TRAINING IN THE GENETICS AND MOLECULAR BIOLOGY OF MENTAL DISORDERS
P John, Professor Of Mathematics In Psychia
Washington Universitycity: Saint Louis country: United States (us)
Grant 2T32MH014677-34 from National Institute Of Mental Health
Abstract: This application requests a further five years of support for an Institutional National Research Service Award to support multidisciplinary post-doctoral training in Genetic Epidemiology, Molecular Genetics and Neurobiology. We request support for four postdoctoral (1 M.D. and 3 Ph.D.) fellows for training in Genetic Methodology, Family Epidemiology and Behavior Genetics, Gene Mapping and Bioinformatics, Molecular Genetics, and Molecular Neurobiology. In addition to training in a primary area, fellows will be encouraged to obtain a broad understanding of the diverse skills in Psychiatric Genetics to facilitate their collaboration in (and leadership of) cross-disciplinary research teams. The fellowship will usually last three years, but one or two years may suffice for those with much pertinent experience. Fellows with a wide variety of backgrounds will be recruited including; Psychology, Psychiatry, Genetics, Statistics, Mathematics, Anthropology, Sociology, Biology, and Neuroscience. The training program uses an apprenticeship model, combining research under the mentorship of one or more experienced mentors with more formal training through seminars, didactic courses and individual reading. Major strengths of the program are; (i) the participation of a large multidisciplinary group of well-funded preceptors (n=21) with expertise in statistical and computational genetics, molecular genetics and neuroscience; (ii) the study of quantitative and qualitative traits and the development of methods for the analysis of multivariate phenotypes and (iii) the availability of major epidemiological and genetic data sets (phenotypes and genotypes). Fellows may participate in ongoing Genome-Wide Association Studies (GWAS) of Schizophrenia, Bipolar Disorder, Alzheimer´s Disease, ADH, Electrophysiological measures of CNS activity, Personality traits and Nicotine Dependence. We anticipate analysis of targeted sequence data to become a future emphasis. Preceptors in this program have many federally and non-federally funded grants providing many opportunities for training in all aspects of Psychiatric Genetics. The program is located in one of the nation´s leading Medical Schools with a rich array of basic and applied genetic research studies and educational opportunities. Thus, we expect the long tradition of successful mentoring and research training of scientists and physician-scientists from diverse intellectual backgrounds to continue. Mental disorders are a major health problem that cause considerable personal suffering and represent a major portion of our health care budget. The time is ripe to focus on training the next generation of scientists to capitalize on recent advances in genetics to advance the prevention and treatment of these disorders
Keywords: Genetic; Mental disorders; Molecular Biology; Training
Relevance: Mental disorders are a major health problem that cause considerable personal suffering and represent a major portion of our health care budget. The time is ripe to focus on training the next generation of scientists to capitalize on recent advances in genetics to advance the prevention and treatment of these disorders
Project start date: 1976-07-01
Project end date: 2016-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-10-036
2T32MH014677-34 (2011): $100775
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to P John
METHAMPHETAMINE, STRESS AND SIV: EFFECTS AT BLOOD-BRAIN BARRIER AND LYMPH NODES
P John, Professor
University Of California Daviscity: Davis country: United States (us)
Grant 5R01DA024441-04 from National Institute On Drug Abuse
Abstract: Worldwide, stimulants such as methamphetamine rank second only to cannabis in number of users, and in North America, the prevalence of amphetamine abuse is double the global rate. Methamphetamine (meth) is being found to play an increasingly important role in AIDS, as well. Evidence suggests that meth and HIV infection have additive effects on neurocognitive impairment and CNS damage. Meth is a sympathomimetic causing release of norepinephrine from peripheral nerves, and we have shown that norepinephrine promotes HIV and SIV replication. Meth´s effects on the CNS, then, could be an indirect consequence of its ability to release norepinephrine from sympathetic varicosities in secondary lymphoid tissue, leading to greater viral replication and higher viral loads, and greater numbers of circulating, infected cells (primarily monocytes) that can enter the CNS. Meth´s effects in the CNS could also result from effects on the blood-brain barrier (BBB). Independent lines of evidence suggest that meth, stress (a precipitating factor for much drug use, including methamphetamine), and HIV/SIV can all contribute to weakening the blood-brain barrier. We propose that these three factors could have additive effects, resulting in increased transport across the BBB of blood borne factors such as infected monocytes and inflammatory cytokines, leading to a greater likelihood of CNS infection and damage, and neuropsychological impairment. Finally, given our demonstrated effects of stress on viral replication in lymph nodes, and the additional effects we anticipate seeing due to the sympathomimetic properties of methamphetamine, we propose that beta adrenergic receptor blockade or administration of recombinant interferon-beta will abrogate the effects of methamphetamine and stress in the lymph node. Our specific aims are 1) to examine the role played by methamphetamine and stress in alterations in innervation patterns, Type I interferon gene expression, and SIV replication in lymph nodes, and disease-related indicators in blood; 2) to examine the role played by methamphetamine and stress in altering permeability of the blood-brain barrier in SIV infected monkeys; 3) to examine whether beta adrenergic receptor blockade or administration of recombinant interferon-beta will abrogate the effects of methamphetamine in lymph nodes and at the BBB.Relevance
Keywords: Acquired Immunodeficiency Syndrome; adrenergic; Adrenergic Agents; Albumins; Amphetamine Abuse; Autopsy; Basal Ganglia; beta-adrenergic receptor; Blood; Blood - brain barrier anatomy; Cannabis; Cells; chemokine; cytokine; density; Disease; Drug usage; Fibrinogen; Frequencies (time pattern); frontal lobe; Gene Expression; Genes; high risk sexual behavior; HIV; HIV Infections; Impairment; Infection; Inflammatory; Interferon Type I; Interferon-alpha; Interferons; Leukocytes; lymph nodes; Lymphoid Tissue; Methamphetamine; Monkeys; monocyte; nerve supply; Neurocognitive; neuropsychological; Norepinephrine; North America; Pattern; Peripheral Nerves; Permeability; Plasma; Play; Precipitating Factors; Prevalence; Process; Property; receptor expression; Recombinant Interferon Beta; Research; Role; Serum; Site; SIV; social stress; Staining method; Stains; Stress; Sympathomimetics; Tight Junctions; Up-Regulation (Physiology); Varicosity; Viral; Viral Load result
Project start date: 2007-09-30
Project end date: 2012-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2012
PFA/PA: RFA-DA-07-002
5R01DA024441-04 (2010): $877318
MULTI-INSTITUTIONAL PEDIATRIC EPILEPSY DECISION SUPPORT
P John, Associate Professor Of Pediatrics
Children´s Hospital Medical Center Cincicity: Cincinnati country: United States (us)
Grant 1R01LM011124-01 from National Library Of Medicine
Abstract: What care is administered relies on what caregivers know and need to know. Lately, biomedical discoveries, advances in biomedical technology, and implementation research have shown an ability to identify the knowledge that is needed when it is needed, but how to put that knowledge in the hands of caregivers has been a challenge. The Institute of Medicine, has one way of dealing with this problem, it is called the a Learning Healthcare System. This proposal presents how one group, 31 site Childhood Absence Epilepsy Network (CAEN), intends to become an LHS. In this proposal we describe how three sites Cincinnati Children´s Hospital Medical Center, Denver Children´s Hospital and Children´s Hospital of Philadelphia have agreed to act as a pilot for implementing NIH sponsored i2b2 technology and developing novel software applications that include natural language processing to extend that technology. This initial collaboration is called the Multi-Institutional Pediatric Epilepsy Decision Support System (MiPeds - pronounced my peads)
Keywords: Absence Epilepsy; base; Biomedical Technology; Caregivers; Caring; Childhood; Clinical; clinical care; Clinical Informatics; Collaborations; Communities; Computational algorithm; Computer software; Consensus; Data; Decision Support Systems; Disease; Electronic Health Record; Epilepsy; Health system; Healthcare Systems; implementation research; improved; innovation; Institute of Medicine (U.S.); Knowledge; Laboratories; Learning; Measurement; Measures; Medical center; Methods; Natural Language Processing; novel; Outcome; Patients; Pediatric Hospitals; Philadelphia; point of care; Positioning Attribute; Quality of Care; Recording of previous events; Research; Resources; Scientist; Site; software development; Technology; Text; tool; United States; United States National Institutes of Health
Relevance: Electronic health records contain information that not only is essential for clinical care, but also provides a learning laboratory to increase the quality of care. We propose to extend the existing i2b2 technology by develop disease specific data marts and tools for pediatric epilepsy
Project start date: 2011-07-22
Project end date: 2014-06-30
Budget start date: 22-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PAR-08-080
1R01LM011124-01 (2011): $342062
STANFORD CAREER DEVELOPMENT IN VASCULAR MEDICINE
P John, Professor Of Medicine
Stanford Universitycity: Stanford country: United States (us)
Grant 5K12HL087746-04 from National Heart, Lung, And Blood Institute
Abstract: Vascular disease is the leading cause of morbidity and mortality in the United States. There is a public health need for increased transfer of knowledge between the various disciplines that constitute this research field, and accelerated application of the basic information to clinical practice. The Stanford program addresses with a multidisciplinary program and faculty performing scientific and clinical work related directly to Vascular Medicine including cardiovascular and pulmonary medicine, endocrinology, hematology, nephrology, immunology, epidemiology and clinical trials design, cell and molecular biology, developmental and stem cell biology, tissue and mechanical engineering, physics and computational modeling, genetics/genomics,proteomics, physiology and molecular pharmacology. This proposal is designed to address the educational and clinical needs in the emerging specialty of Vascular Medicine. The program will produce clinician investigators with a deep fund of knowledge regarding vascular medicine, and a high level of proficiency in clinical research. This new breed of investigators will apply cutting edge technology to clinically relevant questions in vascular medicine, and they will be able to train the next generation of vascular internists. Our Specific aims are to 1) Develop, institute and annually evaluate a one year core clinical training program that confers competency in the management of arterial, venous and lymphatic diseases and associated disorders; 2) Formulate, initiate and annually update a didactic training program in clinical research emphasizing clinical trial design, biostatistics and bioinformatics, genomics and proteomics, regulatory affairs, and responsible conduct of research; 3) Provide a clinical research experience guided by an experienced Mentor, facilitated by a cohort of collaborative Co-mentors, and focused on a clinical research project. Other elements include exposure to trial design, interaction with and direct participation on the Institutional Review Board, database management and analysis, manuscript preparation, and grant writing. Lay Diseases of the arteries and veins cause most of the hospitalizations and deaths in the United States. Stanford University proposes a comprehensive educational program that will train a new breed of doctors that can recognize and treat these diseases, develop new therapies, and train young doctors in the care of people with vessel disease. (End of )
Keywords: ing; Address; Arteries; Bioinformatics; Biometry; Blood Vessels; Breeding; Cardiovascular system; career development; Caring; Cellular biology; Cessation of life; Clinical; clinical practice; Clinical Research; Clinical Trials Design; clinically relevant; cohort; Computer Simulation; Data Base Management; design; Development; Discipline; Disease; Elements; Endocrinology; Engineering; Epidemiology; experience; Exposure to; Faculty; Funding; Genetic; Genomics; Grant; Hematology; Hospitalization; Immunology; Institutes; Institutional Review Boards; Internist; Knowledge; Lymphatic Diseases; Manuscripts; Mechanics; medical specialties; Medicine; Mentors; Molecular; Molecular Biology; Morbidity - disease rate; Mortality Vital Statistics; multidisciplinary; Nephrology; next generation; Pharmacology; Physics; Physiology; Preparation; programs; Proteomics; public health medicine (field); Pulmonary Disease (Specialty); Regulatory Affairs; Research; Research Personnel; Research Project Grants; responsible research conduct; stem cell biology; Technology; Tissues; Training; Training Programs; United States; Universities; Update; Vascular Diseases; Veins; Venous; Work; Writing
Project start date: 2007-04-01
Project end date: 2013-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: RFA-HL-05-002
5K12HL087746-04 (2011): $807332
5K12HL087746-03 (2009): $1169481
BIOBEHAVIORAL CHARACTERIZATION OF INFANT RHESUS MONKEYS
P John, Professor
University Of California Daviscity: Davis country: United States (us)
Grant 5R24RR019970-08 from National Center For Research Resources
Abstract: Three decades of psychobiological research with rodents, nonhuman primates, and humans have documented the existence of individual differences in temperament, emotionality, behavioral and physiological reactivity, and personality, which we refer to as biobehavioral organization. These characteristics influence an individual´s style of adaptation to its environment, and evidence shows that the quality of the animal´s adaptations is associated with indices of psychological and physical health. At the California National Primate Research Center, we have developed a program to assess biobehavioral organization in infant rhesus monkeys. Our protocol includes a) collecting behavioral data in several situations designed to assess memory, responsiveness to mild challenges, and willingness to interact with novel objects; b) genotyping for polymorphisms in the promoter regions of two neuropsychiatric genes, the serotonin transporter and monoamine oxidase-A; c) assessing regulation of the hypothalamic-pituitary-adrenal system; and d) measuring routine hematologic parameters. Data from this resource are available to all CNPRC service and scientific staff via a web interface, to use for scientific and colony management purposes. In the current application, we propose the following specific aims to continue performing our BioBehavioral Assessment on approximately 300 infant rhesus monkeys per year and to make these data available to qualified scientific and management staff through our web page as soon as the processing of the data is complete each year; to continue our ongoing efforts to identify the attributes of former participants in our BBA program that are at risk for poor adaptation to a captive environment as indexed by measures of chronic illness, abnormal behaviors, poor reproduction, and aberrant social function; to use existing statistical methods on our BBA data to establish individual profiles associated with poor outcomes as aids to colony management personnel to prevent health, behavioral, reproductive, and social problems; to continue to develop standardized tests that are shorter, simpler, and easier to administer than our current procedure, yet meet the same standards of reliability and predictive validity for our outcome measures. PUBLIC HEALTH RELEVANCE This project will result in improved nonhuman primate models for health-related research, and will provide a database that will be uniquely able to contribute to the development of primate models of personalized medicine
Keywords: Acquired Immunodeficiency Syndrome; Animals; Behavior; Behavioral; behavioral health; biobehavior; California; Characteristics; Chronic Disease; computerized data processing; Data; Databases; design; Environment; Genes; Genetic Polymorphism; Genotype; Health; Human; Hypothalamic structure; improved; indexing; Individual; Individual Differences; Infant; Macaca mulatta; Measures; Medicine; meetings; Memory; Mental Health; Modeling; Monoamine Oxidase A; neuropsychiatry; nonhuman primate; novel; Outcome; Outcome Measure; Participant; Personality; Personnel Management; physical conditioning; Physiological; Pituitary-Adrenal System; prevent; primate development; Primates; Procedures; programs; Promoter Regions (Genetics); Protocols documentation; psychobiologic; public health relevance; Qualifying; Regulation; Reproduction; reproductive; Research; Resources; Risk; Rodent; serotonin transporter; Services; Social Functioning; Social Problems; Statistical Methods; Temperament; Testing; web interface; web page; willingness
Project start date: 2004-08-10
Project end date: 2014-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
5R24RR019970-08 (2011): $365810
ANNUAL MEETING OF THE INTERNATIONAL BEHAVIORAL NEUROSCIENCE SOCIETY
P John, Professor
Internationl Behavioral Neuroscience Soccity: San Antonio country: United States (us)
Grant 2R13MH065244-09A1 from National Institute Of Mental Health
Abstract: This purpose of this project is to secure funds to help defray the costs associated with the Annual Meeting of the International Behavioral Neuroscience Society (IBNS). This project is a renewal of our existing R13 grant that has been instrumental in vaulting the IBNS into a position of the premiere behavioral neuroscience society in the world (total membership = 736). The Annual Meeting represents a main component of the society´s mission. The meeting is a 4 day event where attendees (~175-250) are housed at or within close walking distance to the meeting site - fostering a close community for scientific exchange. The locations of the meetings are predominantly in the US mainland but every 3-4 years the meeting occurs at an international site to acknowledge its international members (38%). The meeting is comprised of a series of special symposia, keynote addresses, oral and poster presentations and workshops for professional skill development. Special emphasis is devoted in the program to facilitate interactions among basic, preclinical, and clinical investigators on issues related to mental health, addiction, and aging. Young Investigator Travel Award winners (pre- and post-doctoral fellows) are featured prominently in this program with their own session that is attended by all registrants of the meeting. There are no concurrent sessions or programs, again, fostering a sense of communal scientific exchange. In this application, funds are requested for five years in order to support 3 biennial meetings of the Society (2011, 2013, and 2015). The request for biennial support is in accordance with advice from NIMH in terms of their revised funding formula for R13s. The IBNS is currently examining issues related to funding the meetings in ´off years´ of NIH support. R13-related funds will be used to support the following components of the Annual Meeting; Pre- and Post-doctoral Young Investigator Travel Awards, Registration Costs for invited Symposium Speakers, Speaker´s Fee for Keynote Speakers, and money to help defray the costs of Publication of s of the Meeting on the IBNS website. The Annual Meeting of the International Behavioral Neuroscience Society (IBNS) is a showcase for high quality, contemporary research in the field of behavioral neuroscience. Many of the society´s researchers are studying state-of-the-art issues related to public health (esp. Mental Health, Drug Abuse, and Aging - indeed, many are funded by these NIH Institutes). Thus, each year, the selection of several of the Symposia (and Discussants) and Keynote Speakers are guided by the degree to which they focus on the vertical integration of basic behavioral neuroscience, translational studies, and clinical practice. The intent of these selections will be to generate discourse among basic, preclinical, and clinical researchers that is directed toward a better understanding of the origins and treatment of a variety of biomedical illnesses. The Annual IBNS Meeting also places a strong and explicit emphasis on professional development of attending students, post-doctoral fellows, and young faculty by sponsoring a variety of workshops and mentoring experiences
Keywords: addiction; Address; Aging; Award; Behavioral; brain behavior; Budgets; Clinical; Clinical Investigator; clinical practice; Communities; cost; Development; Drug abuse; Educational workshop; Event; experience; Faculty; Fees; Financial Support; Fostering; Funding; Grant; Housing; Human; Institutes; International; Location; meeting s; meetings; member; Mental Health; Mentors; Minority Groups; Mission; National Institute of Mental Health (U.S.); Neurosciences; Oral; Positioning Attribute; Postdoctoral Fellow; posters; pre-clinical; pre-doctoral; programs; public health medicine (field); Publications; Request for Proposals; Research; Research Personnel; Secure; Series; Site; skills; Societies; Students; symposium; translational study; Travel; United States National Institutes of Health; Walking; web site
Relevance: The Annual Meeting of the International Behavioral Neuroscience Society (IBNS) is a showcase for high quality, contemporary research in the field of behavioral neuroscience. Many of the society´s researchers are studying state-of-the-art issues related to public health (esp. Mental Health, Drug Abuse, and Aging - indeed, many are funded by these NIH Institutes). Thus, each year, the selection of several of the Symposia (and Discussants) and Keynote Speakers are guided by the degree to which they focus on the vertical integration of basic behavioral neuroscience, translational studies, and clinical practice. The intent of these selections will be to generate discourse among basic, preclinical, and clinical researchers that is directed toward a better understanding of the origins and treatment of a variety of biomedical illnesses. The Annual IBNS Meeting also places a strong and explicit emphasis on professional development of attending students, post-doctoral fellows, and young faculty by sponsoring a variety of workshops and mentoring experiences
Project start date: 2002-03-01
Project end date: 2012-04-30
Budget start date: 20-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-10-071
2R13MH065244-09A1 (2011): $5000
CENTRAL RHYTHMOGENESIS AND BEHAVIOR
P John, Professor
Seattle Children´s Hospitalcity: Seattle country: United States (us)
Grant 5R01NS031224-17 from National Institute Of Neurological Disorders And Stroke
Abstract: This project will focus on the hypothesis that N-methyl-D-aspartate (NMDA) glutamate receptors and neuronal gap junctions act concertedly to determine the spatio-temporal dynamics of activity within electrically coupled networks in brain. The hypothesis will be tested in the inferior olive, a major afferent of the cerebellum that has the highest density of electrical synapses in the adult brain. Previous work from our laboratory showed that NMDA receptor activation induces high-threshold oscillations in membrane potential in inferior olive neurons and that neuronal gap junctions mediated by connexin36 are critical for the continuity and strength of coherent oscillations in the inferior olive. There are 4 aims. Aim 1 will determine whether NMDA receptors regulate electrical coherence and rhythm within a coupled network by acting on neuronal gap junctions in vivo. Aim 2 will determine whether NMDA receptors shape the spatial dynamics of electrical coupling in vitro. Aim 3 will determine whether there is a correspondence between NMDA receptor upregulation in the inferior olive and hypoxia-induced death of cerebellar neurons. Aim 4 will determine whether the block of NMDA receptor function in the inferior olive alone, or with neuronal gap junctions, will prevent delayed neuronal death in the cerebellum after hypoxia. These aims will be carried out with a combination of multielectrode recording, multibeam multiphoton microscopy, and gene transfer to express proteins with dominant-negative effect and RNA inhibitor sequences in the inferior olive. Recently, the upregulation of the NMDA receptor in the inferior olive and the death of Purkinje cells were independently related to sudden infant death syndrome. The research will establish how these clinically-relevant phenomena are related to one another. PUBLIC HEALTH RELEVANCE The studies proposed in the present application will provide important information about the mechanisms of neuronal oscillation in a specific brain region named the inferior olive, and the potential for pathological activity in that brain area for triggering neuronal death in the cerebellum. The results of these studies will be useful not only for our general understanding of brain function but may be relevant to the sudden infant death syndrome, a tragic result of cumulative hypoxic damage to the brain. The long term goal of these studies is to determine the cell biological and neuronal ensemble mechanisms of normal and pathological oscillations in the brain
Keywords: Adult; Area; Attenuated; attenuation; base; Behavior; Biological; Biological Assay; Brain; Brain Hypoxia-Ischemia; Brain region; Cell Death; Cells; Cerebellum; Cessation of life; Clinical Data; clinically relevant; connexin 36; Coupled; Coupling; Data; Dendrites; density; Dominant-Negative Mutation; Electrical Synapse; Gap Junctions; gene therapy; Gene Transfer; Genetic; Glutamate Receptor; Goals; Health; Hypoxia; Image; Immunofluorescence Microscopy; In Vitro; in vivo; Inferior; inhibitor/antagonist; Killings; knock-down; Laboratories; Mediating; Membrane Potentials; Microscopy; mutant; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Names; Neurons; Normal Range; NR1 gene; Olives - dietary; prevent; Proteins; Purkinje Cells; Rattus; Receptor Activation; receptor function; receptor upregulation; Research; RNA; Shapes; Structure; Sudden infant death syndrome; Testing; Up-Regulation (Physiology); vector; Western Blotting; Work
Relevance: The studies proposed in the present application will provide important information about the mechanisms of neuronal oscillation in a specific brain region named the inferior olive, and the potential for pathological activity in that brain area for triggering neuronal death in the cerebellum. The results of these studies will be useful not only for our general understanding of brain function but may be relevant to the sudden infant death syndrome, a tragic result of cumulative hypoxic damage to the brain. The long term goal of these studies is to determine the cell biological and neuronal ensemble mechanisms of normal and pathological oscillations in the brain
Project start date: 1993-03-01
Project end date: 2014-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R01NS031224-17 (2011): $383906
MECHANISMS IN INNOVATION IN VASCULAR DISEASE
P John, Chief, Vascular Division
Stanford Universitycity: Stanford country: United States (us)
Grant 5T32HL098049-02 from National Heart, Lung, And Blood Institute
Abstract: This program will train 6 postdoctoral fellows annually in mechanisms and Innovation in vascular disease. The program goals include rigorous training in the scientific method, critical analysis, logical reasoning and independent thinking, all within a highly collaborative working group. Trainees will develop a focused area of translational vascular research expertise and will be exposed to a wide range of complementary research techniques. Mentors will provide collegial and productive collaboration, and help to hone skills in oral and written communication, and to instill respect for the responsible conduct of research. Fellows will undergo a minimum two-year education and research program, although we only intend to fund the first year through the institutional T32. Fellows will be encouraged and mentored in their development of funding proposals for the second year. The overarching goal for this program is to produce researchers who are well-schooled in the fundamental problems of vascular disease, and are driven to find innovative strategies to tackle those problems, thereby translating basic research into clinical success. Fellows will receive their training in a multidisciplinary milieu of fundamental, translational and clinical research in vascular biology and disease. The Stanford Cardiovascular Institute (CVI) offers a unique platform by which to train the next generation of basic and translational scientists. Mentors for the proposed program, all members of the CVI, come not only from vascular medicine, but also from materials science, bioengineering, imaging, and health research and policy. Brought together in a collaborative Institute, these scientists share a common interest in the mechanisms behind vascular development and disease
Keywords: innovation; Vascular Diseases
Project start date: 2010-07-01
Project end date: 2015-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-08-226
5T32HL098049-02 (2011): $242499
NEUTRALIZATION OF PRIMARY HIV-1 VIRUSES
P John, Professor
Weill Medical College Of Cornell Univcity: New York country: United States (us)
Grant 5R37AI036082-19 from National Institute Of Allergy And Infectious Diseases
Abstract: This is a revised application for the competitive renewal of R37 AI36082 "Neutralization of primate immunodeficiency viruses", a grant first awarded in 1994, successfully re-competed in 1998, converted into an R37 ("MERIT") award at that time, and now up for re-competition once more. For most of the past 13 years, the emphasis of the research conducted with the support of this grant has been on learning how HIV-1 is neutralized by antibodies (Abs), or resists them, in the hope that such knowledge could facilitate the development of a vaccine based on the induction of neutralizing antibodies (NAbs). Such studies will continue to be an emphasis of the new application, particularly in Specific Aims 1 and 2. However, we now wish to initiate a new area of research, one that still involves learning how the HIV-1 envelope glycoproteins interact with the human immune system, but with no specific focus on neutralizing antibodies per se. Thus, in Specific Aim 3, we seek to characterize the potentially immunosuppressive signals that are transduced when the gp120 glycoprotein, at concentrations relevant to subunit vaccination, binds to human dendritic cells. We propose Specific Aim 1 Mechanism, stoichiometry and kinetic aspects of HIV-1 neutralization by Abs. We seek to generate neutralization data that we will analyze using novel mathematical models, with the goal of better understanding the mechanisms of neutralization at the molecular level. Specific Aim 2 Can neutralizing antibodies synergize in their actions against HIV-1? Neutralization models suggest that the binding of a single Ab to an Env complex is sufficient to impair the fusion activity of that particular complex. Yet synergy has been reported between two or more NAbs, implying that multiple NAbs can bind the same trimer. We plan to analyze this apparent paradox experimentally, studying plausible sources of artifacts that could generate misleading indications of synergy. Specific Aim 3 Induction of immunosuppressive responses by the mannose moieties of gp120 glycans. We propose to examine what consequences vaccine-relevant gp120 concentrations can have on cells of the immune system, particularly dendritic cells. Our emphasis will be on determining whether the binding of gp120 to cell surface receptors, particularly mannose C-type lectin receptors, can generate immunosuppressive or cytokine-polarizing signals that skew the development of immune responses to this, and conceivably other, vaccine immunogens. PUBLIC HEALTH RELEVANCE One of the ways that HIV-1 is fought by the human immune system is via neutralizing antibodies that bind to the viral envelope glycoproteins and prevent it from infecting immune system cells that bear the relevant receptors. Most current vaccine design strategies involve the use of proteins intended to generate neutralizing antibodies, but these strategies are not working well because HIV-1 has evolved multiple mechanisms to resist the actions of these antibodies. In this grant application, we seek to generate new knowledge of how HIV-1 is neutralized by, and resists, antibodies, in the hope that the information could help with the design of better vaccine strategies. We also propose to study how HIV-1 envelope glycoproteins bind directly to some immune system cells and impair their functions, again with the intent of finding ways to make better vaccines that do not have these potentially suppressive effects
Keywords: Affect; Algorithms; Animals; Antibodies; Antigens; Applications Grants; Area; Award; base; Binding (Molecular Function); Biological Assay; C Type Lectin Receptors; Cell Surface Receptors; Cells; Complex; cytokine; Data; Dendritic Cells; design; Development; Effectiveness; Epitopes; Experimental Models; fighting; Genetic; Glycoproteins; Goals; Grant; HIV Envelope Protein gp120; HIV-1; Human; Immune response; Immune system; Immunosuppressive Agents; In Vitro; inhibitor/antagonist; Kinetics; Knowledge; Learning; Mannose; mathematical model; Measurement; Medical; milligram; Modeling; Molecular; Morphologic artifacts; neutralizing antibody; novel; Polysaccharides; prevent; Primate Lentiviruses; Principal Investigator; programs; Property; Proteins; public health relevance; receptor; Reporting; Research; response; Role; Signal Transduction; Source; stoichiometry; Subunit Vaccines; System; Time; Tissues; Ursidae Family; Vaccination; Vaccine Design; vaccine development; Vaccines; Viral; Virion; Virus; Virus Diseases; Work
Project start date: 1994-05-01
Project end date: 2013-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5R37AI036082-19 (2011): $414092
SECOND RECEPTORS FOR PRIMATE IMMUNODEFICIENCY VIRUSES
P John, Professor
Weill Medical College Of Cornell Univcity: New York country: United States (us)
Grant 2R01AI041420-16A1 from National Institute Of Allergy And Infectious Diseases
Abstract: This is a competitive renewal application for an R01 grant. Our goal is to further increase our understanding of how HIV-1 uses coreceptors to enter cells. A specific emphasis will be on learning more about the mechanisms of resistance to small molecule CCR5 or CXCR4 inhibitors and the properties of resistant variants. Such studies will not only increase our knowledge of the HIV-1 replication cycle at the basic science level, they will also assist clinicians in their use of CCR5 inhibitors to treat HIV-1 infection. Building on our work in the general area of coreceptor biology during the past 14 years, we now propose the following research plan In our first Specific Aim, we will investigate whether wild type and CCR5 inhibitor-resistant viruses interact with different sub-populations of CCR5 coreceptors. We will explore whether and how HIV-1 Env, monoclonal antibodies (MAbs) and small-molecule inhibitors interact with different CCR5 sub-populations. These sub-populations may arise through conformational interconversions, post-translational modifications, be located in distinct micro-domains on the cell surface, and have distinguishable links to G-proteins and the endocytic machinery. The sub-populations may be present in different proportions on diverse target cells. We will study how and where parental and inhibitor-resistant viruses interact with inhibitor-bound and -free CCR5 sub-populations. In Specific Aim 2, we propose to define how amino acid changes in the gp41 transmembrane protein of CCR5 inhibitor-resistant viruses affect the interaction of gp120 subunits with CCR5. We have described a resistant virus in which, unexpectedly, the critical changes were located in the gp41 fusion peptide, which is not known to interact with CCR5. We now have evidence for additional, resistance-associated changes in the N-terminal region of gp41. We will study the effects of these various changes on Env topology, CD4-Env interactions with CCR5, Env-mediated fusion rates, and the membrane location of the virus-cell fusion process. Our third Specific Aim is to assess whether Env-mediated signaling via CCR5 or CXCR4 is important for HIV-1 entry. We will use receptor-mutants defective for signal transduction functions, or constitutively active, and viruses that can enter cells in the presence of CCR5 or CXCR4 antagonists, to explore whether transmembrane signaling is essential for, or modifies, entry or post-entry events in the HIV-1 replication cycle. Human immunodeficiency virus type 1 (HIV-1) uses the CCR5 co-receptor to enter the cells it infects. Drugs have now been developed that target CCR5 and thereby interfere with this stage of the HIV-1 replication cycle. These inhibitors are effective both in cell culture systems and when used to treat HIV-1-infected people. As with all drugs, HIV-1 develops resistance, rendering them less effective. We have been studying the resistance process for several years, and now seek to continue and expand our studies. Specifically, we are learning about how sequence changes accumulate in the HIV-1 envelope glycoproteins (which bind CCR5) under drug selection pressure, and how these sequence changes enable to virus to use the drug-CCR5 complex to enter cells. We will study the various sub-populations of CCR5 that exist on the cell surface, as defined by staining with monoclonal antibodies against various CCR5 epitopes, and try to define how these various CCR5 forms are used by wild type and resistant viruses
Keywords: Affect; Amino Acids; Area; Basic Science; Binding (Molecular Function); Biology; CCR5 gene; Cell Culture System; Cell fusion; Cell surface; Cells; Complex; CXCR4 gene; Drug usage; Epitopes; Event; Glycoproteins; Goals; Grant; GTP-Binding Proteins; HIV Envelope Protein gp120; HIV-1; Infection; inhibitor/antagonist; Integral Membrane Protein; Knowledge; Learning; Link; Location; Mediating; Membrane; Monoclonal Antibodies; mutant; N-terminal; Peptides; Pharmaceutical Preparations; Population; Post-Translational Protein Processing; pressure; Primate Lentiviruses; Process; Property; receptor; Research; Resistance; Resistance development; resistance mechanism; Resistance Process; Signal Transduction; small molecule; Staging; Staining method; Stains; Variant; Virus; Work
Relevance: Human immunodeficiency virus type 1 (HIV-1) uses the CCR5 co-receptor to enter the cells it infects. Drugs have now been developed that target CCR5 and thereby interfere with this stage of the HIV-1 replication cycle. These inhibitors are effective both in cell culture systems and when used to treat HIV-1-infected people. As with all drugs, HIV-1 develops resistance, rendering them less effective. We have been studying the resistance process for several years, and now seek to continue and expand our studies. Specifically, we are learning about how sequence changes accumulate in the HIV-1 envelope glycoproteins (which bind CCR5) under drug selection pressure, and how these sequence changes enable to virus to use the drug-CCR5 complex to enter cells. We will study the various sub-populations of CCR5 that exist on the cell surface, as defined by staining with monoclonal antibodies against various CCR5 epitopes, and try to define how these various CCR5 forms are used by wild type and resistant viruses
Project start date: 1997-07-01
Project end date: 2016-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-10-067
2R01AI041420-16A1 (2011): $422500
Sponsored Links Excellgen http://Excellgen.com
A PRACTICAL MICROBICIDE BASED ON HIV-1 ENTRY INHIBITORS
P John, Professor
Weill Medical College Of Cornell Univcity: New York country: United States (us)
Grant 5U19AI076982-04 from National Institute Of Allergy And Infectious Diseases
Abstract: This IPCP-HTM application made in response to RFA Al-07-001 contains three Research Projects, one Scientific Core and an Administrative Core, under the direction of Principal Investigator, John P. Moore, PhD and co-Principal Investigator, Robin A. Shattock, PhD. The purpose of the program is to conduct in vitro and in vivo pre-clinical and animal model-based research intended to facilitate the development of a vaginal microbicide based on the use of inhibitors of HIV-1 entry, applied alone and/or in combination. Our goal is to use our collective knowledge of virology, immunology, formulation chemistry and mammalian biology to help develop a mechanism-based, HIV-1-specific microbicide(s). An emphasis will be the development and evaluation of long-lasting microbicide formulations and delivery methods, such as controlled release vaginal rings that can provide a continuous and constant supply of active compounds in situ for a period of weeks/months after the application of a single device, and semi-solid formulations that could be applied once-daily or even less frequently. The inhibitors that we will study include, but may not be limited to the small molecule CCRs inhibitor, CMPDi67 (Merck); the small molecule attachment inhibitor BMS-C (Bristol-Myers Squibb); the small molecule CXCR4 inhibitor AMD3465 (AnorMED); the GP4i-based peptide fusion inhibitor, T-1249 (Trimeris). We propose Research Project I Robin Shattock, Characterization of entry inhibitors in human cervical and rectal tissue models, and in dendritic cells; Research Project II Karl Malcolm, Practical Formulations of HIV-1 Entry Inhibitors; Research Project III Ronald Veazey, Testing practical microbicides in macaques; Virology and Immunology Core John P. Moore; Administrative Core John P. Moore. Other senior members of the team include Melissa Robbiani and Mark Mitchnick (Particle Sciences, Inc) who will participate in Research Projects I and III, respectively, under Cooperative Agreements, and Steven Wolinsky who will take part in the Virology and Immunology Core, also under a Cooperative Agreement. The involvement of Particle Sciences fulfills the mandated corporate element of the proposed research program. If this application is successfully peer reviewed and approved for support by the NIH, the International Partnership for Microbicides will provide the majority of the funding required to support the research programs headed by Drs. Shattock, Robbiani and Wolinsky, as outlined in the Program Overview section of the application. PROJECT 1 Characterization of entry inhibitors in human cervical and rectal tissue models, and dendritic cells (PI Shattock, Robin J.) PROJECT 1 The potential role of microbicides in preventing the mucosal transmission of HIV-1 has been clearly identified. However, rigorous pre-clinical evaluation of candidate microbicides is essential to the selection of the best compounds for clinical trials, since this will, in the end, provide savings in costs and time, given the expense and length of formal efficacy trials. Concerns with performing efficacy trials with incompletely optimized microbicide candidates have been highlighted by recent failed or halted Phase III trials (COL-1492, SAVVY and Cellulose Sulfate); these trials have suggested that development and formulation of effective microbicides may not be as easy as first thought. While mononuclear cell cultures and animal models may provide important information for the evaluation of microbicides, anatomical, physiological and immunological issues suggest they may not adequately model events that occur in human mucosal tissue. Therefore a comprehensive program for pre-clinical development of microbicide candidates requires that information be accrued from several different model systems. Hence Dr. Shattock´s and Robbiani´s groups have developed in vitro models of the earliest events in HIV-1 infection of human mucosal tissue and dendritic cell driven HIV-1 spread. These models are ideally suited to test the efficacy of agents designed to block HIV-1 sexual transmission and have been widely used to evaluate potential microbicide candidates. Furthermore, experiments described here and cross validation with experiments described in project III, may identify potential biomarkers of efficacy, safety and compliance that could inform future clinical trials. In this project, we will use these established models to evaluate the efficacy and compatibility of HIV-1 entry inhibitors (alone and in combination) and their formulations. This research will be influenced and guided by work carried out within Core A, and will involve extensive interactions and collaborations with the scientists leading Research Projects II and III. The interactions between the different groups will result in the fast-tracking of the most promising inhibitor combinations and formulations for evaluation in the macaque model (Research Project III)
Project start date: 2008-06-23
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: RFA-AI-07-001
5U19AI076982-04 (2011): $1358317
IMPLANTABLE MICROSYSTEMS FOR HUMAN NEUROPROSTHESIS
P John
Brown Universitycity: Providence country: United States (us)
Grant 5R01EB007401-05 from National Institute Of Biomedical Imaging And Bioengineering
Abstract: This BRP grant application describes a pioneering, integrated lightweight neuromotor prosthetic microsystem (NMP) for paralyzed humans NMPs use neural activity as a direct output to machines that run assistive devices. To meet this goal we have assembled an interdisciplinary team that combines leaders in neuroscience (Donoghue) and engineering (Nurmikko), with support from computer science (Black) at Brown University and neurology/neurosurgery at Brown and at Massachusetts General Hospital (Hochberg); experts in NMP design, development, manufacturing and commercialization from Cybernetics, Inc. (CKI), a neurotechnology company; and experts in neural prosthesis development and human application at the Cleveland FES center/Case Western University (H. Peckham/R. Kirsch). We will develop an integrated and implantable microelectronic neurosensor system that features on-chip signal processing and wide bandwidth transcutaneous wireless transmission capabilities. The high performance microsystem incorporates cutting-edge ultralow power microelectronics and is designed to be technologically flexible and modular, to enable scaling to increasingly complex neural signal extraction and manipulation. Its components imbed adaptive processors for automated calibration and set-up which exploit neural decoding algorithms, currently being developed at Brown, to provide a stable, multipurpose output signal. The microsystem implant will be first tested in animal models (motor cortex of monkeys) to establish efficacy, biocompatibility and biostability. We will input learning acquired from ongoing and future human trial patients with the present percutaneous cabling system to establish principles of human NMP operation for adapting the implantable microsystem design, the role of learning in NMP use, and the limits of human NMP control. We will pursue the federal regulatory pathways to gain approval for the NMP microsystem while developing the assistive technology for human patients. The end goal of this BRP grant is to achieve the implantation and testing of the new microsystem chronically in a human patient. t ´ The ultimate vision and guiding light for this BRP proposal is to develop the technological infrastructure to achieve a longer term goal, namely system is the restoration of semi-autonomous, closed-loop, distributed- feedback control of a limb that has lost spinal cord connection to the motor cortex
Keywords: Abdomen; Achievement; Algorithms; Animal Experimentation; Animal Model; Animal Testing; Animals; Applications Grants; Architecture; base; biomaterial compatibility; Bionics; Brain; Calibration; Chest; Clinical; Clinical Trials; commercialization; Communication; Complex; computer science; computerized data processing; Coupled; Cybernetics; Data; data exchange; design; Development; Devices; Diagnostic; Electrodes; Engineering; experience; Feedback; Fiber; Fiber Optics; Figs - dietary; Film; flexibility; FPS-FES Oncogene; Future; General Hospitals; Goals; Grant; Head; Human; Human Development; Implant; implantation; in vivo; Learning; Light; Limb structure; Link; Massachusetts; Measurement; Measures; meetings; Microelectrodes; microsystems; Miniaturization; miniaturize; Monitor; Monkeys; Motor Cortex; Movement; Muscle; Nerve; Nervous system structure; neural prosthesis; Neurology; Neurons; neuroprosthesis; Neurosciences; neurosurgery; neurotechnology; novel; operation; Operative Surgical Procedures; optical fiber; Output; Pacemakers; Paralysed; Pathway interactions; Patients; Pattern; Performance; Persons; pilot trial; Polymers; pre-clinical; Preclinical Testing; Principal Investigator; Process; programs; Prosthesis; Protocols documentation; prototype; Quadriplegia; Real-Time Systems; Regulatory Pathway; relating to nervous system; Research; Research Ethics Committees; Research Infrastructure; Research Personnel; response; restoration; Role; Running; Safety; Scheme; seal; Secure; Self-Help Devices; sensor; Signal Transduction; skills; Source; spatiotemporal; Speed (motion); Spinal Cord; Staging; Stream; subcutaneous; System; Technology; Telemetry; Testing; Tissues; Toxicology; transmission process; Universities; Validation; Vision; Wireless Technology
Project start date: 2007-06-01
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PAR-04-023
5R01EB007401-05 (2011): $1300399
FIFTH FORUM ON OSTEOPOROSIS AND METABOLIC BONE DISEASES FOR FELLOWS IN TRAINING
P John, Md
Columbia University Health Sciencescity: New York country: United States (us)
Grant 1R13AR061970-01 from National Institute Of Arthritis And Musculoskeletal And Skin Diseases
Abstract: This application seeks support for the 5th Fellows Forum on Osteoporosis and Metabolic Bone Diseases. The conference will be held Sept 14-15, 2011, one day before the Annual Meeting of the American Society of Bone and Mineral Research in the San Diego California Convention Center. We expect to have over 60 postdoctoral trainees who are united by their research interests but who are training in a number of different basic and clinical specialties. The faculty will consist of 10 of the most highly valued thought leaders in the world. The ability of young investigators with promise to interact with this faculty in a setting of both didactic and interactive workshops has been and will continue to be seminal experience, leading to a further commitment on the part of these fellows to train in this discipline. The application seeks support for the 5th Fellows Forum on Osteoporosis and Metabolic Bone Diseases that will be held at the San Diego Convention Center, in San Diego, California September 14-15, 2011
Keywords: American; Area; Basic Science; Biochemistry; Biomedical Engineering; bone; bone loss; California; career; Cellular biology; Clinical; Discipline; Educational workshop; Endocrinology; Equilibrium; Event; experience; Exposure to; Faculty; Functional disorder; Genetic; Geriatrics; Health; interest; knowledge base; Learning; medical specialties; meetings; Metabolic Bone Diseases; Minerals; Molecular; Orthopedics; Osteoporosis; Pathway interactions; posters; Principal Investigator; programs; Research; Research Personnel; Rheumatology; Seminal; skeletal; Societies; symposium; Therapeutic; Training; Women`s Health
Relevance: The application seeks support for the 5th Fellows Forum on Osteoporosis and Metabolic Bone Diseases that will be held at the San Diego Convention Center, in San Diego, California: September 14-15, 2011
Project start date: 2011-08-01
Project end date: 2012-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-10-071
1R13AR061970-01 (2011): $18000
RESEARCH EDUCATION PROGRAM IN ASPECTS OF STATISTICAL GENETICS AND ADDICTION
P John, Associate Professor Of Psychiatry
Washington Universitycity: Saint Louis country: United States (us)
Grant 5R25DA027995-03 from National Institute On Drug Abuse
Abstract: This application seeks five years of support to develop, evaluate and fine-tune a new research education program (WU-STAGEM Washington University Statistical Training in Addiction Genetics Methodology), to train postdoctoral level scientists (9 over the 5-year funding period). Trainees ("program participants") will include both US and foreign nationals, drawn from backgrounds such as biostatistics, mathematics, quantitative psychology and statistical genetics. We will provide trainees with both (i) the expertise to develop, test and apply new statistical and computational models to address genetics-based research problems in addiction, and (ii) sufficient training to allow participants to work collaboratively in multidisciplinary teams alongside basic and clinical researchers engaged in addiction research. Program postdoctoral scientists will train under the guidance of mentoring teams composed of (a) clinical researchers in addiction, (b) basic scientists and, most critically, (c) researchers with pertinent statistical or computational modeling expertise, with the support of individually tailored formal coursework. They will work with addiction geneticists at the host institution and elsewhere (e.g., through the NIDA Genetics Consortium) to identify and conduct research in areas where unique and urgently needed contributions to the field of addiction genetics can be made, producing products such as novel computer software, novel algorithms or approaches to statistical genetic analysis, to advance the field of addiction genetics. These priority areas will include (varying according to trainee backgrounds and interests and expert input) 1) incorporation of bioinformatics data in the statistical analysis and interpretation of GWAS data, 2) challenges in the combination of GWAS data across data-sets characterized by differing sampling schemes and somewhat different phenotypic assessments, and 3) modeling of genotype x environment interaction effects, and incorporation of consideration of GxE effects in efforts at gene-discovery. We will take advantage of existing data sets such as those at the NIDA Center for Genetic studies; zork.wustl.edu/nida/ and at dbGap, as well as more extensive data-sets associated with local investigators, in this training effort. Through infrastructure development and continuing evaluation efforts, building upon outstanding existing institutional strengths, we will seek to develop a self-sustaining program, drawing upon the wide-ranging expertise at Washington University that can supply highly trained experts in statistical and computational modeling to the field of addiction genetics. Licit and illicit drug dependence represents a considerable personal and public health burden. The important role of individual genetic vulnerability in contributing to addiction risk is well established. However, there is a critical shortage of investigators with expertise in statistical genetics and computational genomics working in addiction research, a need that this application seeks to address through its postdoctoral research education program
Keywords: addiction; Address; Advisory Committees; Algorithms; Area; base; Basic Science; Bioinformatics; Biological; Biometry; career development; Clinical; Clinical Research; Clinical Sciences; cognitive neuroscience; Communities; computer science; Computer Simulation; Computer software; computerized tools; Computing Methodologies; Consultations; Data; Data Set; database of Genotypes and Phenotypes; Development; disease classification; Drug Addiction; Educational aspects; Educational Curriculum; Educational process of instructing; Environment; Evaluation; experience; Faculty; Fellowship; flexibility; Funding; gene discovery; Genetic; genetic analysis; genetic epidemiology; Genetic Predisposition to Disease; Genetic Research; genome wide association study; Genomics; Genotype; Goals; Health; Human Genetics; Illicit Drugs; Individual; infrastructure development; innovation; Institutes; Institution; interest; International; Mathematics; member; Mentors; method development; Methodology; Modeling; multidisciplinary; National Institute of Drug Abuse; novel; Participant; Play; post-doctoral training; Postdoctoral Fellow; Postdoctoral Individual National Research Service Award; Procedures; Program Development; Program Evaluation; programs; Psychology; public health medicine (field); Qualifying; Recruitment Activity; Research; Research Personnel; Research Training; Resources; Respondent; Risk; Role; Sampling; Scheme; Science; Scientist; Series; Statistical Methods; Statistical Models; Testing; tool; tool development; Training; Training and Education; United States National Institutes of Health; Universities; Visit; Washington; Work
Relevance: NARRATIVE Licit and illicit drug dependence represents a considerable personal and public health burden. The important role of individual genetic vulnerability in contributing to addiction risk is well established. However, there is a critical shortage of investigators with expertise in statistical genetics and computational genomics working in addiction research, a need that this application seeks to address through its postdoctoral research education program
Project start date: 2009-09-01
Project end date: 2014-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PAR-08-081
5R25DA027995-03 (2011): $508396
MULTISITE CONTROLLED TRIAL OF COCAINE VACCINE (5 OF 6) NEW YORK UNIVERSITY TREATM
P John, Professor
New York University School Of Medicinecity: New York country: United States (us)
Grant 5R01DA025248-02 from National Institute On Drug Abuse
Abstract: This 16 week, six site, placebo-controlled randomized, clinical trial (PC-RCT) among 300 cocaine dependent patients is designed to test the efficacy of a newly developed active vaccine against cocaine (TA-CD). All six sites have substantial NIDA experience in conducting PC-RCT with cocaine pharmacotherapies. The primary objective of this study is to evaluate the efficacy of two different doses of TA-CD (100 or 400 ug) versus placebo to increase the number of cocaine-free days across treatment groups in cocaine-dependent patients. Secondary objectives of this study are to evaluate safety and tolerability of five injections of TA-CD, to evaluate immunogenicity of TA-CD, to investigate any correlation between change in levels of cocaine use, craving, or subjective effects of cocaine and antibody levels, and finally, to examine predictors of treatment response. Previous work with the TA-CD vaccine has shown both doses (100 and 400 ug) and a regimen of 5 injections over 12 weeks are clinically safe and produce substantial levels of anti-cocaine antibody. During a previous PC-RCT, cocaine abusers with these anti-cocaine antibodies (AB) substantially reduced their smoked cocaine and had a significant reduction in overall cocaine use. That study also showed an expected variation in AB levels was a determinant of therapeutic response (e.g. higher AB levels were associated with a greater reduction in cocaine use). That previous PC-RCT provided effect size data for calculating the sample size of 300 with a potential dropout of up to 30%. In order to enhance retention in this 16-week study, we will use contingency management (CM), which in a pilot study provided outstanding retention of over 80% for a 16 week study. To complete this study within a 3 year period and have reasonable accrual and retention of this difficult population requires participation of six sites. These six extremely well-qualified research groups have comparable and complementary skills that can examine innovative ways to deliver a medical therapy through vaccination. The six sites are Baylor College of Medicine (BCM), (lead); University of Cincinnati; Johns Hopkins University; University of Pennsylvania; New York University; and, Columbia University. All of these collaborators are working with the pharmaceutical manufacturer--Celtic, and NIDA to help with data management and laboratory-processing for quantitative urine toxicology. New approaches are needed to help treat those addicted to cocaine to successfully keep from relapsing to drug abuse after withdrawal. Vaccines that stimulate strong antibody responses against cocaine will help such individuals by blocking the drug craving that occurs after re-exposure to cocaine in someone who has been abstinent. This research will define ways to make and effectively use such vaccines to stimulate high antibody levels that will have the best chance of success
Keywords: 8-Azabicyclo(3.2.1)octane-2-carboxylic acid, 3-(benzoyloxy)-8-methyl-, methyl ester, (1R-(exo, exo))-; Abstinence; abuse of drugs; abuses drugs; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Active Follow-up; Acute; addiction; Addiction, Drug; Address; Administrative Coordination; Adverse effects; AIDS; AIDS pharmacotherapy; Analysis, Data; Antibodies; antibody biosynthesis; Antibody Formation; Antibody Production; Antibody Response; Antigen-Antibody Complex; Articulation; Assay; Attenuated; Authorship; Back; base; Behavior Therapy, Cognitive; Behavioral Therapy; Benzeneethanamine, N, alpha-dimethyl-, (S)-; benzoyl ecgonine; benzoylecgonine; Binding; Binding (Molecular Function); Bioassay; Biologic Assays; Biological Assay; Blood - brain barrier anatomy; Blood Circulation; Blood-Brain Barrier; Bloodstream; Brain; Censuses; Chemical Dependence; Cholera Toxin B Subunit; Cholera Toxin Protomer B; Choleragenoid; Circulation; clinical investigation; Clinical Trials; Clinical Trials, Unspecified; Cocaine; Cocaine Abuse; cocaine exposure; cocaine use; cognitive behavior intervention; cognitive behavior modification; cognitive behavioral intervention; cognitive behavioral modification; cognitive behavioral therapy; Cognitive Therapy; college; Communication; Complement; Complement Proteins; conference; Connecticut; contingency management; control trial; coping; cost; Coupled; craving; Crystal Meth; Data; Data Analyses; Data Analysis, Statistical; Data Interpretation, Statistical; data management; Deoxyephedrine; Dependence, Drug; Depression; design; designing; Desoxyephedrine; Dorsum; Dose; drip infusion; Dropout; Drug abuse; Drug Addiction; drug craving; Drug Dependency; Drug Therapy; Drug usage; drug use; drug/agent; Drugs; Drugs, Illicit; E-Mail; Educational process of instructing; efficacy testing; electronic data; Electronic Mail; Email; Encephalon; Encephalons; Evaluation; experience; follow-up; Health; heavy metal lead; heavy metal Pb; Hemato-Encephalic Barrier; Human; Human, General; Illicit Drugs; Immune Complex; immunogenicity; immunoglobulin biosynthesis; Immunologic Deficiency Syndrome, Acquired; Immunology; Immunology (Including BRMP); Immunology (NCI Program); Individual; Industry; Injection of therapeutic agent; Injections; innovate; innovation; innovative; intravenous administration; Intravenous Drip; Intravenous Infusion; Investigators; IV drip; Joints; Laboratories; Lead; Letters; Man (Taxonomy); Man, Modern; Manuals; Manufacturer; Manufacturer Name; Measures; Medical; Medication; Medicine; meetings; Mental Depression; Methamphetamine; Methylamphetamine; Molecular Interaction; Monitor; multi-site trial; N-Methylamphetamine; National Institute of Drug Abuse; Nervous System, Brain; new approaches; new vaccines; New York; next generation vaccines; NIDA; novel approaches; novel strategies; novel strategy; novel vaccines; Nucleus Accumbens; Out-patients; Outcome; Outpatients; Paper; Patient Self-Report; Patients; Pb element; PBO; Pennsylvania; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacists; Pharmacologic Substance; Pharmacological Substance; Pharmacotherapy; Phone; Pilot Projects; pilot study; Placebo Control; placebo controlled study; placebo controlled trial; Placebos; Population; prevent; preventing; primary outcome; Procedures; Process; programs; Programs (PT); Programs [Publication Type]; Psychotherapy, Cognitive; public health relevance; Publications; Qualifying; randomisation; randomization; Randomized; Randomized Clinical Trials; randomized placebo controlled study; randomized placebo controlled trial; randomly assigned; rapid method; rapid technique; Recombinants; recruit; Recruitment Activity; Regimen; Relapse; Reporting; Research; Research Personnel; Researchers; response; Risk; Route; Safety; Sample Size; Sampling; SCHED; Schedule; Science of Medicine; Scientific Publication; Self-Report; sham therapy; Sham Treatment; side effect; Site; skills; Smoke; Smoking; Statistical Data Analyses; Statistical Data Interpretation; Structure; Study Section; success; symposium; Teaching; Telephone; Testing; Therapeutic; therapy adverse effect; Therapy, Cognition; Time; TimeLine; Toxicology; Training; treatment adverse effect; treatment response; Treatment Side Effects; Universities; Update; Urinary System, Urine; Urine; Vaccination; vaccine effectiveness; vaccine efficacy; Vaccines; Variant; Variation; vein infusion; Withdrawal; Work; Writing
Project start date: 2008-09-01
Project end date: 2013-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PAR-07-232
5R01DA025248-02 (2011): $377561
INFLUENCE OF MATERNAL ANTIBODIES ON A SENDAI VIRUS-VECTORED RSV VACCINE
P John, Member
St. Jude Children´s Research Hospitalcity: Memphis country: United States (us)
Grant 5R01AI088729-02 from National Institute Of Allergy And Infectious Diseases
Abstract: There is currently no vaccine or standard treatment for RSV. However there is clearly an unmet medical need RSV is responsible for approximately 100,000 hospitalizations per year in the U.S. alone, and is globally responsible for more than 150,000 deaths per year. The continued absence of vaccines and standard treatments for RSV disease represents an important and serious gap in preventive medicine. In response to RFA AI-09-016, investigators from St. Jude Children´s Research Hospital, Novartis Vaccines and Diagnostics, Inc., and Le Bonheur Children´s Medical Center are proposing a partnership to expedite RSV vaccine development. Recombinant murine Sendai virus (SeV) expressing RSV F glycoprotein (rSeV-RSV-F) is an extremely attractive candidate for an RSV vaccine. This xenotropic vaccine elicits rapid and durable protection against RSV in an animal model and is associated with no enhanced immunopathology upon RSV infection. Since an RSV vaccine will need to protect infants, and since maternal antibodies can reduce the efficacy of replicating and non-replicating vaccines, fundamental questions concerning vaccine-antibody interactions must be addressed prior to clinical development of rSeV-RSV-F. Our Central Hypothesis is that the rSeV-RSV-F vaccine will confer RSV protection to infants, even in the presence of maternal antibodies. Our Specific Aims are (1) To determine the relative functional titers of anti-SeV (PIV1) and anti-RSV antibodies in human infants, (2) To determine the influence of maternal antibodies on rSeV-RSV-F vaccine efficacy (in a cotton rat model), and (3) To optimize vaccine by formulation and regimen. When optimized vaccine doses/formulations/regimens are identified, these will be further tested (i) to ensure the absence of enhanced immunopathology, (ii) to measure response durability, and (iii) to measure immune correlates of protection. Data from these experiments will have broad application to the pediatric vaccine field, and will be critical to the launch of clinical trials with rSeV-RSV-F
Keywords: Address; Age; age group; Animal Model; Antibodies; Antibody Binding Sites; Antigen Targeting; Antigens; Attenuated; base; Binding (Molecular Function); Birth; Blocking Antibodies; Blood; Calendar; Cessation of life; Child; Childhood; Clinical; Clinical Trials; Cotton Rats; Crowding; Data; Development; Development Plans; Diagnostic; Discipline of Nursing; Disease; Dose; Drug Formulations; Ensure; Environment; Glycoproteins; Homologous Gene; Hospitalization; Human; Immune; Immunoglobulin G; immunopathology; improved; Infant; Infection; Intramuscular Injections; Life; Maternal antibody; Measures; Medical; Medical center; Modeling; Morbidity - disease rate; Mortality Vital Statistics; Mus; Nasal Lavage Fluid; Needles; neutralizing antibody; Nose; Para-Influenza Virus Type 1; Pattern; Placenta; polymeric IgA; prevent; Preventive Medicine; product development; prophylactic; public health medicine (field); Recombinants; Regimen; Relative (related person); Research; Research Personnel; research study; Respiratory Syncytial Virus Vaccines; Respiratory System; Respiratory tract structure; response; Safety; Saint Jude Children`s Research Hospital; Sendai virus; Serum; Source; standard care; Testing; Time; Toddler; trafficking; transcytosis; Upper respiratory tract; vaccine candidate; vaccine development; vaccine efficacy; Vaccines; Vertebral column; Virus; Work
Relevance: Public Health Statement: Despite decades of work, no successful RSV vaccine has yet been developed. The long-term objectives of our research is to develop an RSV vaccine to prevent RSV- induced morbidity and mortality in humans
Project start date: 2010-04-01
Project end date: 2015-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: RFA-AI-09-016
5R01AI088729-02 (2011): $576912
TRANSLATIONAL ONCOLOGY PROGRAM
P John, Clinical Professor
University Of California Irvinecity: Irvine country: United States (us)
Abstract: The Translational Oncology (TO) Program´s mission is to develop clinical trials that promote interaction between basic scientists, translational scientists, and clinicians to facilitate improved clinical outcomes. During the last review period the Program was organized into the following three thematic areas that are emphasized in disease-specific working groups (1) Develop and carry out early phase clinical trials with a goal to translate findings into the cooperative group or phase III setting; (2) Facilitate inclusion of predictive and prognostic biomarker profiles in clinical trials; (3) Develop novel therapeutic approaches related to antiangiogenesis agents, signaling pathways and reactive oxygen species (ROS). In order to promote interprogrammatic and intra-programmatic interactions and translational activities, disease specific translational working groups (TWGs) were recently established for melanoma, breast, Gl, prostate and cervical/GYN cancers. Clinical trials coupled to translational endpoints have been developed through inter-programatic collaborations with other Programs, including Oncoimaging (Neoadjuvant breast), and Cacinogenesis and Signaling (CML, prostate). Over the past five years, our Program has focused on accrual to clinical research trials, including Hypothesis-driven, investigator-initiated trials (HDII), cooperative group, and pharmaceutical sponsored trials. Emphasis has been placed on HDII trials to exploit UCI´s rich Comprehensive Cancer Center resources to develop novel approaches to cancer care. HDII accrual over the past six years has grown dramatically from 60 in 2002-2004 to 175 in 2005-2007. Overall interventional clinical trials accrual, excluding chemoprevention trials, was 142 in 2002-2003, increasing to 218 in 2004-2005, and 387 to date in 2005-2007, Of particular significance, this growth in accrual was linked to translational endpoints that led to peer reviewed funding and increased numbers of publications in high impact journals. The TO Program has 25 Members, representing eight Departments and one School, and has $2,024,203 in direct cancer-related peer-reviewed funding, 10 projects of which are funded by NCI for a direct total of $1,187,498. In 2007, Members published a total of 71 publications with 62 of those being cancer-related of which 44% were inter- and 16% were intra-related
Keywords: Active Oxygen; Angiogenesis Antagonists; Angiogenesis Blockers; Angiogenesis Inhibitors; Angiogenetic Antagonists; Angiogenic Antagonists; Angiostatic Agents; Anti-Angiogenetic Agents; Anti-Angiogenic Agents; Anti-Angiogenic Drugs; Antiangiogenesis Agents; antiangiogenic; Antiangiogenic Agents; Area; biological signal transduction; biomarker; Breast; Breast Melanoma; cancer care; Cancer Center; Cancer Center of University of California Irvine; Cancer Center Support Grant; Cancer, Oncology; Cancers; CCOP; CCSG; Cell Communication and Signaling; Cell Signaling; Cervical; Chao Family Comprehensive Cancer Center of University of California Irvine; Chemoprevention; Clinical; clinical applicability; clinical application; clinical investigation; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Collaborations; Community Clinical Oncology Program; Community Oncology; Comprehensive Cancer Center; Core Grant; Coupled; Development; Disease; disease/disorder; Disorder; Funding; Generalized Growth; Genital System, Male, Prostate; Goals; Grant; Growth; heavy metal lead; heavy metal Pb; Human Prostate; Human Prostate Gland; improved; Individual; Induction Therapy; Inhibitors, Angiogenetic; Inhibitors, Angiogenic; interest; Intracellular Communication and Signaling; Investigators; Journals; language translation; Lead; Link; Magazine; malignancy; Malignant Melanoma of the Breast; Malignant Neoplasms; Malignant Tumor; Manuscripts; member; Mission; Monitor; NEOADJ; Neoadjuvant; Neoadjuvant Therapy; Neoadjuvant Treatment; neoplasm/cancer; Neovascularization Inhibitors; new approaches; novel; novel approaches; novel strategies; novel strategy; novel therapeutic intervention; oncology; Oncology Programs; ontogeny; Outcome; Oxygen Radicals; P30 Grant; Pb element; Peer Review; Pharmaceutical Agent; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phase; Pro-Oxidants; prognostic; programs; Programs (PT); Programs [Publication Type]; Prostate; Prostate Gland; Prostatic Gland; Publications; Publishing; Reactive Oxygen Species; Research Personnel; Research Resources; Researchers; Resources; Schools; Scientific Publication; Scientist; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Tissue Growth; Translating; Translatings; translation research enterprise; Translational Research; Translational Research Enterprise; Translational Science; University of California Irvine Cancer Center; working group
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
5P30CA062203-16_5594 (2011): $21349
NEW ALKENE DIFUNCTIONALIZATION REACTIONS FOR ORGANIC SYNTHESIS
P John, Associate Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 1R01GM098314-01 from National Institute Of General Medical Sciences
Abstract: The stereoselective construction of saturated heterocycles remains an important challenge in organic synthesis, as many biologically active natural molecules contain these subunits. Although the development of methods for the construction of heterocycles has been of longstanding interest, a number of important targets are difficult to generate in a stereoselective manner using existing transformations. In addition, many methods are not readily amenable to the preparation of numerous analogs from a single precursor. The long-term goal of our research program is to develop new reactions for the construction of enantiomerically enriched, biologically active heterocycles. The objectives of the research outlined in this proposal, which represent significant steps toward our long term goal, are to develop new alkene carboheterofunctionalization reactions for the synthesis of several specific classes of biologically relevant heterocycles, and to develop new catalysts for asymmetric carboheterofunctionalization reactions. These objectives will be achieved by pursuing three specific aims (1) to develop new alkene carboheterofunctionalization reactions for the construction of complex bicyclic heterocycles; (2) to develop new asymmetric alkene carboheterofunctionalization reactions; and (3) to develop new alkene carboheterofunctionalization reactions for the enantioselective synthesis of molecules bearing acetal or aminal stereocenters. All three aims involve the invention of new types of Pd-catalyzed reactions of aryl/alkenyl halides with amines/alcohols bearing pendant alkenes. These reactions will form two bonds and two stereocenters in one step to generate the desired heterocycles in an efficient and stereoselective manner, and will be applied to the synthesis of biologically significant targets. The proposed studies are innovative because they will lead new strategy-level disconnections that can be applied to complex molecule synthesis by a variety of chemists in both industry and academia. In addition, these studies will extend the forefront of alkene carboheterofunctionalization processes, and will provide insight into factors that can be used to control asymmetric induction in this important class of transformations. The knowledge gained can be used for the future development of other new reactions. The proposed research is significant because the new transformations developed during these studies will provide facile access to important biologically active compounds that are difficult to generate with existing methods. This will broaden the range of heterocyclic building blocks available for use in medicinal chemistry/drug development. In addition, these new transformations will also allow for facile generation of analogs of interesting molecules, which can be used to optimize biological or pharmaceutical properties of lead compounds. The proposed research is relevant to public health, because these studies will lead to new methods for the synthesis of medicinally relevant compounds. These new synthetic methods will provide access to biologically active molecules that cannot be prepared using existing chemical transformations, which will be of great utility for the development of new pharmaceuticals that are beneficial to human health
Keywords: Academia; Acetals; Alcohols; Alkaloids; Alkenes; Amines; analog; Anti-Arrhythmia Agents; Anti-inflammatory; Anti-Inflammatory Agents; Biological; Biological Factors; Carbon; catalyst; Chemicals; Complex; Development; drug development; Electronics; Esters; Exhibits; functional group; Funding; Future; Generations; Goals; Health; Human; Industry; innovation; insight; interest; Knowledge; Lead; Ligands; Local Anesthetics; Metals; method development; Methods; One-Step dentin bonding system; Organic Synthesis; Pharmaceutical Chemistry; Pharmacologic Substance; Phosphites; phosphoramidite; Phosphorous; pi bond; Positioning Attribute; Preparation; Process; programs; Property; public health medicine (field); pyrrolidine; Pyrrolidines; Reaction; Relative (related person); Research; Route; scaffold; Series; stereochemistry; Stereoisomer; tetrahydrofuran
Relevance: The proposed research is relevant to public health, because these studies will lead to new methods for the synthesis of medicinally relevant compounds. These new synthetic methods will provide access to biologically active molecules that cannot be prepared using existing chemical transformations, which will be of great utility for the development of new pharmaceuticals that are beneficial to human health
Project start date: 2011-09-01
Project end date: 2015-04-30
Budget start date: 1-SEP-2011
Budget end date: 30-APR-2012
PFA/PA: PA-10-067
1R01GM098314-01 (2011): $280656
BASIC AND TRANSLATIONAL RESEARCH IPSC-BASED HEMATOLOGIC AND VASCULAR THERAPIES
P John, Professor Of Medicine
Stanford Universitycity: Stanford country: United States (us)
Grant 5U01HL100397-03 from National Heart, Lung, And Blood Institute
Abstract: The Stanford-Johns Hopkins Research Hub intends to gain a deeper understanding of molecular pathways to enhance the efficiency of nuclear reprogramming, to ensure the function and safety of induced pluripotential cells (IPSCs), to provide robust protocols for differentiation and purification of hematopoietic and endothelial lineages, and to guide pioneering work in pre-clinical studies of safety and efficacy. The Stanford group proposes three research projects. Project 1 Novel Regulators to enhance IPSC Derivation and Differentiation to EC (Helen Blau, Wing Wong). Using a novel cell fusion approach, we will identify the early epigenetic and transcriptional changes occurring during nuclear reprogramming of the human fibroblast nucleus after cell fusion with mouse ESC. Species-specific transcriptome amplification of the human RNA within the heterokaryon transcripts permits identification of the earliest transcriptional events in the human nucleus during reprogramming. Using the same cell fusion strategy, we will also elucidate the earliest events of directed differentiation toward endothelial cells. In Project 2 IPSC Engineering and Characterization (Renee Reijo Pera, James Swartz) we will develop and refine a protein-based strategy for generating iPSCs. We will synthesize cell-permeant fusion proteins comprising the Yamanaka factors with transduction domains, and optimize their dose, duration and timing to induce optimal reprogramming. Novel factors identified in Project 1 will be incorporated to enhance reprogramming. Comprehensive characterization of the safety and efficacy of these cells will include spectral karyotyping, mitochondrial gene expression and function, and epigenetic, transcriptional and tumorigenic profiling. In Project 3 iPSC-ECs for Therapeutic Angiogenesis Determinants of Differentiation and Function (John Cooke), we will utilize the IPSC generated in Project 2, and the insights from Project 1 (and our Hopkins colleagues), to efficiently direct differentiation of the IPSC to endothelial lineage. EC function will be assessed in vitro and in vivo, and their therapeutic efficacy studied using molecular imaging and laser Doppler perfusion in a murine model of peripheral arterial disease. We intend that the insights from these projects ultimately lead to novel vascular therapies
Project start date: 2009-09-30
Project end date: 2016-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: RFA-HL-09-004
5U01HL100397-03 (2011): $1188317
3U01HL100397-03S1 (2011): $49566
Sponsored Links Excellgen http://Excellgen.com
MOLECULAR DEFINITION OF THE SLOW AHP CHANNELS IN CA1 NEURONS
P John, Senior Scientist
Oregon Health And Science Universitycity: Portland country: United States (us)
Grant 5R21NS071314-02 from National Institute Of Neurological Disorders And Stroke
Abstract: The slow afterhyperpolarization (sAHP) that follows an action potential in many central and peripheral neurons is due to the activation of voltage-independent, Ca2+-activated K+ channels. Hippocampal CA1 neurons have served as models for studying the sAHP and the underlying current, the IsAHP. The results of studies performed over the past two decades show that the sAHP has a profound influence on neuronal intrinsic excitability, being responsible for spike-frequency adaptation that regulates burst frequency. The sAHP is one of the principal targets for the ascending modulatory neurotransmitter systems that are involved in regulating the sleep-wake cycle, arousal, attention, and in modulating sensory processing, behaviors, emotions and memory consolidation. Importantly, the (I)sAHP decreases following learning, increasing intrinsic excitability. In addition, the (I)sAHP increases with age, reducing intrinsic excitability, and this age-related increase plays an integral role in the learning impairments that accompany normal aging. A similar increase in the (I)sAHP occurs in Alzheimer´s disease models. The (I)sAHP channels are defined by Ca2+-dependence, voltage-independence, K+-selectivity, and invariant slow activation kinetics. Indistinguishable (I)sAHPs have been recorded from hippocampal CA1and CA3, layers II-III of the cortex, (lateral) amygdala, and (midline) thalamus. SK channels and M-channels have been suggested to form the (I)sAHP channels, but there is abundant contradictory evidence. Therefore, despite decades of work, the molecular identity of the (I)sAHP channels remains to be determined. We have used bioinformatic genome analysis coupled with the functional characteristics of cloned channels, results from knockout mice, and detailed cell-type expression data for all K+ channel genes to identify 2 high priority candidates for the (I)sAHP channels. We propose to use a combination of molecular biological and electrophysiological techniques to test these candidates and identify clones encoding the pore-forming subunits of the (I)sAHP channels. Determining the identities of the (I)sAHP channels will provide a powerful target for therapeutic approaches to multiple central pathologies such as Alzheimer´s disease, schizophrenia, epilepsy, attention deficit syndrome, and sleep disorders, as well as for cognitive impairment during normal aging. The slow afterhyperpolization (AHP) channels regulate intrinsic excitability in many central neurons, and their activity is important for normal sleep-wake cycle, arousal, attention, and in modulating sensory processing, behaviors, emotions and memory consolidation. We will clone the slow AHP channels and define their requisite components. Determining the identities of the slow AHP channels will provide a powerful target for therapeutic approaches to multiple central pathologies such as Alzheimer´s disease, schizophrenia, epilepsy, attention deficit syndrome, and sleep disorders, as well as for cognitive impairment during normal aging
Keywords: Action Potentials; Age; age related; Alzheimer`s Disease; Alzheimer`s disease model; Amygdaloid structure; Area; Arousal; Attention; base; Behavior; Bioinformatics; Biological; Calcium-Activated Potassium Channel; Candidate Disease Gene; cell type; Characteristics; Chinese Hamster Ovary Cell; Coupled; Data; deficit syndrome; Dependence; Dominant-Negative Mutation; Emotions; Epilepsy; Frequencies (time pattern); Future; Genes; Genome; Health; Hippocampus (Brain); Impaired cognition; Impairment; Injection of therapeutic agent; Kinetics; Knock-out; Knockout Mice; Lateral; Learning; Measures; Memory; Molecular; Neurons; Neurotransmitters; normal aging; Pathology; Peripheral; Play; Potassium Channel; Proteomics; research study; Role; Schizophrenia; Sensory Process; Sleep Disorders; Sleep Wake Cycle; Small Interfering RNA; Study models; System; Techniques; Testing; Thalamic structure; therapeutic target; Transgenic Mice; Viral; Virus; voltage; Whole-Cell Recordings; Work
Relevance: The slow afterhyperpolization (AHP) channels regulate intrinsic excitability in many central neurons, and their activity is important for normal sleep-wake cycle, arousal, attention, and in modulating sensory processing, behaviors, emotions and memory consolidation. We will clone the slow AHP channels and define their requisite components. Determining the identities of the slow AHP channels will provide a powerful target for therapeutic approaches to multiple central pathologies such as Alzheimer´s disease, schizophrenia, epilepsy, attention deficit syndrome, and sleep disorders, as well as for cognitive impairment during normal aging
Project start date: 2010-05-01
Project end date: 2012-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-09-164
5R21NS071314-02 (2011): $188650
1R21NS071314-01 (2010): $231000
RUNT-DEPENDENT REGULATION OF ENHANCER-PROMOTER INTERACTIONS
P John, Professor
State University New York Stony Brookcity: Stony Brook country: United States (us)
Grant 1R01GM094401-01A1 from National Institute Of General Medical Sciences
Abstract: The regulation of gene transcription is critical for the development of multi-cellular organisms and aberrations in transcriptional regulation are frequently associated with disease. The regulation of transcription involves cis-regulatory DNA sequences that interact with DNA-binding transcription factors and integrate information that is communicated to the promoter to control the synthesis of mRNA transcripts by RNA polymerase. Cis-regulatory elements in eukaryotes can be located upstream, downstream, or even within the transcribed region of a gene, and in animal systems extending from fruit fly to man are frequently many kilobases removed from the transcription start site. The expression of genes in different cell types at different stages of development is reflected by the occurrence of multiple cis-regulatory elements, each of which interacts with different sets of transcription factors to integrate the control signals that eventually result in gene transcription. Although interactions between different cis-elements and the transcription unit are central to this strategy of controlling gene expression, there is as of yet no clear understanding of how enhancer-promoter interactions are regulated. The tools available in the Drosophila system in conjunction with the framework of knowledge on the pathway responsible for generating the segmented body pattern of the early embryo provide a valuable model for investigating the in vivo mechanisms of transcription regulation. A key player in the segmentation pathway is Runt, the founding member of a family of transcriptional regulators with wide-ranging roles in animal development and human disease. The work in this proposal emanates from studies on sloppy-paired-1 (slp1), a target of Runt in the segmentation pathway that offers numerous advantages for dissecting transcriptional control mechanisms. The initial metameric expression of slp1 is generated in response to a simple combinatorial code that is mediated by two distinct cis-elements. Importantly, the two elements together generate a pattern beyond what is expected from the additive combination of their independent patterns. A model accounting for the functional interplay between these elements proposes a novel role for Runt in regulating interactions between these two elements and the slp1 promoter. The proposed work further investigates the molecular basis for this regulatory phenomenon and includes experiments asking whether a similar regulation of enhancer-promoter interactions contributes to the expression of other genes in the early embryo. The results will provide new insights on the mechanisms of regulation by Runt and other transcription factors that are likely to have widespread implications for understanding the roles of related proteins in human development and disease. The proper regulation of gene expression is critical for development and aberrations in gene regulation are frequently associated with disease. This project takes advantage of the genetic framework and tools available in the Drosophila system to investigate basic mechanisms used to regulate gene expression during embryonic development. The work focuses on understanding the regulation of non-additive interactions between distinct cis-regulatory DNA elements by Runt, the founding member of a protein family with profound roles in human development and disease
Keywords: Accounting; Animals; base; Binding Sites; Biochemical; Biological Assay; Blastoderm; Body Patterning; cell type; Cells; Chromatin; Code; combinatorial; Development; Disease; Distal; DNA; DNA Binding; DNA Sequence; DNA-Directed RNA Polymerase; Drosophila genus; Elements; Embryo; Embryonic Development; Enhancer Elements (Genetics); Enhancers; Eukaryota; Family; Fushi tarazu transcription factors; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; homeodomain; Human Development; human disease; Imaging Techniques; In Situ; in vivo; Indium; Individual; insight; Knowledge; Laboratories; man; Mediating; member; Messenger RNA; Modeling; Molecular; Molecular Conformation; Mutate; novel; Organism; Output; Pathway interactions; Pattern; Promotor (Genetics); Property; Protein Family; Proteins; public health relevance; Regulation; Regulatory Element; Reporter Genes; Research; research study; response; Response Elements; Role; Signal Transduction; Site; Staging; Structure; System; Testing; tool; Transcript; transcription factor; Transcription Factor 3; Transcription Initiation Site; Transcriptional Regulation; Transgenic Organisms; Work
Relevance: The proper regulation of gene expression is critical for development and aberrations in gene regulation are frequently associated with disease. This project takes advantage of the genetic framework and tools available in the Drosophila system to investigate basic mechanisms used to regulate gene expression during embryonic development. The work focuses on understanding the regulation of non-additive interactions between distinct cis-regulatory DNA elements by Runt, the founding member of a protein family with profound roles in human development and disease
Project start date: 2011-04-01
Project end date: 2015-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-10-067
1R01GM094401-01A1 (2011): $240540
TRAINING PROGRAM IN ENDOCRINOLOGY AND METABOLISM
P John, Md
Columbia University Health Sciencescity: New York country: United States (us)
Grant 3T32DK007271-33S1 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The purpose of this training program in endocrinology and metabolism is to provide an opportunity for promising post-doctoral individuals of exceptional quality to train for careers in academic endocrinology and biomedical research. The Program has been supported by this training grant mechanism for over 45 years and presents a record among its graduates of superb training and major academic achievement. The central features of the Program include intensive research in the laboratory of the participating faculty member and didactic exposure to basic science and clinical investigation. Research areas span a wide range of endocrinological disciplines with centers of excellence in neuroendocrinology, metabolic bone diseases, diabetes, reproductive endocrinology, endocrine genetics, lipoprotein metabolism, molecular endocrinology, endocrine protein and glycoprotein chemistry, and signal transduction. The scientific methods of the faculty include classical endocrinological techniques of basic and clinical investigation as well as the most modern biochemical and molecular studies of hormone action. Expertise in biochemistry, cell biology, molecular biology, mouse genetics, and physiology are all well-represented by the faculty. Highly experienced clinical investigators provide expertise to fellows in a wide variety of subspecialties with neuroendocrinology, metabolic bone diseases, diabetes, and lipoprotein metabolism featured as particular strengths. Primary facilities are centralized in the Division of Endocrinology in the Department of Medicine. Participating laboratories outside the Division of Endocrinology extend opportunities for endocrinology training to laboratories in the Departments of Physiology and Biophysics, Genetics and Development, Pediatrics, Microbiology, Anatomy and Cell Biology, Pharmacology, and Nutrition. Trainees are selected from a very competitive pool of applicants after a thorough review of their credentials and interviews with the directors of the Program. Fewer than 2% of applicants are selected. The majority of trainees go on to careers in investigative endocrinology. The Program focuses upon applicants who hold the MD or MD/PhD degree and have a strong interest in or prior exposure to research
Keywords: Endocrinology; Training Programs
Project start date: 1977-09-30
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-06-468
3T32DK007271-33S1 (2011): $61813
5T32DK007271-33 (2011): $236793
3T32DK007271-33S2 (2011): $28944
3T32DK007271-33S3 (2011): $32184
OBESITY PREVENTION/CONTROL /COMMUNITY RECREATION CENTERS
P John, Professor
San Diego State Universitycity: San Diego country: United States (us)
Grant 5R01DK072994-05 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The purpose of this study is to design, implement, and evaluate a recreation site-based obesity preventio and control intervention for 7-9 year old children and their families by targeting physical activity and dietar behaviors. The intervention will target the home as well as community environment (specifically urba recreation centers; but also, other aspects of the neighborhood). This study will produce innovations i obesity interventions and the understanding of mediators of change. Recreationcenters are an importan public resource whose contribution to physical activity promotion is unknown but has the potential to b significant The primary aim is to evaluate the effectiveness of a multi-level intervention to prevent the onset o overweight and obesity in 7-9 year old children. The recreation center site intervention emphasizes change in quantity and quality of physical activity and nutrition-related offerings within the centers. The home sit intervention will target the home and household rule setting delivered via recreation center-based communit health advisors and tailored to the needs of the family. Community health advisors will work in home an neighborhood environments to advocate environmental change Secondary research aims include 1. To modify the setting and enforcement of rules and to establish home environmental controls o childhood nutrition and physical activity behaviors; and to assess the extent to which changes in thes mediators lead to changes in proximal outcomes (physical activity, sedentary behavior, and nutrition) 2. To determine and attempt to modify patterns of setting and enforcement of rules and hom environmental control of childhood nutrition and physical activity, and to assess the extent to which change in these mediators lead to changes in proximal outcomes (physical activity, sedentary behavior, an nutrition) 3. To determine mediators (barriers and facilitators) of healthy and unhealthy eating and physica activity/sedentary behavior in recreation centers, and to assess the extent to which changes in thes mediators lead to changes in proximal outcomes (physical activity, sedentary behavior, and nutrition) 4. To develop and apply observational measures of physical activity and dietary behaviors (adapted fro SOPLAY) appropriate for recreation centers and parks 5. To assess the impact of hypothesized intervention moderator variables (e.g., race/ethnicity demographics, acculturation, immutable environmental factors) on behavioral and weight outcomes
Keywords: 0-11 years old; 9 year old; Acculturation; Acculturations; adiposity; Advocate; base; Behavior; Behavioral; Beverages; Child; Child Youth; Childhood; children; Children (0-21); Communities; Community Health; Conditional Variables; corpulence; corpulency; corpulentia; Cultural Assimilation; demographics; design; designing; Eating; Eating Behavior; Effect Modifiers (Epidemiology); Effectiveness; Environment; environmental change; Environmental Factor; environmental risk; Environmental Risk Factor; Ethnic Origin; Ethnicity; Ethnicity aspects; Family; Food Intake; fruits and vegetables; Health; heavy metal lead; heavy metal Pb; Home; Home environment; Household; Human, Child; innovate; innovation; innovative; Intervention; Intervention Strategies; interventional strategy; Lead; Measures; Mediator; Mediator of Activation; Mediator of activation protein; Moderator Variables; Modifiers, Epidemiologic Effect; Neighborhoods; nine year old; nutrition; Nutrition; Nutritional Science; obese; obese people; obese person; obese population; Obesity; obesity prevention; Outcome; Over weight; Overweight; Pattern; Pb element; pediatric; Physical activity; prevent; preventing; Race; Racial Group; Recreation; Research; Research Resources; Resources; Science of nutrition; sedentary; Site; Stocks, Racial; sugar; Weight; Work; youngster
Project start date: 2006-03-10
Project end date: 2011-10-31
Budget start date: 1-FEB-2010
Budget end date: 31-OCT-2011
PFA/PA: RFA-DK-04-013
5R01DK072994-05 (2010): $701453
ANNUAL MEETING OF THE INTERNATIONAL BEHAVIORAL NEUROSCIENCE SOCIETY
P John, Professor
Internationl Behavioral Neuroscience Soccity: San Antonio country: United States (us)
Grant 5R13MH065244-08 from National Institute Of Mental Health
Abstract: The purpose of this project is to secure funds to help defray the costs associated with the Annual Meeting of the International Behavioral Neuroscience Society (IBNS). This project is a renewal of our existing R13 grant that has been instrumental in vaulting the IBNS into a position of the premiere behavioral neuroscience society in the world. The Annual Meeting represents a main component of the society´s mission. The meeting is a 4 day event where attendees (~150-200) are housed at or within close walking distance to the meeting site - fostering a close community for scientific exchange. The locations of the meetings are predominantly in the US mainland but every 3-4 years the meeting occurs at some international site to acknowledge its international members. The meeting is comprised of a series of special symposia, keynote addresses, oral and poster presentations and workshops for professional skill development. Student Travel Award winners are featured prominently in this program with their own session that is attended by all registrants of the meeting. There are no concurrent sessions or programs, again, fostering a sense of communal scientific exchange. In this application, funds are requested for five years in order to support the following components of the Annual Meeting; Young Investigator Travel Awards, Registration Costs for invited Symposium Speakers, Speaker´s Fee for Keynote Speakers, and money to help defray the costs of Publication of s of the Meeting on the IBNS website
Keywords: Address; Award; Behavioral; Communities; conference; cost; Development; Educational workshop; Event; Fees; Fostering; Funding; Grant; Housing; International; Investigators; Location; meeting s; Meeting s (PT); Meeting s [Publication Type]; meetings; member; Mission; Neurosciences; Oral; Position; Positioning Attribute; Posters; posters; Posters [Publication Type]; programs; Programs (PT); Programs [Publication Type]; Publications; Research Personnel; Researchers; Scientific Publication; Secure; Series; Site; skills; Societies; Students; symposium; Travel; Walking; web site; Workshop
Project start date: 2002-03-01
Project end date: 2011-03-31
Budget start date: 1-APR-2009
Budget end date: 31-MAR-2011
PFA/PA: PA-06-041
5R13MH065244-08 (2009): $26217
ENDOTHELIAL CELL FACTORS AND REPAIR OF THE IRRADIATION HEMATOPOIETIC COMPARTMENT
P John, Professor
Duke Universitycity: Durham country: United States (us)
Abstract: The potential severity of a terrorist-driven nuclear or radiological catastrophe may be judged by the recent estimate that 50% of individuals exposed to 400 cGy will die within 60 days unless there is medical intervention. While a percentage of individuals closest to the epicenter of a radiation blast would be killed by incineration or trauma, a significant percentage of victims will be exposed to primarily ionizing radiation exposure. The majority of deaths in these individuals will likely occur due to the deleterious effects of radiation on the bone marrow and immune system. Unfortunately, individuals exposed to radiation doses ranging from 400 cGy - 1000 cGy will frequently die from the sequelae of bone marrow failure (infections, bleeding complications) despite maximal supportive care. Our laboratory has developed methods to cultivate and expand normal murine, primate, and human hematopoietic stem cells via co-culture with primary endothelial cells. Primary ECs support a 1-2 log expansion of human stem cells in the absence of cell-to-cell contact, indicating that EC-derived soluble factors account for this effect. Conditioned medium from primary ECs also supports the functional recovery of BM stem cells following harvest from lethally irradiated animals. In this proposal we aim to characterize the capacity for administered serum free EC-CM alone to rescue in vivo hematopoietic activity and improve survival in animals after exposure to high dose ionizing radiation. Second, we will apply subtractive gene expression analysis and RNA interference methods to identify the EC genes responsible for the uniquely soluble hematopoietic and radioprotective effect produced by ECs. Third, we will apply protein fractionation methods to purify and identify the candidate soluble factors as a complementary and synergistic strategy with our gene expression and siRNA approach. We anticipate that the completion of this project will lead to a deliverable therapeutic not only for radiation sickness, but more broadly, to accelerate hematopoietic recovery following medically indicated therapies (e.g. chemotherapy, radiotherapy, transplantation)
Keywords: Accounting; Adult; Adverse effects; Affect; Amino Acid Sequence; Anemia; Animals; Anions; Antibiotics; Biological Assay; Blast Cell; Bone Marrow; Bone Marrow Stem Cell; Bone Marrow Suppression; Brain; Cations; Cells; Cessation of life; chemotherapy; Chromatography; Coculture Techniques; Conditioned Culture Media; Development; Dose; Endocrine; Endothelial Cells; Exposure to; Fractionation; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Growth Factor; Harvest; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hematopoietic System; Hemorrhage; Human; human stem cells; Hypoxia; Immune system; improved; in vivo; Incineration; Individual; Infection; Injury; Intervention; Ionizing radiation; irradiation; Killings; Laboratories; Lead; Leukopenia; loss of function; Lymphocyte; Maintenance; Mediating; Medical; Methods; Mortality Vital Statistics; Mus; novel; Nuclear; Oxidative Stress; Pancytopenia; paracrine; Physiological; pre-clinical; Primates; Protein Sequence Analysis; Proteins; Radiation; radiation effect; Radiation Injuries; Radiation Sicknesses; Radiation therapy; Recovery; Recovery of Function; repaired; reversed phase chromatography; Risk; RNA Interference; Secondary to; self-renewal; Serum; Severities; Signal Transduction; Small Interfering RNA; Source; stem; Stem cells; Supportive care; Testing; Therapeutic; Tissues; Transfusion; Transplantation; Trauma; Vascular Endothelial Cell
Budget start date: 1-AUG-2009
Budget end date: 31-JUL-2010
PFA/PA: RFA-AI-04-045
5U19AI067798-05_0007 (2009): $0
Sponsored Links Excellgen http://Excellgen.com
5U19AI067798-04_0007 (2008): $288777
5U19AI067798-03_0007 (2007): $311214
ENDOTHELIAL CELL FACTORS MEDIATE THE REPAIR OF THE IRRADIATION HEMATOPOIETIC COMP
P John, Professor
Duke Universitycity: Durham country: United States (us)
Abstract: The potential severity of a terrorist-driven nuclear or radiological catastrophe may be judged by the recent estimate that 50% of individuals exposed to 400 cGy will die within 60 days unless there is medical intervention. While a percentage of individuals closest to the epicenter of a radiation blast would be killed by incineration or trauma, a significant percentage of victims will be exposed to primarily ionizing radiation exposure. The majority of deaths in these individuals will likely occur due to the deleterious effects of radiation on the bone marrow and immune system. Unfortunately, individuals exposed to radiation doses ranging from 400 cGy - 1000 cGy will frequently die from the sequelae of bone marrow failure (infections, bleeding complications) despite maximal supportive care. Our laboratory has developed methods to cultivate and expand normal murine, primate, and human hematopoietic stem cells via co-culture with primary endothelial cells. Primary ECs support a 1-2 log expansion of human stem cells in the absence of cell-to-cell contact, indicating that EC-derived soluble factors account for this effect. Conditioned medium from primary ECs also supports the functional recovery of BM stem cells following harvest from lethally irradiated animals. In this proposal we aim to characterize the capacity for administered serum free EC-CM alone to rescue in vivo hematopoietic activity and improve survival in animals after exposure to high dose ionizing radiation. Second, we will apply subtractive gene expression analysis and RNA interference methods to identify the EC genes responsible for the uniquely soluble hematopoietic and radioprotective effect produced by ECs. Third, we will apply protein fractionation methods to purify and identify the candidate soluble factors as a complementary and synergistic strategy with our gene expression and siRNA approach. We anticipate that the completion of this project will lead to a deliverable therapeutic not only for radiation sickness, but more broadly, to accelerate hematopoietic recovery following medically indicated therapies (e.g. chemotherapy, radiotherapy, transplantation)
Keywords: bioterrorism /chemical warfare; cooperative study; gene expression; growth media; hematopoiesis; hematopoietic stem cells; ionizing radiation; laboratory mouse; Macaca; mixed tissue /cell culture; protein purification; radiation dosage; radiation protection; radiation recovery; small interfering RNA; vascular endothelium
Budget start date: 1-AUG-2006
Budget end date: 31-JUL-2007
5U19AI067798-02_0007 (2006): $291001
RELATING SYNAPTIC PLASTICITY TO CHANGES IN ODOR REPRESENTATION AND PERCEPTION
P John, Assistant Professor
Rutgers The St Univ Of Nj New Brunswickcity: New Brunswick country: United States (us)
Grant 5R00DC009442-05 from National Institute On Deafness And Other Communication Disorders
Abstract: The olfactory system provides a uniquely powerful environment in which to explore sensory plasticity in mammals, because the earliest central processing in the olfactory system takes place in the glomeruli of the olfactory bulb, a structure that is physically and optically accessible in vivo in animal models, and because recent advances in molecular genetic technology have produced excellent experimental tools for studies in this area. Using a combination of molecular genetic tools and in vivo optical imaging techniques, I have recently shown that the olfactory system exhibits rapid feedback presynaptic inhibition of transmitter release from the olfactory nerve. I hypothesize that the rapid plasticity of this circuit provides adaptive gain control for the primary sensory input from the nose, and thus plays a major role in the encoding of odorant concentration and the perception of odor intensity. Moreover, preliminary data suggest that this inhibitory circuitry may change over time to accommodate changes in the olfactory environment. The first aim of these experiments is to test the hypothesis that this presynaptic modulation of primary sensory input to the olfactory bulb contributes to the encoding of odor concentration. The second aim of these experiments is to use optical imaging techniques to test the hypothesis that changes in sensory environment induces plasticity in the representation of odors at the input to the olfactory bulb. The final aim of these experiments is to use behavioral assays to test how this plasticity affects the perception of odor quality and intensity
Keywords: Affect; Afferent Neurons; Animal Model; Animals; Anterior; Area; base; Basic Science; Behavioral; Behavioral Assay; Brain; Brain Stem; Chronic; Data; Data Collection; deprivation; Development; Discrimination (Psychology); Environment; Exhibits; experience; Exposure to; Feedback; follow-up; genetic technology; Image; Imaging Techniques; improved; in vivo; Individual; Infusion procedures; insight; Mammals; Methods; Molecular Genetics; Mus; neurochemistry; neurophysiology; Nose; novel; Odors; olfactory bulb; Olfactory Nerve; olfactory stimulus; optic imaging; Organ; Pathology; patient population; Patients; Pattern; Perception; Play; presynaptic; Process; Prosthesis; Publications; receptor; Receptor Gene; relating to nervous system; Relative (related person); research study; Role; sensor; Sensory; sensory stimulus; sensory system; Series; Stimulus; Structure; Synapses; synaptic inhibition; Synaptic plasticity; System; Technology; Testing; Thalamic structure; Time; tool; Training; Transgenic Mice; Work
Relevance: Mammalian sensory systems constantly change to adapt to their environment and experience. While adaptation in some sensory organs is well understood, much less is knwn about how circuitry in the brain changes to handle different sensory situations. Basic research into this question is needed to better inform the treatment of patients with sensory problems and to enhance the development of artificial sensors
Project start date: 2009-07-15
Project end date: 2013-03-31
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5R00DC009442-05 (2011): $244044
A PRACTICAL MICROBICIDE BASED ON HIV-1 ENTRY INHIBITORS
P John, Professor
Weill Medical College Of Cornell Univcity: New York country: United States (us)
Abstract: The objectives of the Virology and Immunology Core are i) To obtain and characterize stocks of the various HIV-i entry inhibitors that will be evaluated in the in vitro and macaque model systems in Research Projects I and III, or provided to Research Project II for formulation studies. 2) To characterize the antiviral potency and cytotoxicity of inhibitor formulations created in Research Project II. 3) To perform viral load assays for the dual virus-challenge experiments outlined in Research Projects I and III (under a Consortium Agreement with Dr. Steven Wolinsky at Northwestern University). 4) To support Dr. Veazey´s studies in Research Project III that are aimed at determining whether local immune responses are stimulated by mucosally applied viruses and/or viral antigens. The Core Leader will be John P. Moore, Ph.D, and the Core will be located at the Weill Medical College of Cornell University, New York, NY. Its function will be to act as a central resource to support the individual Research Projects. The Core will obtain sufficient quantities of suitable entry inhibitors for use in all three Research Projects, and determine the potency of these inhibitors against a range of HIV-i isolates in vitro, using well-established assays based on primary human and rhesus macaque lymphocytes, macrophages and dendritic cells. This work will ensure that only bonafide, active reagents are used in each of the Research Projects. The Core will identify which combinations of inhibitors are most suitable for further evaluation in the in vitro model systems (Research Project I). The Core will help to evaluate new entry inhibitor formulations and delivery methods created in Research Project II. The Core will participate in the determining the outcome of experiments using the rhesus macaque vaginal challenge model (Research Project III), particularly when the animals are challenged with more than one virus simultaneously, and will also assist with the analyses of HIV-i virus- or antigen-induced mucosal immune responses. Dr. Steven Wolinsky of Northwestern University will contribute to the work of the Core under a Consortium Agreement. Dr. Wolinsky´s specific role will be based around the design and use of PCR-based assays for the detection and quantification of viral genomes, both for use in Project III (to analyze the outcome of macaque vaginal challenges involving more than one virus) and Project I (to analyze the infection of cell culture and cervical tissue explant systems with defined challenge viruses). The majority of Dr. Wolinsky´s funding for this work will be provided by the International Partnership for Microbicides, as outlined in the Program Overview section of this application
Keywords: Agreement; Animals; Antigens; Antiviral Agents; base; Biological Assay; Biological Models; Cell Culture Techniques; Cervical; cytotoxicity; Dendritic Cells; design; Detection; Doctor of Philosophy; Drug Formulations; Ensure; Evaluation; Funding; HIV; HIV-1; Human; Immune response; Immunology; In Vitro; in vitro Model; Individual; Infection; inhibitor/antagonist; International; Lymphocyte; Macaca; Macaca mulatta; macrophage; medical schools; Methods; microbicide; Modeling; Mucosal Immune Responses; New York; Outcome; programs; Reagent; Research Project Grants; research study; Resources; Role; System; systems research; Tissues; Universities; Vagina; Viral Antigens; Viral Genome; Viral Load result; virology; Virus; Work
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
5U19AI076982-04_9001 (2011): $177650
NOVEL OPTRODE DEVICES FOR NEUROSCIENTISTS: PACKAGING AND WAVEGUIDE SOLUTIONS TO M
P John
Neuronexus Technologiescity: Ann Arbor country: United States (us)
Grant 1R43NS073185-01 from National Institute Of Neurological Disorders And Stroke
Abstract: The objective of this application is to develop advanced optrode solutions for neuroscientists that fulfill the potential of optogenetic technology-achieving highly specific neural circuit control. Once developed, the neuroscientist´s experimental options for optical stimulation will grow to two dimensions with no limits on the recording site placement. Our approach develops (i) practical, yet novel solutions for the packaging issues currently plaguing users, and (ii) custom waveguides capable of region-specific illumination with no electrical artifact, and is modularly integrated onto any existing NeuroNexus recording array. As an alternative to wafer- level integration, we have devised an approach that lowers cost by improving yield while increasing design options. This project will further optogenic techniques, which have shown excellent promise as tools that allow temporally precise, non-invasive control of activity in well- defined neuronal populations. This degree of control over neural firing allows specific monitoring of temporal activity patterns in the context of circuit dynamics, understanding changes due to plasticity, and responses to behavior and external cues, which is critically important for studying disease models as well. The objective of this application is to develop advanced optrode solutions for neuroscientists that fulfill the potential of optogenetic technology-achieving highly specific neural circuit control. Once developed, the neuroscientist´s experimental options for optical stimulation will grow to two dimensions with no limits on the recording site placement. Our approach develops (i) practical, yet novel solutions for the packaging issues currently plaguing users, and (ii) custom waveguides capable of region-specific illumination with no electrical artifact, and is modularly integrated onto any existing NeuroNexus recording array. As an alternative to wafer- level integration, we have devised an approach that lowers cost by improving yield while increasing design options. This project will further optogenic techniques, which have shown excellent promise as tools that allow temporally precise, non-invasive control of activity in well- defined neuronal populations. This degree of control over neural firing allows specific monitoring of temporal activity patterns in the context of circuit dynamics, understanding changes due to plasticity, and responses to behavior and external cues, which is critically important for studying disease models as well
Keywords: Abscission; Animals; Articulation; Artifacts; Automobile Driving; base; Behavior; Behavioral; Body Tissues; cell type; Communities; cost; cost effective; cost effectiveness; Couples; Cristobalite; Cues; Custom; density; design; designing; Devices; Diffusion; Dimensions; Disease model; disorder model; driving; Drivings, Automobile; Excision; experiment; experimental research; experimental study; Extirpation; Face; facial; Financial Support; Future; Hand; Illumination; improved; innovate; innovation; innovative; Investigators; Ion Channel; Ionic Channels; Joints; Laboratories; language translation; Lesion; Light; light intensity; Lighting; Mammals, Mice; Mammals, Rodents; Measures; meetings; Membrane Channels; Methods; Methods and Techniques; Methods, Other; Mice; Modeling; Modification; Monitor; Morphologic artifacts; Murine; Mus; National Institutes of Health; National Institutes of Health (U.S.); Nerve Cells; Nerve Unit; Nervous; neural; Neural Cell; neural circuit; neural circuitry; Neurocyte; neuronal; Neurons; Neurosciences; Neurosciences Research; NIH; novel; Operation; Operative Procedures; Operative Surgical Procedures; optical fiber; Optics; Output; Pattern; Photoradiation; Plague; Polymers; Population; Productivity; Protocol; Protocols documentation; public health relevance; relating to nervous system; Removal; Research Personnel; research study; Researchers; resection; response; Rodent; Rodentia; Rodentias; Sand; Science; Silica; Silicon Dioxide; Site; Solutions; Specificity; Surface Properties; surgery; Surgical; Surgical Interventions; Surgical Procedure; Surgical Removal; System; System, LOINC Axis 4; Techniques; Technology; Tissues; tool; Translating; Translatings; Tridymite; United States National Institutes of Health; Work; Yersinia pestis disease
Relevance: The objective of this application is to develop advanced optrode solutions for neuroscientists that fulfill the potential of optogenetic technology-achieving highly specific neural circuit control. Once developed, the neuroscientist´s experimental options for optical stimulation will grow to two dimensions with no limits on the recording site placement. Our approach develops (i) practical, yet novel solutions for the packaging issues currently plaguing users, and (ii) custom waveguides capable of region-specific illumination with no electrical artifact, and is modularly integrated onto any existing NeuroNexus recording array. As an alternative to wafer- level integration, we have devised an approach that lowers cost by improving yield while increasing design options. This project will further optogenic techniques, which have shown excellent promise as tools that allow temporally precise, non-invasive control of activity in well- defined neuronal populations. This degree of control over neural firing allows specific monitoring of temporal activity patterns in the context of circuit dynamics, understanding changes due to plasticity, and responses to behavior and external cues, which is critically important for studying disease models as well
Project start date: 2011-03-15
Project end date: 2011-08-31
Budget start date: 15-MAR-2011
Budget end date: 31-AUG-2011
PFA/PA: PA-07-389
1R43NS073185-01 (2011): $175576
P John, Professor
Weill Medical College Of Cornell Univcity: New York country: United States (us)
Abstract: The objective of the Administrative Core is to support the performance of the research outlined in this IPCP-HTM application. The Core will be directed by the Principal Investigator, John P. Moore, PhD, and will be located in the Department of Microbiology and Immunology at the Weill Medical College of Cornell University, New York, NY. It will coordinate all the operations of the IPCP-HTM group, and ensure that the overall goals of the research team are carried out by the Project Leaders. It will also ensure that all necessary support services are provided to the Research Project Leaders to further their work. The Chief Administrator of this Core will be Mrs. Angie Leitch, who will also act as Secretary to the Internal Steering Committee. The Core will help to obtain and maintain IACUC and IRB approvals for the work outlined in the proposal. It will coordinate the creation and maintenance of the Patent Plan, the Public Access to Data Plan, and the Sharing Research Resources Plan. The Core will facilitate the obtainment of specialist research reagents for the use of the Research Project Leaders. This will involve making any appropriate and necessary arrangements for the provision of inhibitors from corporate collaborators via Material Transfer Agreements or other legal agreements. The Core will liaise with the Internal Steering Committee and the Scientific Advisory Panel, to make arrangements for conference calls, for the annual meeting, and for any other meeting that may be called by the Principal Investigator, the Co-Principal Investigator or the Research Project Leaders. The Core will maintain a database of critical information derived from the individual research projects, particularly Research Project III, and it will assist with the publication of research papers as and when such a service is requested
Keywords: Administrator; Agreement; base; Clinical; college; Data; Databases; direct application; Doctor of Philosophy; Ensure; Goals; HIV; HIV-1; IACUC; Immunology; Individual; inhibitor/antagonist; Institutional Review Boards; Legal; Legal patent; Letters; Local Microbicides; Maintenance; material transfer agreement; medical schools; meetings; microbicide; Microbiology; New York; operation; Paper; Performance; pre-clinical; Principal Investigator; programs; Publications; Reagent; Research; Research Project Grants; Resources; Services; Specialist; symposium; U-Series Cooperative Agreements; Universities; Work
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
5U19AI076982-04_9002 (2011): $104238
EFFECT OF VITAMIN D AND OMEGA-3 FATTY ACIDS ON BLOOD PRESSURE AND HYPERTENSION
P John
Brigham And Women´s Hospitalcity: Boston country: United States (us)
Grant 5R01HL102122-02 from National Heart, Lung, And Blood Institute
Abstract: The human toll of hypertension (HTN) is staggering, and effective preventive measures are needed. Experimental studies suggest that inadequate vitamin D and I-3 fatty acid (FA) levels may be involved in the pathogenesis of HTN through multiple biological mechanisms. Observational studies have shown inverse associations of plasma 25-hydroxyvitamin D (25[OH]D) levels and dietary I-3 FA intake with blood pressure (BP) and HTN. Small intervention trials of vitamin D and fish oil rich in I-3 FA suggest possible BP-lowering effects; however, larger trials using adequately high doses of vitamin D and I-3 FA for the primary prevention of HTN are lacking. The VITamin D and OmegA-3 TriaL (VITAL), an NIH-supported, large, randomized, double-blind, placebo-controlled, 2x2 factorial trial, will test 2000 IU/day of vitamin D (as vitamin D3 [cholecalciferol]) and 1 g/day of marine I-3 FA (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) supplements on incident cardiovascular disease and cancer in 20,000 multiethnic men and women with 5 years of treatment and follow-up. VITAL provides an optimal cost-effective setting to examine the effects of both interventions on changes in BP and incident HTN. Further, as this project would begin in parallel with enrollment into the parent VITAL trial, pre-randomization assessments of BP and biomarkers will be possible. In this proposed ancillary study, we will recruit a representative subcohort of 1,000 VITAL participants without baseline HTN from 5 major US metropolitan areas to conduct home-based examinations at baseline and 2 years follow-up through Examination Management Services, Inc (EMSI). We will obtain 24-hour ambulatory BP (ABP), fasting bloods, 24-hour urines, and other clinical assessments in this EMSI subcohort. We will also ascertain incident HTN cases in the overall VITAL trial. We will test the following hypotheses (1) whether vitamin D and fish oil supplementation lowers 24-hour ABP compared to placebo in the EMSI subcohort of 1,000 participants; (2) whether vitamin D and fish oil supplementation reduces the risk of incident HTN compared to placebo among all randomized VITAL participants without baseline HTN; and (3) whether vitamin D and fish oil supplementation favorably changes HTN-related biomarkers that are putative mechanistic mediators linking vitamin D and I-3 FAs with HTN compared to placebo. This proposed study will provide definitive evidence to support or refute the potential preventive roles of vitamin D and I-3 FA on BP and the development of HTN. Prior research suggests that vitamin D and fish oil (which contains nutrients called omega-3 fatty acids) might help lower blood pressure and prevent hypertension; however, this remains unproven because large and more definitive research studies have not been done. This proposed study will be a large-scale and long-term randomized trial that will demonstrate whether taking vitamin D or fish oil supplements can lower someone´s blood pressure or prevent the development of hypertension. Because high blood pressure is responsible for one out of every six deaths in the United States, the results of this study could possibly improve the health of many people
Keywords: 25-hydroxyvitamin D; Address; Affect; aged; Aldosterone; Ancillary Study; Angiotensin II; Area; attenuation; base; Biological; biomarker; Blood; Blood Pressure; Blood specimen; Blood Vessels; Calcium; Cardiovascular Diseases; Cessation of life; Cholecalciferol; Chronic Disease; Clinical assessments; Cohort Studies; Consumption; cost effective; Creatinine; design; Development; Docosahexaenoic Acids; Dose; Double-Blind Method; E-Selectin; Eicosapentaenoic Acid; eligible participant; Enrollment; Excretory function; falls; Fasting; fasting glucose; Fatty Acids; Fish Oils; follow-up; Funding; Glycosylated hemoglobin A; Health; high risk; Home environment; Hour; Human; Hypertension; hypertension prevention; Hypotension; improved; Incidence; Individual; Inflammation; Insulin; insulin sensitivity; Intake; Intercellular adhesion molecule 1; Intervention; Intervention Trial; Link; Malignant Neoplasms; Marines; Measures; Mediator of activation protein; men; Meta-Analysis; metropolitan; normotensive; Nutrient; Nutritional; Observational Study; Omega-3 Fatty Acids; Parents; Participant; Pathogenesis; Phase; Placebo Control; Placebos; Plasma; Potassium; prevent; Preventive; Primary Prevention; public health medicine (field); public health relevance; Randomized; randomized trial; Recruitment Activity; Renin; Renin-Angiotensin System; Research; research study; Risk; Role; Running; Sample Size; Services; Sodium; Supplementation; Testing; TNF gene; United States; United States National Institutes of Health; urinary; Urine; Vitamin D; Woman
Relevance: Prior research suggests that vitamin D and fish oil (which contains nutrients called omega-3 fatty acids) might help lower blood pressure and prevent hypertension; however, this remains unproven because large and more definitive research studies have not been done. This proposed study will be a large-scale and long-term randomized trial that will demonstrate whether taking vitamin D or fish oil supplements can lower someone´s blood pressure or prevent the development of hypertension. Because high blood pressure is responsible for one out of every six deaths in the United States, the results of this study could possibly improve the health of many people
Project start date: 2011-02-04
Project end date: 2015-11-30
Budget start date: 1-DEC-2011
Budget end date: 30-NOV-2012
5R01HL102122-02 (2012): $579973
1R01HL102122-01A1 (2011): $636438
REACTIVE INTERMEDIATES OF ENZYMATIC REACTIONS
P John, Professor Of Chemistry
State University Of New York At Buffalocity: Buffalo country: United States (us)
Grant 5R01GM039754-25 from National Institute Of General Medical Sciences
Abstract: The hallmark of enzyme catalysis is the high affinity of enzymes for their transition states, but the origin of this tight binding is generally not well understood. This application describes experiments to probe the mechanism by which the large intrinsic binding energy of substrate phosphodianion groups is utilized by a variety of enzymes to stabilize the transition state for formation of an unstable carbanion intermediate. Our central hypothesis is that flexible "phosphate gripper" loops are wide-spread conserved protein elements that provide binding energy that may be utilized for stabilization of the transition state for formation of an enzyme-bound carbanion. The enzymatic reactions of interest include aldose-ketose isomerization, sugar epimerization, aldol condensation and decarboxylation. We will use our "two-part substrate" protocol, where the substrate phosphodianion group, modeled by exogenous phosphite dianion, is detached from the portion of the substrate that undergoes chemical reaction. The specific transition state stabilization from phosphodianion binding interactions can then be quantified from the observed activation of the enzyme by exogenous phosphite dianion towards catalysis of the reaction of the second substrate fragment. Four projects are described to examine both the generality and the mechanism of transition state stabilization arising from flexible loop-phosphite interactions. (1) We will examine members of the orotidine 5´-monophosphate decarboxylase (OMPDC) superfamily. The goal is to determine whether the structurally conserved phosphate gripper loops of these enzymes share the common function of providing specific stabilization of carbanion intermediates. (2) We will examine the relationship between the length of the phosphate gripper loop and the utilization of enzyme-phosphodianion binding interactions for two enzymes that catalyze epimerization of phosphorylated sugars differing in length by only one carbon atom. (3) We will probe the mechanism by which OMPDC achieves its enormous 1017-fold rate acceleration for the chemically difficult decarboxylation of orotidine 5´-monophosphate. We will probe the mechanism by which interactions between the enzyme and the substrate phosphodianion are utilized in stabilization of the transition state for decarboxylation at the distant pyrimidine ring, and address other questions about the enigmatic mechanism of action of this enzyme. (4) We will continue our studies of the role of flexible loop-phosphodianion interactions in stabilization of the transition state for formation of the enediol(ate) intermediate of the aldose-ketose isomerization of triose phosphates catalyzed by triose phosphate isomerase. A major goal is to provide a full of the physical mechanism by which the movement of flexible catalytic loops acts as a "switch" to turn on stabilizing transition state interactions. Enzyme catalysts are one of the principal components of all living systems, and there are many diseases that arise from the malfunction or deficiency of only a single enzyme. Advances in the understanding of enzyme catalysis from mechanistic studies of enzymes and of nzymatic reactions may prove critical for drug design, to the understanding of metabolic pathways and diseases, and to the resolution of other health-related issues. The focus of this application is the critical role of flexible phosphate gripper loops in enzymatic catalysis and the results may spur efforts to develop novel enzyme inhibitors that specifically target these loops
Keywords: 3-hydroxybutanal; 5 fluorouridine; Acceleration; Active Sites; Address; Affinity; Amino Acids; base; Binding (Molecular Function); Binding Sites; Biochemical Reaction; Buffaloes; carbanion; Carbon; Carboxy-Lyases; carboxylate; Catalysis; catalyst; chemical reaction; Complement; Complex; Decarboxylation; deprotonation; design; Disease; Distant; Drug Design; Eating; Elements; Enzyme Activation; Enzyme Inhibitor Drugs; Enzyme Inhibitors; enzyme substrate; Enzymes; epimerase; epimerization; flexibility; Goals; Health; Homologous Gene; inorganic phosphate; interest; Isomerase; Ketoses; Ketosis; Kinetics; Knowledge; Length; Ligands; Maps; member; Metabolic Diseases; Metabolic Pathway; Metric; Modeling; Molecular; Motion; Movement; Mutation; novel; Organism; orotidylic acid; Phosphites; Physical condensation; Protein Dynamics; Proteins; Protocols documentation; Protons; Pyrimidine; Pyrimidines; Reaction; Relative (related person); research study; Resolution; ribulose 5-phosphate; Role; Side; Site; Site-Directed Mutagenesis; Specificity; sugar; transmission process; Triose-Phosphate Isomerase; Trioses
Project start date: 1988-05-01
Project end date: 2013-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01GM039754-25 (2011): $324093
Sponsored Links Excellgen http://Excellgen.com
CLINICAL TRIALS NETWORK: GREATER NEW YORK NODE
P John, Associate Professor
New York State Psychiatric Institutecity: New York country: United States (us)
Grant 3U10DA013035-09S2 from National Institute On Drug Abuse
Abstract: The Greater New York Node of the NIDA Clinical Trials Network (CTN), under the shared leadership of Drs. Edward Nunes and John Rotrosen, represents a merger of the Long Island and New York Nodes. Over the past decade we have built a network of collaborating researchers from Columbia University, New York University and The Rockefeller University, and from community-based treatment programs (CTPs) spanning the Nation´s largest and most diverse metropolitan area. We have made substantial contributions to the CTN, leading 5 CTN studies, contributing 22 performance sites to CTN clinical trials, providing leadership in the CTN organization at the national level in multiple areas, and implementing numerous studies on the local CTN platform. Our vision for the CTN of the future includes (a) a continued focus on effectiveness research, (b) an additional focus on earlier stage 2 / phase 2 research where CTN resources can be efficiently used, (c) an enhanced research-to-practice model to foster sustainable adoption of innovation, and (d) a platform on which focused- and population- level genetics-, clinical neuroscience-, epidemiology- and services- research can be conducted. We bring to the table the expertise, resources and partners necessary to support this vision. Our research team has complementary strengths in pharmacotherapy, behavioral therapy, co-occurring psychiatric and medical disorders, gender issues, HIV risk reduction and treatment, technology-based treatment, mainstream healthcare settings, clinical neuroscience and genetics. Our CTPs include large public and private hospital-based healthcare systems with focused addiction treatment services (Bellevue, North Shore-LIJ, St.Lukes Roosevelt, and VA NYHHS), to which-we are adding the Albert Einstein system in the Bronx, and SUNY Upstate, the major provider for a large portion of upstate New York, as well as traditional free-standing addictions programs (ARTC, Gracie Square, LESC, Odyssey House, Narco-Freedom, Phoenix House). We continue to engage leaders of very large systems, including the NY State SSA (OASAS) and the NY City Health and Hospitals Corporation, as well as the NeATTG, as members of our Executive Committee so that their input can inform the research agenda and foster adoption. ´ Addictions, including nicotine, drugs, and alcohol, represent a major public health problem. Research is needed to translate new basic and therapeutic advances into effective and accessible treatment in our communities, The NIDA Clinical Trials Network, and the Greater New York Node proposed here, seek to fill this gap by engaging researchers and community-based providers collaboratively in treatment research
Keywords: abuse of substances; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; addiction; Address; Adoption; AIDS Virus; Alcohols; Area; base; Behavior Conditioning Therapy; behavior intervention; Behavior Modification; Behavior or Life Style Modifications; Behavior Therapy; Behavior Treatment; Behavioral Conditioning Therapy; behavioral intervention; Behavioral Modification; Behavioral Therapy; Behavioral Treatment; Care, Health; Chemical Class, Alcohol; Clinical; clinical investigation; Clinical Trials; Clinical Trials Network; Clinical Trials, Unspecified; Communities; community based treatment; Conditioning Therapy; Disease; disease/disorder; Disorder; Drug Therapy; drug/agent; Drugs; Educational Mainstreaming; effectiveness research; Epidemiology; Evidence based practice; experience; Fostering; Freedom; Future; Gender Issues; Genetic; Health; Health Care Research; Health Services Evaluation; Health Services Research; Healthcare; Healthcare Research; Healthcare Systems; heavy metal lead; heavy metal Pb; HIV; HOSP; Hospitals; Housing; HTLV-III; Human Immunodeficiency Viruses; Human Resources; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; innovate; innovation; innovative; Investigators; language translation; LAV-HTLV-III; Lead; Leadership; Liberty; Life Style Modification; Long Island; Lymphadenopathy-Associated Virus; Mainstream Education, achievement; Mainstreaming; Mainstreaming (Education); Manpower; Medical; Medical Care Research; Medication; meetings; member; metropolitan; Mission; Modeling; National Institute of Drug Abuse; Neurosciences; New York; New York City; Nicotine; NIDA; Pb element; performance site; personnel; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacotherapy; Phase; Policies; Population; Private Hospitals; Productivity; programs; Programs (PT); Programs [Publication Type]; Protocol; protocol development; Protocols documentation; PROV; Provider; Public Health; public health medicine (field); public health relevance; Public Hospitals; Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, (S)-; quality assurance; Regulatory Affairs; Research; Research Activity; Research Personnel; Research Resources; Research Support; research to practice; Researchers; Resources; Risk; Risk Reduction; Scientist; Services; services research; Sight; Site; Staging; Structure; substance abuse; Substance abuse problem; Supervision; System; System, LOINC Axis 4; Systems, Health Care; Technology; Therapeutic; Training; Translating; Translatings; treatment program; Universities; Virus-HIV; Vision
Project start date: 1999-09-01
Project end date: 2015-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: RFA-DA-10-009
3U10DA013035-09S2 (2011): $1055724
3U10DA013035-09S3 (2011): $937369
5U10DA013035-10 (2011): $1429091
3U10DA013035-10S1 (2011): $970323
P John, Professor
Progenics Pharmaceuticals, Inc.city: Tarrytown country: United States (us)
Abstract: The goal of Project 1 of the HIVRAD is to design vaccines intended to induce NAbs, based on accumulated and emerging knowledge of structure-function relationships within the HIV-1Env complex and of how Env proteins interact with cells of the immune system, in vitro and in vivo. We propose three inter-related Specific Aims. Aim 1 To further modify the amino acid sequence of HFV-1 envelope glycoproteins. to create novel forms that improve the immunogenicity of neutralization epitopes and facilitate structural studies. We will build on the SOSIP method for making stable, cleaved gp!40 trimers, by identifying and testing additional substitutions that stabilize gp41-gp41 interactions, by introducing other sequence changes into gp!20 and/or gp41 that are intended to create or better expose NAb epitopes, and by eliminating immunosuppressive regions of the Env complex. The latter studies will be coordinated with research outlined in Aim 2, and will lead to the creation of new immunogens for testing in small animals in Aim 3, and also in the MIMIC system within Core B. We will also make modifications to Env trimers that are intended to reduce protein heterogeneity and/or flexibility, and thereby facilitateX-ray crystallography studies to be conducted by Ian Wilson (Project 2). Aim 2 To study in vitro how to overcome immunosuppressive effects of gp!20 by the use of adjuvants and TLR activators. We will study the immunosuppressive effects of the mannose moieties of gp!20 glycans in vitro, using both human and murine cell-based systems, particularly dendritic cells (DCs). The abilities of TLR activators and other adjuvant-associated molecules to overcome these adverse effects will then be tested. We will, in addition, collaborate with the groups headed by Eric Mishkin and Sunil Ahuja, to derive additional immunologic and genetic information using the VaxDesign MIMIC system (Core B). The outcome of these experiments will facilitate the construction of new immunogens in Aim 1, and the rational design of immunization regimens in Aim 3 and Core B that are intended to maximize the antibody response to Env.Aim 3 To evaluate the immunogenicity of modified Env trimers in small animals. We will design and evaluate rabbit and mouse immunization studies that will be conducted within Core B, to determine whether the various modifications to Env glycoproteins that we identified and evaluated in Aims 1 and 2, can alter the immune response to these and co-administered antigens. We will also compare the immunogenicity of Env proteins with other antigens, alone and co-administered, to determine whether Env proteins can suppress or modify immune responses, including the IgG subclass pattern, to themselves and other antigens (HTV-1 derived or unrelated). The design of some experiments will also take into account information on adjuvants and TLR activators generated in Aim 2 and by using the VaxDesign MIMIC system in Core B. In an iterative process, the immunization experiments will themselves guide the design of additional studies to be carried out by VaxDesign using the MIMIC system (seeCore B). The overall outcome of these various studies will help design additional Env sequence modifications in Aim 1 that are intended to further improve immunogenicity or eliminate the causes of immunosuppression. RELEVANCE (See instructions) Nearly 1 % of the world´s population is infected with HTV,and a preventive vaccine is urgently needed. Most efficacious vaccines elicit antibodies that can neutralize the pathogen, but current-generation HIV vaccines are not effective in this regard. Obstacles include our limited understanding of the structure and immunology of HIV-1 envelope trimers. This HIVRAD represents an innovative approach to addressing these challenges in order to provide a fundamental advance in our ability to elicit HFV-neutralizingantibodies with a vaccine
Keywords: Accounting; Address; Adjuvant; Adverse effects; Amino Acid Sequence; Animals; Antibodies; Antibody Formation; Antigens; base; Cells; Cleaved cell; Complex; Contracts; Crystallography; Dendritic Cells; design; efficacy trial; Elements; env Gene Products; env Glycoproteins; Epitopes; Failure (biologic function); flexibility; Generations; Genetic; Glycoproteins; Goals; Head; Heterogeneity; HIV; HIV Antigens; HIV vaccine; HIV-1; Human; Immune; Immune response; Immune system; Immunization; immunogenicity; Immunoglobulin G; Immunologics; Immunology; Immunosuppressive Agents; improved; In Vitro; in vivo; innovation; Instruction; Knowledge; Lead; Mannose; Methods; Modification; Mus; Natural immunosuppression; neutralizing antibody; novel; Oryctolagus cuniculus; Outcome; pathogen; Pattern; Polysaccharides; Population; Preventive; Process; Production; Proteins; Regimen; Research; Research Project Grants; research study; Solutions; Structure; Structure-Activity Relationship; System; T-Lymphocyte; Testing; Texas; Vaccine Antigen; Vaccine Design; Vaccines; X-Ray Crystallography
Relevance: Nearly 1 % of the world´s population is infected with HTV, and a preventive vaccine is urgently needed. Most efficacious vaccines elicit antibodies that can neutralize the pathogen, but current-generation HIV vaccines are not effective in this regard. Obstacles include our limited understanding of the structure and immunology of HIV-1envelope trimers. This HIVRAD represents an innovative approach to addressing these challenges in order to provide a fundamental advance in our ability to elicit HFV-neutralizing antibodies with a vaccine
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
5P01AI082362-03_8834 (2011): $754887
P John, Professor
Northwestern Universitycity: Chicago country: United States (us)
Grant 5U01AI035039-19 from National Institute Of Allergy And Infectious Diseases
Abstract: The Chicago component of the Multicenter AIDS Cohort Study (MACS) is composed of a representative sample of men infected with HIV or at risk for such infection. We are in the third decade of research with three clinical sites located at the Howard Brown Health Center, the Northwestern University HIV/AIDS Clinic and the CORE Center of Cook County Hospital. The collected data and specimens from the participants have provided and will continue to provide detailed information about the role of host and environmental factors in HIV disease. During the next funding cycle (2009 to 2014), we will support studies of the natural and treated history of HIV infection and HIV-associated disease in the era of highly active antiretroviral therapy (HAART) through standardized and detailed data and specimen collection at 6-month intervals to characterize exposures and risk factors. We will support ongoing MACS-wide research projects and initiate new projects on behaviors enhancing transmission of HIV-1; the responses, effects, and predictors of response to HAART including the impact of illicit drug use; the effects of aging on the clinical course of HIV, HIV therapy, and response to HIV therapy; the host environment interaction between host genetics and HIV and other exposures; and the impact of aging, HAART and/or HIV infection on end-organ disease, cancer (both AIDS-related and non-related) upon long-term survival of infected men. We will contribute to each of the aims through scientific leadership, development and implementation of the overall MACS scientific agenda, retention and maintenance of the cohort and development of a state of the art facility using novel technology to conduct MACS-wide investigations of host genetics
Keywords: Accounting; Acquired Immunodeficiency Syndrome; Affect; African American; age effect; age group; Aging; antiretroviral therapy; Behavior; Behavioral; Biological; Biological Markers; Cardiovascular Diseases; Chicago; Clinic; Clinical; clinical research site; cohort; Cohort Studies; Combined Modality Therapy; Competence; cooking; County Hospitals; Data; Data Collection; design; Development; Diabetes Mellitus; Disease; Disease Marker; Disease Progression; Drug usage; Environment; Environmental Risk Factor; Exposure to; Funding; Genetic; Genotype; Goals; Health; high throughput technology; Highly Active Antiretroviral Therapy; Hispanics; HIV; HIV-1; Illicit Drugs; Immune; Immune system; Immunologics; Incidence; Infection; Integration Host Factors; Investigation; Kidney Diseases; Leadership; Learning; Lipodystrophy; Liver diseases; Long-Term Effects; Maintenance; Malignant Neoplasms; men; men who have sex with men; Neoplasms; Neurocognitive; new technology; Organ; Outcome; Participant; Pathogenesis; Persons; physical process; prospective; psychologic; Race; Recording of previous events; Research; Research Project Grants; Resistance; response; Risk; Risk Factors; Role; sample collection; Sampling; Specimen; transmission process; Universities; Virus; Virus Diseases; virus pathogenesis; Woman
Project start date: 1993-04-01
Project end date: 2014-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: RFA-AI-08-008
5U01AI035039-19 (2011): $3370683
CELLULAR AND MOLECULAR NEUROSCIENCE CORE
P John, Associate Professor
University Of Wisconsin Madisoncity: Madison country: United States (us)
Abstract: The Cellular and Molecular Neuroscience Core is designed to facilitate the research objectives of the IDDRC and the scientific progress of individual IDDRC projects by providing state-of-the-art equipment, training, and expertise for IDDRC investigators employing, or wishing to employ, cellular and molecular biology in their research programs. In-house equipment includes advanced microscopy (laser scanning confocal and fluorescence microscopy with Stereology), genomic and proteomic analysis both in situ (flow cytometry) and in cell lysates (phosphonmaging and quantitative PCR), and informatics. During the current project period, the Waisman Center committed $500,000 of gift funds to upgrade the Core´s existing proteomics and confocal microscopy capabilities. In addition, the CMN Core has well-established partnerships with nearby UW-Madison core facilities (UW-Biotechnology Center and UW-Cancer Center) to offer cost effective, state-of-the-art genomic and proteomic technology, such as 2-dimensional gel analysis, mass spectrometry, DNA sequencing and synthesis, DNA array and SNP analysis, NextGen sequencing, tiled array analysis of chromatin immunoprecipitation (ChIP) assays, and small molecule drug screening. In response to the growing interest for human-derived IDD models, in 2009 we created a new service of the CMN Core (with ARRA support) to generate induced pluripotent stem cells (iPSCs) from individuals with IDD conditions for IDDRC investigators. The IPSC service leverages the IDDRC´s long-standing expertise in stem cell biology, access to well characterized patients with IDD (via the Research Participation Core), and clinical biomanufacturing (Waisman Biomanufacturing) for the production of IPSC viral vectors. Using these complementary resources, the iPSC service has successfully created 23 cell lines from patients with IDD including Rett syndrome, Alexander disease, FXS, DS, SMA, retinitis pigmentosa. Best disease, and others, and provided guidance and expertise in differentiating the cell lines into neuronal sub-types and astrocytes
Keywords: Alexander Disease; Astrocytes; Biological Assay; Biomanufacturing; Biotechnology; Cancer Center; Cell Line; Cells; chromatin immunoprecipitation; Clinical; Commit; Confocal Microscopy; Core Facility; cost effective; design; Developmental Disabilities; DNA; DNA biosynthesis; DNA Sequence; Equipment; Flow Cytometry; Fluorescence Microscopy; Funding; Gel; Generations; Genomics; Gifts; Housing; Human; Human Cell Line; In Situ; Individual; induced pluripotent stem cell; Informatics; Intellectual functioning disability; interest; Laser Scanning Confocal Microscopy; Mass Spectrum Analysis; Mental Retardation and Developmental Disabilities Research Centers; Microscopy; Modeling; Molecular; Molecular and Cellular Biology; Neurons; Neurosciences; new technology; Patients; Preclinical Drug Evaluation; Production; programs; Proteomics; Research; Research Personnel; Resources; response; Retinitis Pigmentosa; Rett Syndrome; Services; small molecule; stem cell biology; Technology; Training; two-dimensional; Viral Vector; Vitelliform macular dystrophy
Project start date: 2011-09-26
Project end date: 2016-06-30
Budget start date: 26-SEP-2011
Budget end date: 30-JUN-2012
PFA/PA: RFA-HD-10-022
2P30HD003352-45_8098 (2011): $319237
IMPACT OF AMP-ACTIVATED KINASE ON SEX DIFFERENCES IN HYPERTROPHIC CARDIOMYOPATHY
P John, Assistant Professor
University Of Arizonacity: Tucson country: United States (us)
Grant 1K02HL105799-01 from National Heart, Lung, And Blood Institute
Abstract: The candidate, John P. Konhilas, Ph.D., is a newly appointed Assistant Professor with a newly funded R01 that synthesizes his pre- and post-doctoral training by studying the physiological impact brought about by changes in the molecular and biochemical biology of the heart in response to disease and sex. Dr. Konhilas´ immediate career goal is to acquire the research and professional skills necessary for achieving his long-term goal of developing an integrative and translational research program to explore the metabolic, molecular and physiologic adaptation of the heart to disease and sex. The proposed K02 research and development plan will provide Dr. Konhilas with the protected time and additional resources to achieve this goal. Career Development Plan The career development and research plan outlined in this proposal builds upon my R01 and will provide the scientific foundation upon which to guide future research efforts whereby we can more clearly define the mechanism underlying sex dimorphisms in the clinical HCM population. Training activities during the award period include, (1) acquiring new and refining present research skills, (2) structured activities including coursework in scientific integrity, biostatistics, and attendance/presentation at journal clubs, scientific meetings, and mentoring interactions. Environment The foundation for Dr. Konhilas´ newly established his laboratory is built. Dr. Konhilas has also assembled a team of consultants to provide guidance in every facet of the proposal. Research Sex/gender differences exist in human cardiac disease resulting from many disease etoilogies including hypertension, myocardial infarction, and hypertrophic cardiomyopathy (HCM). The hearts of women with these disorders maintain, at least, adequate cardiac function whereas men typically demonstrate increased chamber dilation and wall thinning, all signs of progressively deteriorating cardiac disease. Humans with HCM caused by an autosomal dominant mutation (R403Q) in the predominant motor protein in the heart (1-myosin heavy chain) show a similar sex difference in cardiac disease progression. Like their human counterparts, male mice expressing the R403Q mutation in the heart develop HCM characterized by progressive left-ventricular dilation and cardiac dysfunction whereas females show hypertrophy without dilation or dysfunction. However, the mechanisms that underlie these differences remain unknown. Because the R403Q mutation resides in the motor protein of the cellular contractile apparatus, hearts expressing the R403Q mutation are energy deprived and that this may be due to the increased energetic cost of contraction when expressing the R403Q mutation. Therefore, the prediction is that the observed sex difference may result from the inability of male hearts to match this increased energetic demand compared to females. In support of this idea, male R403Q hearts show metabolic abnormalities consistent with an energy-deprived state. Adenosine monophosphate-activated kinase (AMPK) may be a central regulator of this sex difference because of its established role in (1) sensing changes in cellular energy state, (2) regulating mediators of energy producing pathways, and, (3) directly modifying contractile proteins by phosphorylation. Yet, no studies have systematically addressed AMPK sex dimorphisms in mice with the R403Q mutation. Therefore, the outlined experimental plan is designed to concisely test the hypothesis that male hearts do not adapt appropriately to the increase in energetic demand caused by the R403Q HCM mutation, which leads to progressively worsening cardiac dysfunction. The hypothesis to be tested is that the key mechanism that underlies this sexual dimorphism is an altered AMPK signaling axis in males compared to females. Moreover, these studies will provide a critical foundation upon which to guide future research into defining fundamental differences in metabolic and oxidative capacities of male and female hearts in order to more completely elucidate sex differences in cardiovascular disease etiology and treatment in the human population. Males and females respond differently to cardiac disease such that males typically show signs of worsening cardiac function and females do not. The way males and females uniquely handle the energetic deficiencies associated with cardiac disease underlies these differences. Therefore, it is of major clinical significance that the mechanistic link be determined between cardiac disease, sex/gender differences and energetic regulators in the heart. )
Keywords: 5`-AMP-activated protein kinase; Address; Adenosine Monophosphate; Affinity; Age-Months; Award; base; Biochemical; Biology; Biometry; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; career; career development; Clinical; clinically significant; Complement; Contractile Proteins; cost; design; Development; Development Plans; Diamond; Disease; Disease Progression; Doctor of Philosophy; Electrophoresis; Environment; Estrogens; Etiology; Failure (biologic function); Female; Foundations; Functional disorder; Funding; Goals; Heart; Heart Diseases; heart function; Human; Hypertension; Hypertrophic Cardiomyopathy; Hypertrophy; inhibitor/antagonist; Intervention; Journals; Laboratories; Left; Link; male; Mass Spectrum Analysis; Measurement; Measures; Mechanics; Mediator of activation protein; meetings; men; Mentors; Metabolic; Microfilaments; Modeling; Molecular; Monitor; Motor; Mus; Mutation; Myocardial Infarction; Myocardium; Myosin Heavy Chains; novel; Ovarian; parent grant; Parents; Pathogenesis; Pathology; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Physiological Adaptation; Population; post-doctoral training; Post-Translational Protein Processing; pre-doctoral; Production; professor; programs; Property; protective effect; Proteins; Proteomics; public health relevance; Research; research and development; Resolution; Resources; response; Role; sex; Sex Characteristics; sexual dimorphism; Signal Transduction; Site; skills; Structure; Techniques; Testing; Time; Training Activity; Translational Research; Ultrasonography; Ventricular; Woman
Project start date: 2011-04-18
Project end date: 2016-03-31
Budget start date: 18-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-10-057
1K02HL105799-01 (2011): $103113
ENDOTHELIAL PROGENITOR CELL TRANSPLANT TO ACCELERATE HEMATOPOIETIC RECOVERY
P John, Professor
Duke Universitycity: Durham country: United States (us)
Grant 5R01HL086998-04 from National Heart, Lung, And Blood Institute
Abstract: The broad, long-term objective of this project is to determine whether transplantation of endothelial progenitor cells (EPCs) can accelerate hematopoietic recovery in vivo. Dose intense radiation and chemotherapy as applied in the treatment of hematologic malignancies commonly result in prolonged cytopenias as a function of bone marrow (BM) suppression. In the setting of cord blood transplantation (CBT) in adults, delayed donor cell engraftment can result in profound and persistent neutropenia, thrombocytopenia and immune suppression leading to increased mortality risk. Since most transplant conditioning regimens involve the administration of myeloablative chemotherapy with or without radiotherapy, we hypothesize that a contributing factor to the delay in hematopoietic recovery post-CBT is the damage incurred by the bone marrow niche (endothelial cells, stromal cells). Since hematopoietic stem and progenitor cells depend upon the BM niche to provide regenerative and proliferative signals, we sought to determine whether therapies aimed at replacing BM niche function could translate into more rapid hematologic recovery in the setting of CB transplantation. Increasing evidence suggests that BM vascular endothelial cells provide proliferative and differentiative signals to hematopoietic stem and progenitor cells in vitro and in vivo. Therefore, we hypothesize that targeted replacement of vascular endothelial cell activity can accelerate hematopoietic recovery in vivo. In order to test this hypothesis in a highly clinically relevant model, we propose the following Specific Aims 1) Determine whether transplantation of primary fetal blood EPCs can enhance hematopoietic recovery in a murine model of fetal blood transplantation, 2) Determine whether transplantation of human CB EPCs can enhance the homing and engraftment of human CB stem cells in immune deficient mice. Our Preliminary Results indicate that transplantation of primary EPCs alone significantly accelerates endogenous hematopoietic recovery in irradiated mice in both the autologous and allogeneic setting. This proposal provides a novel and potentially potent strategy to accelerate hematologic recovery in recipients of CB transplantation and, more broadly, provides the basis for therapies to replace endothelial cell activity in order to augment hematologic recovery following myelotoxic chemo- or radiotherapy. PUBLIC HEALTH RELEVANCE Many patients with leukemia and lymphoma who undergo high dose chemotherapy and radiotherapy in the treatment of their disease will suffer prolonged suppression of their blood and immune systems, resulting in increased risk of infections, bleeding and hospitalization. Such prolonged depression of the blood and immune systems also commonly occurs in adult patients who undergo cord blood transplantation in the treatment of their disease. We propose that cellular therapy aimed at replacing the activity of vascular endothelial cells in the bone marrow will accelerate blood and immune system recovery in these patients and our preliminary results indicate this strategy is highly effective
Keywords: Address; Adult; Allogenic; Autologous; base; Blood; Blood Vessels; Bone Marrow; Bone Marrow Stem Cell; Bone Marrow Suppression; Cell Transplants; Cells; chemotherapy; Child; Clinical; Clinical Research; Clinical Trials; clinically relevant; conditioning; cytopenia; Disease; Dose; Endothelial Cells; Engraftment; Exposure to; fetal blood; Fluorouracil; Goals; graft failure; Health; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hematopoietic System; Hemorrhage; High Dose Chemotherapy; Homing; Hospitalization; Human; Human Biology; Immune; Immune system; improved; In Vitro; in vivo; Infection; Ionizing radiation; leukemia/lymphoma; Mediating; Mental Depression; Modeling; Morbidity - disease rate; Mortality Vital Statistics; mouse model; Mus; Myeloablative Chemotherapy; Natural immunosuppression; Neutropenia; novel; novel strategies; Outcome; Patients; Radiation; Radiation therapy; reconstitution; Recovery; regenerative; Regimen; Regulation; Research; restoration; Risk; Role; Signal Transduction; Source; stem; stem cell niche; Stem cell transplant; Stem cells; Stromal Cells; Testing; Thrombocytopenia; Time; Translating; Translations; Transplant Recipients; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Vascular Endothelial Cell
Project start date: 2008-08-15
Project end date: 2012-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
5R01HL086998-04 (2011): $390000
5R01HL086998-03 (2010): $390000
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