive tissue. In previous work in our laboratory, we have shown that PEDOT coatings can help to improve the performance of biomedical devices such as microfabricated cortical probes in vivo. We have also demonstrated that PEDOT can be electrochemically polymerized around living cells both in-vitro and in-vivo. In slice cultures, we have shown that PEDOT can be grown out and into cortical tissue for 1000 microns or more, much larger than the ~100 micron size typical of the reactive cell layer. However many questions remain about the detailed methods of polymerization, including monomer delivery rates, influence of healing, and the viability and remodeling of cells in the polymerization zone. In this project we will investigate the in-vivo polymerization of PEDOT into living tissue, and will evaluate its impact on the performance of the biomedical devices of interest. We will investigate the role of wound healing around the probe on the subsequent polymerization and associated cell physiology in the reactive zone by waiting for different periods of time before initiating the reaction. We will focus our attention on microfabricated cortical electrodes of interest to the Center for Neural Communications Technology at the University of Michigan, directed by Daryl Kipke. This method has the potential to revolutionize the performance of a wide variety of implantable electronic biomedical devices including cortical probes, retinal implants, deep brain stimulators, and cardiac pacemakers. If this novel research eventually proves to be successful, there is considerable potential to move these methods from the laboratory to further development. Certain aspects of this work are related to inventions disclosed to the University of Michigan Technology Transfer Office, and under commercial development by Biotectix LLC, a spin-off company. Prof. Martin is a Co- Founder and Chief Scientific Officer for Biotectix LLC (www.biotectix.com). This project describes the design and evaluation of materials and methods for improving the integration of hard, inert, electronic biomedical devices with soft, ionically- conducting living cortical tissue via the direct polymerization of conducting polymers. These methods may help improve the long-term performance of microfabricated cortical electrodes. This work also has implications for the design and performance of a wide variety of therapeutic medical devices including peripheral nerve interfaces, cochlear implants, and cardiac pacemakers. The NIDA/NIMH/NINDS EUREKA applications were reviewed differently from more traditional NIH grant mechanisms. Specifically, the review process consisted of two phases. During the first (i.e., electronic) phase a selected panel of reviewers were given the following guidelines by which to assess the applications. They were asked to determine whether they Strongly Agree, Moderately Agree, Neither Agree nor Disagree, Moderately Disagree, or Strongly Disagree with these descriptions. Their ratings and any additional comments are below. These initial ratings also provided the basis for the review panel to determine whether an application would be discussed during an in person meeting. Because of the very stringent review criteria and limited pool of funds set aside for this program, the review panel chose only to discuss applications that garnered the most enthusiasm. The Resume and Summary of the Discussion above summarizes opinions of the person meeting and forms the basis of the final score. Significance This study addresses an important problem and the outcome of the proposed studies will drive the field. The potential impact of the proposed research is exceptional, in terms of the magnitude of the impact and the size of the community affected. Innovation The project is highly original and exceptionally innovative and seriously challenges existing paradigms or clinical practice. The project addresses a major barrier to progress in the field or it develops or employs exceptionally novel concepts, approaches, methodologies, tools, or technologies. Approach The logic of the approach is sufficiently compelling despite the lack of experimental detail. The conceptual (or clinical) framework, design, methods, and analyses are adequately developed, well integrated and reasoned, and are appropriate for the aims of the project. acknowledges potential problem areas and considers alternative tactics. The information in the timeline inspires confidence that the PI will be able to document progress in each year of the award and either complete the project or demonstrate conclusively that it cannot be completed, despite good-faith efforts, during the term of the award. The requested duration of the award is appropriate for the proposed research. Investigators The PD/PI(s) and other key personnel are appropriately trained and well-suited to carry out this work. Past achievements of the PI(s) suggest that the investigator(s) is/are exceptionally innovative and likely to make paradigm-shifting, high-impact discoveries. If the PI does not have a history of doing exceptionally innovative, high-impact research, the logic of the experimental plan suggests that there is at least some likelihood of success. The project is high priority for the PI(s), as indicated by the person-months of effort that the PI(s) will devote to it. For applications designating multiple PDs/PIs, the leadership plan, including the designated roles and responsibilities, governance, and organizational structure, are consistent with and justified by the aims of the project and the expertise of each of the PDs/PIs. Environment The scientific environment(s), in which the work will be performed, contributes to the probability of success. The proposed studies benefit from unique features of the scientific environment, subject populations, or employ useful collaborative arrangements. There is evidence of institutional support
Keywords: ing; Achievement; Address; Affect; Anti-Inflammatory Agents; Area; Artificial cardiac pacemaker; Astrocytes; Attention; Award; base; Cell physiology; Cell Survival; Cells; Charge; Cicatrix; Clinical; clinical practice; Cochlear Implants; Communication; Communities; deep brain stimulator; Deposition; design; Development; Devices; Electrodes; Electronics; Engineering; Environment; Evaluation; Filament; Funding; Grant; Guidelines; Healed; healing; Human Resources; Implant; implantable device; improved; In Vitro; in vivo; Inflammatory; innovation; interest; Laboratories; Leadership; Life; Logic; Medical Device; meetings; Metals; Methodology; Methods; Michigan; Microglia; monomer; nanoscale; National Institute of Drug Abuse; National Institute of Mental Health (U.S.); National Institute of Neurological Disorders and Stroke; Neurons; neurotrophic factor; novel; organizational structure; Outcome; Performance; Peripheral Nerves; Persons; Phase; polymerization; Polymers; Population; Probability; Process; Program Reviews; public health relevance; Published Comment; Reaction; Recording of previous events; relating to nervous system; Research; Research Personnel; response; Retinal; Role; Slice; success; Surface; Technology; Technology Transfer; Therapeutic; Time; TimeLine; Tissues; tool; Training; United States National Institutes of Health; Universities; Work; Wound Healing
Relevance: This project describes the design and evaluation of materials and methods for improving the integration of hard, inert, electronic biomedical devices with soft, ionically- conducting living cortical tissue via the direct polymerization of conducting polymers. These methods may help improve the long-term performance of microfabricated cortical electrodes. This work also has implications for the design and performance of a wide variety of therapeutic medical devices including peripheral nerve interfaces, cochlear implants, and cardiac pacemakers
Project start date: 2010-06-01
Project end date: 2014-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: RFA-GM-09-008
5R01EB010892-02 (2011): $264714
ANTIMICROBIALS AND EFFLUX PUMPS IN STAPHYLOCOCCUS AUREUS INFECTION
C David, Professor Of Medicine, Physician
Massachusetts Eye And Ear Infirmarycity: Boston country: United States (us)
Abstract: PROJECT SUMMARY (See Instructions) The longterm goals of the project are to identify the full array of efflux pumps of Staphylococcus aureus that contribute to multiple antimicrobial resistance and to elucidate the determinants of their expression, their role in microbial physiology and their effect on bacterial response to antimicrobials in infection. The work will focus on genetic analysis of regulatory elements and on bacterial fitness and response to antimicrobials in a subcutaneous abscess model, collaborating with other project groups to assess the efficacy of novel antimicrobial compounds in abscesses and the extent to which efflux pumps affect that efficacy. There are four specific aims 1) assess the effects of NorB, NorD, and Tet38 efflux pumps and their regulators on response to antimicrobials in animal models of infection; 2) evaluate the regulation of expression of abcA encoding an ABC family efflux pump and assess its effects on membrane and cell wall-targeting agents; 3) analyze the global array of pumps over expressed in an abscess environment and determine their contribution to resistance to established agents and novel compounds; and 4) test novel compounds discovered in other subprojects of the program project for resistance to efflux pump expression and for efficacy and development of resistance in mammalian infection models. The work will utilize genetic manipulation and allelic exchange in S. aureus, measurements of gene expression with RT-PCR, and established murine models of infection (subcutaneous abscess, renal abscess, lethality) utilizing a genomically defined strains of methicillin resistant and other S. aureus. The overall goal of the program project is to take a well-integrated, multidisciplinary approach to understanding antibiotic resistance development and transmission, and to integrate that effort with the search for compounds that compromise resistant pathogens, including methicillin-resistant S. aureus (MRSA), by inhibiting novel targets and pathways. This project will add to understanding of resistance mechanisms related to multidrug efflux pumps and provide strains for testing the effect of such pumps on novel compounds active against new targets and pathways. It will also utilize mammalian models of a common MRSA infection to test compound activity in vivo
Keywords: Abscess; Affect; Animal Model; Antibiotic Resistance; Antibiotics; antimicrobial; Antimicrobial Resistance; Architecture; Bacteria; Bambermycins; base; Cell Wall; Cessation of life; Clinical; Collaborations; Community Hospitals; Daptomycin; design; Development; Drainage procedure; Drug Efflux; effective therapy; efflux pump; Environment; Exposure to; Family; fitness; Gene Expression; Genes; genetic analysis; genetic manipulation; genome sequencing; Goals; Growth; HIV Infections; Implant; In Vitro; in vivo; Infection; Injection of therapeutic agent; Instruction; interdisciplinary approach; Laboratories; Lactams; Linezolid; local drug delivery; Measurement; Membrane; Methicillin Resistance; methicillin resistant Staphylococcus aureus (organism); Microbial Biofilms; Microbial Physiology; Modeling; Mortality Vital Statistics; mouse model; Multi-Drug Resistance; Mus; mutant; Nafcillin; new therapeutic target; novel; novel therapeutics; Operative Surgical Procedures; overexpression; pathogen; Pathway interactions; Pharmaceutical Preparations; Plasmids; Polymethyl Methacrylate; Predisposition; prevent; programs; public health medicine (field); Pump; Quinolones; Regulation; Regulatory Element; Regulon; renal abscess; Resistance; Resistance development; resistance mechanism; response; Reverse Transcriptase Polymerase Chain Reaction; Role; Staphylococcus aureus; Stress; subcutaneous; Testing; Tetracyclines; Transcript; transmission process; Up-Regulation (Physiology); Vancomycin; Vancomycin-resistant S. aureus; Walkers; Work
Relevance: RELEVANCE (See instructions): Multidrug resistance in S. aureus is an increasing clinical and public health problem that requires additional understanding of its mechanisms of development and spread and establishment of novel targets that may be exploited to develop new effective therapies
Project start date: 2011-09-01
Project end date: 2016-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PAR-10-271
2P01AI083214-04_8355 (2011): $412915
RESEARCH PROJECT 2: ROLE OF CK2 AND THE WNT SIGNALING PATHWAY IN THE PROGRESSION
C David, Chief
Tufts University Bostoncity: Boston country: United States (us)
Abstract: Project 2 focuses on the interaction of protein kinase CK2 (casein kinase II) and the Wnt signaling pathway with carcinogens in the process of mammary tumorigenesis. In the prior granting period, we demonstrated that the serine-threonine kinases CK2 and GSK3(3 have opposing effects on Wnt signaling, and that CK2 and a kinase inactive (Kl) form of GSK3(3 can promote mammary tumorigenesis in vivo that is associated with activated Wnt signaling. With our P01 collaborators, we established a model of carcinogen-induced mammary tumorigenesis in FVB mice, and found upregulation of Wnt signaling, CK2, the aryl hydrocarbon receptor, and NF-KB in the tumors. Thus, activation of CK2 and inhibition of GSK33 are demonstrated to have the potential to contribute to mammary tumorigenesis and to the regulation of multiple signaling pathways. The central hypothesis of this renewal is that CK2 and Wnt signaling are constitutivelv activated by genetic and epiqenetic events in breast cancer and are regulators of epithelial to mesenchymal transition (EMT). leading to tumor invasion and to metastasis. This hypothesis will be tested through three specific aims Aim 1. We will study the interaction of a prototypical polycyclic aromatic hydrocarbon, DMBA with CK2 and Wnt signaling in vivo, using MMTV-CK2a transgenic mice and LEF-EGFP Wnt reporter transgenic mice. Aim 2. One of the features of tumor progression is the loss of normal epithelial morphology and alteration in cell adhesion molecules, through the process of EMT. In this aim we will explore the mechanism by which CK2 and NF-KB collaborate to promote the EMT phenotype, and determine whether antagonizing CK2 can reverse the invasive and/or metastastatic phenotype of tumor cells. Aim 3. Here we will investigate the mechanism of upregulation of CK2 after exposure to carcinogens. The kinetics, level of regulation, and requirement for AhR, NF-KB, and Wnt signaling in the process of upregulation of CK2 will be assessed. Signficance Identifying collaborating events in the process of tumor progression to the EMT-like phenotype is of tremendous translational potential for preventing or curing invasive and/or metastatic cancer. If a kinase is an important contributor in model systems, with evidence that this may also be the case in human breast cancer, it provides a potential target for therapeutic intervention
Keywords: 9, 10-Dimethyl-1, 2-benzanthracene; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Biological Models; carcinogenesis; Carcinogens; casein kinase II; Cell Adhesion Molecules; Cell Line; Cells; Chemosensitization; Collaborations; Colon Carcinoma; Data; Development; Disseminated Malignant Neoplasm; Dominant-Negative Mutation; Embryo; Environmental Carcinogens; Epithelial; epithelial to mesenchymal transition; Event; Exposure to; Funding; FVB Mouse; Genes; Genetic; Genetic Determinism; Grant; Heat-Shock Response; Human; In Vitro; in vivo; inhibitor/antagonist; interest; Kinetics; Laboratories; malignant breast neoplasm; Mammary gland; Mammary Neoplasms; Mammary Tumorigenesis; Modeling; Morphology; Mouse Mammary Tumor Virus; Mus; Mutation; Neoplasm Metastasis; neoplastic cell; Oncogenic; overexpression; Pathway interactions; Phenotype; Phosphotransferases; Play; prevent; Process; Promotor (Genetics); Protein-Serine-Threonine Kinases; Proteins; Published Comment; Reagent; Regulation; Reporter; Reporting; Research Project Grants; research study; response; RNA; RNA Splicing; Role; Signal Pathway; Signal Transduction; snail protein; Staging; System; Techniques; Testing; Therapeutic Intervention; Transformed Cell Line; Transgenic Mice; Transgenic Organisms; tumor; Tumor Cell Invasion; Tumor Cell Line; tumor progression; tumorigenesis; Up-Regulation (Physiology); Xenopus laevis
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5P01ES011624-10_0005 (2011): $288665
7P01ES011624-08_0005 (2009): $290690
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