DIETARY INTAKE AND EATING BEHAVIOR IN ADOLESCENTS WHO UNDERGO BARIATRIC SURGERY
B David, Associate Professor
University Of Pennsylvaniacity: Philadelphia country: United States (us)
Grant 5R01DK080738-04 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: This is an initial submission in response to PAR-07-024 (originally PAR-06-216) titled "Ancillary Studies to Obesity-Related Clinical Trials." This application is designed to serve as an ancillary study to the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS; U01 DK072493; PI Thomas Inge, M.D.) consortium. Teen-LABS is a four-center consortium working in cooperation with NIH scientific staff to conduct coordinated clinical research in adolescents who undergo bariatric surgery. This ancillary study, approved by the Teen-LABS Ancillary Study Committee, proposes to investigate changes in dietary intake and eating behavior in 110 Teen-LABS participants and compare them with responses in 110 obese adolescents treated with a lifestyle modification program. As America´s obesity problem continues to grow, there is a need for additional research on the effectiveness of innovative treatments. Bariatric surgery for adults with extreme obesity has exploded in popularity over the past decade. The sizable weight losses seen with bariatric surgery are well maintained and accompanied by improvement, if not resolution, of several obesity-related comorbidities and psychosocial status. Postoperative changes in dietary intake and eating behavior, which are thought to play a critical role in postoperative outcomes, have received less attention. The dietary and eating behavior outcomes of bariatric surgery in adolescents are virtually unknown. These issues may be particularly important because of adolescents´ developmental status at the time of surgery as well as their longer life expectancy. The main trial of the Teen-LABS consortium will not specifically study changes in dietary intake and eating behavior before and after bariatric surgery. We propose to study postoperative changes in these areas in a subset of 110 adolescents who undergo bariatric surgery in Teen-LABS. We predict that these adolescents will report significant improvements in their dietary intake (including reduced total calories per day and decreases in percentage of calories from sugar) at 6, 12, and 24 months postoperatively as compared to obese adolescents treated with a lifestyle modification program. We also anticipate that adolescents who undergo bariatric surgery will report greater improvements in eating behavior (including less frequent binge eating, higher levels of dietary restraint, as well as lower levels of disinhibition and hunger) as compared to obese adolescents treated in the lifestyle modification program. The Teen-LABS consortium provides an ideal opportunity to complete this innovative ancillary study in a large and diverse sample of adolescents who undergo bariatric surgery. In the proposed ancillary study to the Teen-LABS consortium, we plan to investigate changes in dietary intake and eating behavior in adolescents who undergo bariatric surgery
Keywords: Adolescent; Adult; American; Americas; Ancillary Study; Area; Attention; bariatric surgery; Behavior Therapy; Behavioral; Binge Eating; Body Weight decreased; Calories; Clinical Research; Clinical Trials; Comorbidity; Country; Coupled; design; Development; Diet Habits; Dietary intake; Disease; Disinhibition; Doctor of Medicine; Eating Behavior; Educational Background; Effectiveness; Epidemic; Ethnicity aspects; experience; Family; Health; health related quality of life; Hunger; Impairment; Income; innovation; interest; Intervention Studies; Life Expectancy; Morbid Obesity; Nausea and Vomiting; Obesity; Operative Surgical Procedures; Outcome; Participant; Patient Self-Report; Patients; Pharmacological Treatment; Physical activity; physical conditioning; Play; Postoperative Period; Prevalence; programs; psychosocial; public health relevance; Quality of life; Reporting; Research; Resolution; response; restraint; Role; Safety; Sampling; Schools; Stomach; sugar; Teenagers; Time; United States National Institutes of Health; Weight; Work; Youth
Project start date: 2008-07-01
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PAR-07-024
5R01DK080738-04 (2011): $321680
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to B David
UAB CLINICAL NUTRITION RESEARCH UNIT
B David, Professor
University Of Alabama At Birminghamcity: Birmingham country: United States (us)
Grant 3P30DK056336-10S1 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: We request renewed funding to continue the documented success achieved in the first cycle of UAB´s Clinical Nutrition Research Unit (CNRU). Inaugurated through NIH funding in 2000 and supported by UAB´s formal system of University-wide Interdisciplinary Research Centers, our CNRU fosters multidisciplinary, collaborative approaches to basic clinical and translational nutrition research, with emphasis on obesity. In1996, UAB established an intramurally-funded University-Wide Obesity-Nutrition Research Center which, with NIH funding, evolved into the present CNRU. Since first funded by NIDDK, our research base has grown from $44M (88% federal; 11 R01s) to $72M (92% federal; 40 R01s) in annual direct funding for nutrition/obesity studies-an overall increase of 61% in research funding. UAB´s CNRU has directly helped recruit at least 16 new and established obesity and nutrition investigators in the past funding cycle. Currently, our CNRU leadership oversees an NIDDK-funded T32 post-doctoral training grant for obesity research, a newly awarded industry sponsored pre-doctoral obesity training grant, an NIH-funded R25 Cancer Prevention and Control Training Program emphasizing nutrition, an endowed professorship and endowed chair in nutrition sciences, an NIH-funded U54 Center for Nutrient-Gene Interaction, and an annual series of NIH-funded nutrition and obesity-related short courses and conferences. Our CNRU funds at least four P/F studies per year, a New Investigator, and an extensive Enrichment Program. UAB has granted the CNRU over $1.6M since its inception as an NIH-funded CNRU, developing CNRU Cores in Energy Metabolism/Body Composition, Genetics, Small Animal Phenotyping and Biostatistics, for shared instrumentation, operating expenses and recruitment, resulting in cost-effective research and enhanced access to cutting-edge technology. Approximately 85% of the funded nutrition/obesity studies in our research base use CNRU Cores. Our secondary foci or points of converging research interests including gene-nutrient interaction, dietary effects on oxidative stress, and health effects of phytonutrients and micronutrients are nurtured in synergistic collaboration with other centers on campus including our NCI-funded Comprehensive Cancer Center and our Center for Free-Radical Biology. Backed by exceptional institutional support and academic infrastructure, we request renewed funding to continue our successful nutrition/obesity research
Keywords: Animals; Award; Back; base; Biology; Biometry; Body Composition; Cancer Control; cancer prevention; Clinical; Clinical Nutrition; Collaborations; Comprehensive Cancer Center; cost effective; Energy Metabolism; Food Interactions; Fostering; Free Radicals; Funding; gene interaction; Genes; Genetic; Grant; Health; Industry; instrumentation; Interdisciplinary Study; interest; Leadership; Micronutrients; multidisciplinary; National Institute of Diabetes and Digestive and Kidney Diseases; Nutrient; nutrition; Nutritional Study; Obesity; Oxidative Stress; Phenotype; post-doctoral training; pre-doctoral; programs; Recruitment Activity; Research; Research Infrastructure; Research Personnel; Science; Series; success; symposium; System; Technology; Training; Training Programs; United States National Institutes of Health; Universities
Project start date: 2000-06-01
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: RFA-DK-06-013
3P30DK056336-10S1 (2011): $87263
5P30DK056336-10 (2011): $1087500
ADMINISTRATIVE AND ENRICHMENT CORE
B David, Professor
University Of Alabama At Birminghamcity: Birmingham country: United States (us)
Abstract: We request renewed funding to continue the documented success achieved in the first cycle of UAB´s Clinical Nutrition Research Unit (CNRU). Inaugurated through NIH funding in 2000 and supported by UAB´s formal system of University-wide Interdisciplinary Research Centers, our CNRU fosters multidisciplinary, collaborative approaches to basic clinical and translational nutrition research, with emphasis on obesity. In 1996, UAB established an intramurally-funded University-Wide Obesity-Nutrition Research Center which, with NIH funding, evolved into the present CNRU. Since first funded by NIDDK, our research base has grown from $44M (88% federal; 11 R01s) to $72M (92% federal; 40 R01s) in annual direct funding for nutrition/obesity studies¿an overall increase of 61% in research funding. UAB´s CNRU has directly helped recruit at least 16 new and established obesity and nutrition investigators in the past funding cycle. Currently, our CNRU leadership oversees an NIDDK-funded T32 post-doctoral training grant for obesity research, a newly awarded industry sponsored pre-doctoral obesity training grant, an NIH-funded R25 Cancer Prevention and Control Training Program emphasizing nutrition, an endowed professorship and endowed chair in nutrition sciences, an NIH-funded U54 Center for Nutrient-Gene Interaction, and an annual series of NIH-funded nutrition and obesity-related short courses and conferences. Our CNRU funds at least four P/F studies per year, a New Investigator, and an extensive Enrichment Program. UAB has granted the CNRU over $1.6M since its inception as an NIH-funded CNRU, developing CNRU Cores in Energy Metabolism/Body Composition, Genetics, Small Animal Phenotyping and Biostatistics, for shared instrumentation, operating expenses and recruitment, resulting in cost-effective research and enhanced access to cutting-edge technology. Approximately 85% of the funded nutrition/obesity studies in our research base use CNRU Cores. Our secondary foci or points of converging research interests including gene-nutrient interaction, dietary effects on oxidative stress, and health effects of phytonutrients and micronutrients are nurtured in synergistic collaboration with other centers on campus including our NCI-funded Comprehensive Cancer Center and our Center for Free-Radical Biology. Backed by exceptional institutional support and academic infrastructure, we request renewed funding to continue our successful nutrition/obesity research
Keywords: Acquired Immunodeficiency Syndrome; Aging; Alabama; Animals; Area; Arthritis; Award; Back; Baptist Church; base; Biology; Biomedical Research; Biometry; Body Composition; Budgets; Burn Centers; Cancer Control; cancer prevention; Cardiovascular system; Cities; Clinical; Clinical Nutrition; Clinical Research; Collaborations; college; Communities; Community Outreach; Complement; Comprehensive Cancer Center; Contracts; cost effective; Cystic Fibrosis; Dentistry; Development; Diabetes Mellitus; Direct Costs; Discipline; Discipline of Nursing; Disease; Educational aspects; Elderly; Energy Metabolism; Enrollment; Environment; Epidemiology; Extramural Activities; Faculty; falls; Food Interactions; Fostering; Free Radicals; Funding; gene interaction; Genes; Genetic; graduate student; Grant; Growth; Health; Health Maintenance Organizations; Health Occupations; Health Promotion; Health Resources; Healthcare Industry; Hospitals; Immunity; Immunobiology; Industry; Infection; Institution; instrumentation; Interdisciplinary Study; interest; international center; Investigation; Laboratories; Laboratory Personnel; Leadership; Measures; Medical center; Medicine; member; Methodist Church; Micronutrients; Mission; multidisciplinary; National Center for Research Resources; National Institute of Diabetes and Digestive and Kidney Diseases; Neurobiology; Nutrient; nutrition; Nutritional Study; Obesity; Optometry; Organ Transplantation; Oxidative Stress; Pediatric Hospitals; Phenotype; post-doctoral training; pre-doctoral; Process; Productivity; programs; Public Health Education; public health medicine (field); Recording of previous events; Recovery; Recruitment Activity; Reporting; Research; Research Infrastructure; Research Personnel; Research Project Grants; Research Training; Resource Development; Resources; Schools; Science; Scientist; Series; Services; Sexually Transmitted Diseases; Sickle Cell; Social Medicine; Students; success; symposium; System; Technology; Training; Training Programs; trend; United States National Institutes of Health; Universities; Vaccines; Veterans; Work
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
5P30DK056336-10_9001 (2011): $234952
5P30DK056336-09_9001 (2010): $217500
UAB CLINICAL NUTRITION RESEARCH UNIT
B David, Professor
University Of Alabama At Birminghamcity: Birmingham country: United States (us)
Grant 5P30DK056336-09 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: We request renewed funding to continue the documented success achieved in the first cycle of UAB´s Clinical Nutrition Research Unit (CNRU). Inaugurated through NIH funding in 2000 and supported by UAB´s formal system of University-wide Interdisciplinary Research Centers, our CNRU fosters multidisciplinary, collaborative approaches to basic clinical and translational nutrition research, with emphasis on obesity. In1996, UAB established an intramurally-funded University-Wide Obesity-Nutrition Research Center which, with NIH funding, evolved into the present CNRU. Since first funded by NIDDK, our research base has grown from $44M (88% federal; 11 R01s) to $72M (92% federal; 40 R01s) in annual direct funding for nutrition/obesity studies-an overall increase of 61% in research funding. UAB´s CNRU has directly helped recruit at least 16 new and established obesity and nutrition investigators in the past funding cycle. Currently, our CNRU leadership oversees an NIDDK-funded T32 post-doctoral training grant for obesity research, a newly awarded industry sponsored pre-doctoral obesity training grant, an NIH-funded R25 Cancer Prevention and Control Training Program emphasizing nutrition, an endowed professorship and endowed chair in nutrition sciences, an NIH-funded U54 Center for Nutrient-Gene Interaction, and an annual series of NIH-funded nutrition and obesity-related short courses and conferences. Our CNRU funds at least four P/F studies per year, a New Investigator, and an extensive Enrichment Program. UAB has granted the CNRU over $1.6M since its inception as an NIH-funded CNRU, developing CNRU Cores in Energy Metabolism/Body Composition, Genetics, Small Animal Phenotyping and Biostatistics, for shared instrumentation, operating expenses and recruitment, resulting in cost-effective research and enhanced access to cutting-edge technology. Approximately 85% of the funded nutrition/obesity studies in our research base use CNRU Cores. Our secondary foci or points of converging research interests including gene-nutrient interaction, dietary effects on oxidative stress, and health effects of phytonutrients and micronutrients are nurtured in synergistic collaboration with other centers on campus including our NCI-funded Comprehensive Cancer Center and our Center for Free-Radical Biology. Backed by exceptional institutional support and academic infrastructure, we request renewed funding to continue our successful nutrition/obesity research
Project start date: 2000-06-01
Project end date: 2012-05-31
Budget start date: 1-JUN-2010
Budget end date: 31-MAY-2011
PFA/PA: RFA-DK-06-013
5P30DK056336-09 (2010): $1087500
STRUCTURAL BIOLOGY OF AMYLOID BETA-PROTEIN
B David, Professor
University Of California Los Angelescity: Los Angeles country: United States (us)
Grant 5R01NS038328-10 from National Institute Of Neurological Disorders And Stroke
Abstract: We hypothesize that amyloid ¿-protein (A¿) assembly into neurotoxic oligomers and polymers is a seminal neuropathogenetic process in Alzheimer´s disease (AD). If so, assembly inhibition or dissociation of existing assemblies could be effective therapeutic approaches. To test our hypothesis, the structural biology of A¿ must be elucidated in detail. What conformers form oligomers? By what mechanism? What are the structures of the oligomers thus formed? What is the relative toxicity of each oligomer species? Many, including ourselves, have striven to correlate structure with measures of biological activity. Recent work has suggested that dimeric or trimeric assemblies are important neurotoxins, but hexameric, nonameric, dodecameric, and larger oligomers also have been shown to be potent neurotoxins. The long-term goal of this proposal is to move past simple quaternary structure determination to elucidation of A¿ monomer secondary and tertiary structure dynamics and the determination of mechanisms of monomer oligomerization. This means eventually understanding the interatomic interactions that control the dynamics, and in doing so, identifying therapeutic targets at atomic resolution. This "knowledge-based" approach is distinct from, but complementary to, high-throughput screening strategies. Both approaches should be executed to maximize the chances for identifying efficacious, disease-modifying therapeutic agents. We propose here to (1) elucidate the physical biochemistry of A¿ monomer folding and self-assembly; and (2) establish structure-neurotoxicity relationships of the A¿ assemblies thus formed. To do so, we will chemically synthesize A¿ peptides in which specific amino acids and chemical bonds are altered and then study the conformational dynamics and assembly of these peptides. The positions of these alterations, and the alterations themselves, have been chosen carefully so as to reveal the key structural features of the A¿ molecule that control its assembly into structures that damage or kill neurons. We will identify, isolate, and structurally characterize specific types of assemblies and then determine quantitatively the toxic activity of each assembly by treating primary neurons in culture. The depth of understanding of the structures of the assemblies obtained in the first aim will be unprecedented. Thus the knowledge gained through this "structure-activity correlation" process is expected to provide the most accurate assessment of which assemblies, and which structures (at atomic resolution) on these assemblies, should be targeted therapeutically. In addition to its contributions to an improved understanding of AD and its treatment, results of the proposed project should have relevance for studies of other neurodegenerative diseases linked to aberrant protein assembly. These include Parkinson´s, Huntington´s, amyotrophic lateral sclerosis, familial amyloid polyneuropathy, and the prionoses. This project will advance our understanding of how a protein, the amyloid-protein, causes Alzheimers disease. This understanding can be translated directly into the development of a new class of drugs that have the potential to modify or cure the disease. The project also will be of relevance to Parkinsons, Huntingtons, amyotrophic lateral sclerosis, familial amyloid polyneuropathy, the prionoses, and other neurodegenerative diseases of aging
Keywords: Affect; Aging; Alzheimer disease prevention; Alzheimer`s Disease; Amino Acid Substitution; Amino Acids; Amyloid; Amyloid beta-Protein; Amyloid Proteins; Amyotrophic Lateral Sclerosis; Biochemistry; Biological; chemical bond; Chemistry; conformer; crosslink; Data; design; Development; Dipeptides; Disease; Dissociation; Failure (biologic function); Familial Amyloid Neuropathies; Fractionation; Goals; high throughput screening; Huntington Disease; improved; In Situ; Isomerism; Killings; Kinetics; Knowledge; knowledge base; Link; Measures; Mediating; monomer; Mutation; Neurodegenerative Disorders; Neurons; neurotoxic; neurotoxicity; neurotoxin 5; Neurotoxins; novel; Parkinson Disease; Peptides; Pharmaceutical Preparations; Polymers; Positioning Attribute; Procedures; Process; Proteins; public health medicine (field); public health relevance; Reaction; Relative (related person); research study; Resolution; Role; Sampling; Scanning; self assembly; Seminal; Site; structural biology; Structure; System; Testing; Therapeutic; Therapeutic Agents; therapeutic target; Toxic effect; Translating; Work
Relevance: Relevance to Public Health This project will advance our understanding of how a protein, the amyloid -protein, causes Alzheimers disease. This understanding can be translated directly into the development of a new class of drugs that have the potential to modify or cure the disease. The project also will be of relevance to Parkinsons, Huntingtons, amyotrophic lateral sclerosis, familial amyloid polyneuropathy, the prionoses, and other neurodegenerative diseases of aging
Project start date: 1998-12-10
Project end date: 2015-02-28
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: PA-07-070
5R01NS038328-10 (2011): $303188
NOVEL SUBSTRATE OXIDATION BY ENZYME ENGINEERING
B David
University Of California Daviscity: Davis country: United States (us)
Grant 2R01GM041049-24A1 from National Institute Of General Medical Sciences
Abstract: Understanding the diverse chemistry displayed by P450s is a central issue in biomedical science and requires understanding their notorious propensity for specificity and promiscuity. Drug metabolizing P450s display a remarkable promiscuity in substrate recognition, while enzymes involved in steroid biosynthesis are often very specific with respect to substrate binding and catalysis. However, the molecular mechanism by which these different forms control this promiscuity or specificity is not well understood. How does structure encode such diversity? It is known that significant conformational changes occur in many, if not all, P450s during substrate recognition. These changes may also play a role in gating the reactions following O2 activation to produce reactive intermediates. However, we know very little about how substrates are recognized by a particular P450 or how these changes are coupled to function. Does a P450 recognize its substrate by induced fit or by dynamically sampling only a few preferred conformations? Results in the past period have produced significant insights into the conformational changes that occur upon substrate binding to P450, they suggest how these changes may be coupled to function, and they provide a platform for development of novel catalysts with designed specificity. The current aims will use a library of molecular probes for the P450 active site to control the formation and properties of proposed reactive intermediates. These studies will test specific hypotheses, based on our recent progress, about how conformational changes at the active site may help control the O2 activation step. We will develop these approaches to investigate the electrochemical behavior of P450s specifically wired to electrode surfaces. Finally, we will explore the potential for using specific probes for molecular evolution of novel catalysts with designed substrate specificity. These studies will contribute to a better understanding how the protein structure of these important enzymes is coupled to function and substrate specificity. P450s are a diverse class of enzymes of critical importance to human health because they are responsible for the biosynthesis of important compounds and drug metabolism. Our long term goal is to develop a general method for introducing new activities into these enzymes, as evolved P450 catalysts have the potential for producing novel drugs and antibiotics. In the process, we will gain a deeper understanding of how the substrates are recognized and how the enzymatic reactions are controlled
Keywords: Active Sites; Address; Anabolism; Antibiotics; base; Behavior; Binding (Molecular Function); Biochemical Reaction; Catalysis; catalyst; chemical reaction; Chemicals; Chemistry; cofactor; Complex; Coupled; Cytochrome P450; design; Development; drug metabolism; Electrodes; Electron Transport; Engineering; enzyme substrate; Enzymes; Exhibits; Forms Controls; Goals; Health; Heme; heme a; high throughput screening; Human; Hydrocarbons; Hydroxylation; insight; Kinetics; Learning; Libraries; member; Methods; Molecular; Molecular Conformation; Molecular Evolution; Molecular Probes; mutant; Nature; novel; oxidation; Oxidation-Reduction; oxidative damage; Phage Display; Pharmaceutical Preparations; Play; Population; Positioning Attribute; prevent; Process; Property; protein structure; Proteins; Reaction; Regulation; Role; Sampling; Science; Series; Site; small molecule; Specificity; Steroid biosynthesis; Structure; Substrate Interaction; Substrate Specificity; Surface; System; Testing; Variant
Relevance: P450s are a diverse class of enzymes of critical importance to human health because they are responsible for the biosynthesis of important compounds and drug metabolism. Our long term goal is to develop a general method for introducing new activities into these enzymes, as evolved P450 catalysts have the potential for producing novel drugs and antibiotics. In the process, we will gain a deeper understanding of how the substrates are recognized and how the enzymatic reactions are controlled
Project start date: 1989-01-01
Project end date: 2015-04-30
Budget start date: 1-AUG-2011
Budget end date: 30-APR-2012
PFA/PA: PA-10-067
2R01GM041049-24A1 (2011): $343095
NORMS AND BUILT ENVIRONMENT: USE OF SHADE IN U.S. AND AUSTRALIAN CITY PARKS
B David, Research Director
Klein Buendel, Inc.city: Golden country: United States (us)
Grant 5R01CA140367-02 from National Cancer Institute
Abstract: This study is designed to understand the value of shade development in skin cancer prevention and test predictions from social ecologic models that health behavior results from the interplay among the built environment, social environment, individual factors, setting features, and perceived environment. Use of shade is recommended by health authorities worldwide; however, shade provision requires expensive physical environment changes and may be effective only when health education has created a social environment (e.g., norms) and individual factors (e.g., habits) that motivates its use. A multi-national research team will explore the use of built shade in passive recreation areas (PRAs; areas for sitting/ standing while socializing, preparing/eating a meal, watching or coaching sports, watching a concert, taking a class, or waiting, or areas where people stroll for sightseeing, while observing outdoor displays, or shopping) within public parks and compare use between the United States and Australia to prospectively test the moderating influence of social environment on the built environment. Pilot studies confirmed that adults in Melbourne, Victoria, Australia had stronger sun protection habits and norms than adults in Denver, Colorado, USA. The specific aims of the project are to a) introduce built shade structures (i.e., shade sails) in public parks in Denver and Melbourne; b) compare the use of PRAs with and without built shade; c) compare the change in use of the PRAs in Denver and Melbourne after introduction of built shade, and d) examine the relationship among social environment, individual factors, other physical features of the environment micro-climate (i.e., setting), and perceived environment and built shade in posttest with PRA users. In this 60-month project, the research team will build shade sails at PRAs in public parks and compare use of PRAs to unshaded PRAs in a randomized pretest- posttest controlled design. PRAs will be stratified by location (80 in Denver and 80 in Melbourne) and randomized to one of 3 sample waves over 3 years. In each wave, areas will be pretested in a first summer, further stratified based on baseline use, and randomized to construction of a shade sail during the fall, winter, and spring. A park audit will describe the park, PRA and neighborhood setting. Post testing will occur the following summer. In total, 40 PRAs will be randomized to shade sail construction (20 per city) and 120 PRAs to control with no shade sails (60 per city). The primary outcome measures will be observation of the number of individuals using the PRAs and their average UV exposure (in minimal erythemal doses [MEDs]). Observers will record use of other PRAs, number of park users, social group, sun protection, gender, and age. Intercept surveys with PRA users will collect data on social environment, individual factors, and perceived environment. UV meters will measure UV levels. Data collection will occur on 4 weekdays and 4 weekend days over 16-weeks in the summer. Primary analyses will be performed on the weighted average use of PRAs and MEDs per day; analyses will be conducted on moderating and mediating factors to test theoretically-derived hypotheses. Use of shade when outdoors is recommended by health authorities worldwide to reduce overall exposure to ultraviolet radiation; however, expensive physical environment changes are often required to provide shade and may be effective only when health education has created a social environment and individual factors that motivate shade use. A multi-national research team will explore the use of built shade in passive recreation areas (PRAs) within public parks and compare use of built shade between the United States and Australia. The specific aims of the project are to a) introduce built shade structures (i.e., shade sails) in public parks in Denver and Melbourne; b) compare the use of PRAs with and without built shade; c) compare the change in use of the PRAs in Denver and Melbourne after introduction of built shade, and d) examine the relationship among social environment, individual factors, other physical features of the environment micro-climate (i.e., setting), and perceived environment and built shade in posttest with PRA users
Keywords: Academy; Adult; Age; American; American Cancer Society; Area; Attitude; Australia; authority; base; Behavior; behavior influence; Cities; Climate; college; Colorado; Communities; Controlled Study; Country; Cross-Sectional Studies; Data; Data Collection; Dermatologist; Dermatology; design; Development; disorder risk; Dose; Eating; Educational aspects; Effectiveness; Environment; Evolution; expectation; falls; family structure; Gender; Government; Habits; Health; Health behavior; Health Campaign; Health education; Image; Individual; Intercept; Investments; Jogging; Location; Malignant Neoplasms; Measures; Mediating; meter; Modeling; National Cancer Institute; Neighborhoods; Organizational Policy; Outcome Measure; Perception; Physical environment; Pilot Projects; Plants; Policies; Population; Preparation; Prevention Research; primary outcome; Process; programs; public health relevance; Randomized; Recording of previous events; Recreation; Research; Research Project Grants; Resistance; Risk; Safety; Sampling; Schools; Scientist; skin cancer prevention; social; Social Environment; social group; Sports; Structure; sun protection; Sunburn; Sunlight; Surveys; System; Testing; The Sun; Time; Trees; Ultraviolet Rays; United States; UV Radiation Exposure; Visit; Weight; Work; Workplace; World Health Organization
Relevance: Use of shade when outdoors is recommended by health authorities worldwide to reduce overall exposure to ultraviolet radiation; however, expensive physical environment changes are often required to provide shade and may be effective only when health education has created a social environment and individual factors that motivate shade use. A multi-national research team will explore the use of built shade in passive recreation areas (PRAs) within public parks and compare use of built shade between the United States and Australia. The specific aims of the project are to: a) introduce built shade structures (i.e., shade sails) in public parks in Denver and Melbourne; b) compare the use of PRAs with and without built shade; c) compare the change in use of the PRAs in Denver and Melbourne after introduction of built shade, and d) examine the relationship among social environment, individual factors, other physical features of the environment micro-climate (i.e., setting), and perceived environment and built shade in posttest with PRA users
Project start date: 2010-07-15
Project end date: 2015-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5R01CA140367-02 (2011): $505172
NEUROCOGNITIVE PROCESSES IN DEAF CHILDREN WITH COCHLEAR IMPLANTS
B David, Adjunct Professor
Indiana Univ-purdue Univ At Indianapoliscity: Indianapolis country: United States (us)
Grant 5R01DC009581-03 from National Institute On Deafness And Other Communication Disorders
Abstract: This revised application requests support for a program of research on neurocognitive processes underlying speech and language outcomes in prelingually deaf children following cochlear implantation. Past research on cochlear implants has been narrowly focused on speech and language outcomes and efficacy of cochlear implantation as a medical treatment for profound hearing loss. As noted in the two previous NIH consensus statements on cochlear implants, little, if any, basic or clinical research has investigated the underlying neurobiological and neurocognitive factors that are responsible for the enormous individual differences and variability in the effectiveness of cochlear implants. The primary objective of this research project is to demonstrate that domain-general neurocognitive processes related to executive functioning, such as working memory, fluency-speed, concentration-inhibition and organization-integration skills, are strongly associated with traditional clinical speech and language outcome measures. These executive function/cognitive control processes involve the global coordination, integration and functional connectivity of multiple underlying brain systems used in speech perception, production and spoken language processing. In two related projects, we test the hypothesis that executive function and organization- integration (EOI) processes contribute an additional unique modality-independent source of variance to speech and language outcomes above and beyond the traditional demographic, medical and educational factors. The first project uses a cross-sectional design to assess EOI functioning in long term cochlear implant users; the second project uses longitudinal methods to investigate the development of EOI functioning. The new findings obtained from this project on the underlying sources of variability in spoken language processing will help clinicians and researchers understand, explain and predict individual differences in speech and language outcomes following cochlear implantation. The results of this project have direct clinical implications for improving the diagnosis, treatment and early identification of young deaf children who may be at high risk for poor speech and language outcomes following cochlear implantation. The enormous variability in speech and language outcomes of deaf children who receive cochlear implants is a significant clinical problem. The proposed research project on neurocognitive processes in deaf children with cochlear implants will provide new fundamental knowledge about the sources of variability and underlying neurocognitive factors that are responsible for individual differences in speech and language outcomes. These findings will have direct implications for the diagnosis, treatment and early identification of deaf children who may be at high risk for poor outcomes following implantation
Keywords: Age-Years; Attention; base; Basic Science; Behavioral; Brain; brain behavior; Child; Clinical; Clinical Research; Cochlear implant procedure; Cochlear Implants; cognitive control; Cognitive Science; Consensus; Cross-Sectional Studies; design; Development; Diagnosis; Early identification; Effectiveness; executive function; Goals; Hearing; Hearing Impaired Persons; hearing impairment; high risk; Implant; implantation; improved; Individual Differences; Informal Social Control; information processing; Knowledge; Language; language processing; Learning; Longitudinal Studies; Measures; Medical; Memory; Methods; Modality; Neurobiology; Neurocognitive; Neuropsychology; Outcome; Outcome Measure; Preschool Child; Process; processing speed; Production; programs; public health relevance; Request for Applications; Request for Proposals; Research; Research Personnel; Research Project Grants; Short-Term Memory; skills; Source; Speech; Speech Perception; Speed (motion); System; Testing; theories; Time; Translational Research; United States National Institutes of Health; Work
Relevance: /Relevance The enormous variability in speech and language outcomes of deaf children who receive cochlear implants is a significant clinical problem. The proposed research project on neurocognitive processes in deaf children with cochlear implants will provide new fundamental knowledge about the sources of variability and underlying neurocognitive factors that are responsible for individual differences in speech and language outcomes. These findings will have direct implications for the diagnosis, treatment and early identification of deaf children who may be at high risk for poor outcomes following implantation
Project start date: 2009-09-20
Project end date: 2014-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-07-070
5R01DC009581-03 (2011): $587724
TRAINING IN SPEECH, HEARING, AND SENSORY COMMUNICATION
B David, Adjunct Professor
Indiana University Bloomingtoncity: Bloomington country: United States (us)
Grant 5T32DC000012-33 from National Institute On Deafness And Other Communication Disorders
Abstract: This proposal requests support to continue the multidisciplinary NRSA T32 training program in Speech, Hearing and Sensory Communication at Indiana University. The training program provides specialized research training in the Communications Sciences and Disorders for postdoctoral, predoctoral and medical students. Faculty and laboratory facilities will be drawn from Psychological & Brain Sciences, Linguistics, Speech & Hearing Sciences, Cognitive Science and Neuroscience in Bloomington and Otolaryngology, Radiology and Psychiatry in the School of Medicine in Indianapolis. The program has 10 core faculty members and an additional 26 affiliated and supporting faculty. Trainees carry out basic and/or clinical research in one of the core or affiliated laboratories and gain specialized knowledge in areas such as speech analysis, synthesis and perception; anatomy and physiology of the auditory system; psychophysics of hearing; acoustic and articulatory phonetics; clinical phonology; perceptual development, phonological acquisition and development; clinical audiology, speech- language pathology, hearing impairment and cochlear implants; spoken word recognition and lexical access; and neuroimaging and computational modeling of spoken language processing. Postdoctoral trainees will be drawn from Speech & Hearing Sciences, Linguistics, Cognitive, and Developmental Psychology. Predoctoral trainees will be drawn from the current Ph.D. programs in Psychological & Brain Sciences, Linguistics, Speech & Hearing Sciences, Cognitive and Neuroscience. As in the past, training activities will consist of (1) individual and collaborative research projects; (2) participation in weekly laboratory meetings, research seminars, journal clubs and workshops, (3) attendance at scientific or professional meetings; and (4) formal coursework as needed. Access to several different clinical populations for research is available through the Speech and Hearing Clinic in Bloomington and the ENT Clinics at the IU Medical Center in Indianapolis. Our long-term objectives remain fundamentally the same- to provide highly specialized research training in the Communication Sciences and Disorders in order to increase the number of qualified biomedical research scientists working on basic and clinical problems in Speech, Hearing and Sensory Communication. RELEVANCE This application requests support to continue the NIDCD-sponsored NRSA T32 training program at Indiana University. The program provides research training in the Communication Sciences and Disorders for post- doctoral, pre-doctoral and medical students and is designed to increase the number of biomedical scientists working on basic and clinical problems in speech, hearing and spoken language processing
Keywords: Communication; Hearing; Sensory; Speech; Training
Project start date: 1989-09-25
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-06-468
5T32DC000012-33 (2011): $627287
Sponsored Links Excellgen http://Excellgen.com
MULTIDISCIPLINARY RESEARCH TRAINING IN PULMONARY MEDICINE
B David, Division Head
Oregon Health And Science Universitycity: Portland country: United States (us)
Grant 5T32HL083808-04 from National Heart, Lung, And Blood Institute
Abstract: This proposal describes our research training program in the Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University. In this program, we offer state of the art, multidisciplinary research training in a wide range of disciplines including cell and molecular biology, whole organ pathophysiology, and both human based research and epidemiological research. Six post-doctoral fellows (primarily MD pulmonary fellows) and two graduate students will be offered funding for two years of research training each. Research will be supplemented by trainee participation in program wide research seminars and journal clubs. It is our belief that such program wide meetings and interactions are vital to providing young scientists with a broad perspective on research outside their own projects, avoiding early overspecialization and an inappropriately narrow research focus. Course work is also offered, and includes a mandatory course in Responsible Conduct of Research, as well as a wide range of courses appropriate to trainees embarking on a research career. These include statisics, experimental design, grant writing, manuscript writing, public speaking, and epidemiological methods, and are offered both in our graduate programs and in our Human Investigations Program. Research mentorship is provided by a faculty of seasoned scientists with extensive experience in training young scientists. About half the faculty conducts research primarily or principally involving the lung. The remainder have specific areas of expertise in cell and molecular biology that have either been applied to the study of lung disease or are easily applicable to it. Interactions and synergy among the laboratories in this program add to the rich and broad training environment. A well established system for regularly tracking the progress of trainees ensures their continued development, and broadens the sources of guidance and advice in this crucial stage of their careers. This approach will produce clinical and basic researchers prepared for the challenges of academic medicine and biomedical research, and will help fill the need in the next generation of scientists. These scientists will be prepared to address the public health issues raised by the increasing burden of asthma, chronic bronchitis, emphysema, acute respiratory distress syndrome, and other lung diseases
Keywords: Interdisciplinary Study; Pulmonary Disease (Specialty); Research Training
Project start date: 2008-04-01
Project end date: 2013-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-06-468
5T32HL083808-04 (2011): $350201
UAB BIOSTATISTICS PRE-DOCTORAL TRAINING PROGRAM
B David, Associate Professor
University Of Alabama At Birminghamcity: Birmingham country: United States (us)
Grant 5T32HL079888-07 from National Heart, Lung, And Blood Institute
Abstract: This is a request for continuation of support for a training program in Biostatistics launched in 2005 at the University of Alabama at Birmingham (UAB) to provide support for two pre-doctoral trainees per year for a training period of 4 years. A recent NHLBI RFA-HL-09-009 stated "The current demand for biostatisticians far exceeds the supply, and the gap continues to widen." Recommendations of two workshops (2001, 2003) held by the National Institutes of Health (NIH) were published as a Training of the next generation of biostatisticians a call to action in the U.S. (Statistics In Medicine 25(20) 3415-3429. 2006). The workshops examined the need to train more biostatisticians to meet the increasing opportunities in the biomedical research enterprise. The supply of new PhD graduates in biostatistics in the U.S. has been relatively steady for the past two decades while the demand has increased dramatically. These workshops concluded that a renewed effort must be made in the U.S., led in part by the NIH, to add to and expand the existing training programs to increase the supply. The Biostatistics Department at UAB is well poised to help meet the recognized need. Our department has undergone a renaissance in the past 9 years and developed significant strength in Statistical Genetics; Clinical Trials Design & Analysis; and Design & Analysis of Epidemiologic Studies. We have a large, well-funded, ^highly active department that is evenly split between methodological and applied research. Both our university and department have evidenced strong commitments to training the next generation of biostatisticians through allocation of substantial effort and financial resources to building a vital educational program. The proposed structured training program offers pre-doctoral fellowships to prepare scientists for careers in biostatistics specifically aimed at heart, lung and blood (HLB) research. The program aims to develop independent investigative skills in the development, evaluation, and application of advanced statistical methods. To support this goal, applied experience is provided via co-mentorship by UAB´s well established NHLBI-funded investigators
Keywords: Biometry; pre-doctoral; Training Programs
Project start date: 2005-09-01
Project end date: 2015-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-08-226
5T32HL079888-07 (2011): $281952
B David, Professor
University Of Alabama At Birminghamcity: Birmingham country: United States (us)
Grant 5T32DK062710-08 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: This is a renewal application for a successful training program offering 2-3 year fellowships that prepare post-doctoral scientists for careers in obesity research. Early career investigators enroll in a formal program tailored to individual interests aimed to promote development of independent research careers. Trainees are incorporated into the investigative programs of UAB´s Clinical Nutrition Research Unit. Trainees may elect to work with a single faculty member or be jointly mentored by more than one faculty. The faculty´s multidisciplinary nature (physicians, psychologists, statisticians, physiologists, geneticists, epidemiologists, nutritionists, etc) allows a multidisciplinary approach on the part of the trainees. Strong collaborative ties among the faculty facilitate this multidisciplinary approach. Trainees have available techniques in cell culture, animal models, statistical methodology, molecular genetics, body composition, calorimetry, metabolic balance, nutritional assessment, stable isotope methodology, hormone and metabolite assays, hormone receptor biochemistry, and many more. Trainees will be physicians or recent Ph.D. (or equivalent) recipients in disciplines including (but not limited to) genetics, biochemistry, nutrition, psychology, physiology, statistics, epidemiology, neuroscience or pharmacology. Individuals are selected based on demonstrated competence in graduate school, recommendations of their previous faculty, and consideration of the degree to which their interests fit with those of the faculty and with ongoing research programs. All trainees must have as a future plan an investigative career in obesity-related research. Each cooperating laboratory is well equipped and funded to support trainees´ research and scholarly development. The program promotes independent investigative skills and a rigorous approach to investigation through research and didactic seminars. Many courses are available to trainees. Regular reviews of individual trainees are completed by the training program directors to insure that adequate progress toward the development of an independent research career is made. Funding is requested for six post-doctoral trainee slots. Obesity, a problem of enormous public health relevance, afflicts millions of American adults and children, decreases quality of life, impairs health, and shortens lifespan. Its causes remain incompletely understood and available treatment and prevention approaches leave much room for improvement. These facts underscore the importance of training new scholars and scientists to address this challenging problem
Keywords: Obesity; Training Programs
Project start date: 2002-09-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-06-468
5T32DK062710-08 (2011): $134170
3T32DK062710-08S2 (2011): $40230
3T32DK062710-07S1 (2010): $39663
5T32DK062710-07 (2010): $224864
SUN VALLEY WORKSHOP ON SKELETAL BIOLOGY
B David
Indiana Univ-purdue Univ At Indianapoliscity: Indianapolis country: United States (us)
Grant 1R13AR061926-01 from National Institute Of Arthritis And Musculoskeletal And Skin Diseases
Abstract: This application requests support for the annual meeting of the Sun Valley Workshop on Skeletal Biology held in Sun Valley, Idaho, July 31-August 3, 2011. The Sun Valley Workshops have a 40 year tradition and originally grew out of an attempt to provide multidisciplinary training to younger scientists. The Workshops continue to emphasize active participation of junior faculty and students. The Workshops have been successful in promoting interdisciplinary communication, and are unusual in that discussion time equals or exceeds time allotted for formal presentation. The goals of the Workshop are to (1) work toward a multidisciplinary basic and clinical synthesis of molecular, tissue and biomechanical processes related to the pathogenesis, prevention and treatment of bone and joint diseases; (2) develop a dialogue between basic and clinical investigators; (3) provide training workshops for junior faculty and students that help bridge the gaps between disciplines; (4) provide a forum for student training and the opportunity for junior faculty and students to talk with more senior scientists in a small group setting. A partnership between the Workshop and the International Bone and Mineral Society (IBMS) has improved marketing of the Workshop, especially internationally, and provides maximum visibility through IBMS BoneKEy broadcast emails and links on the IBMS website. The 41st Sun Valley Workshop is focused on inflammatory and repair processes in skeletal tissue, and on cellular cross-talk. Numerous opportunities are provided for junior investigators to interact with more senior investigators. The Sunday evening session is set aside for a Plenary Lecture, which is followed by a Poster Session highlighting submitted s, The Monday evening session is devoted to presentations by six ASBMR/Harold M. Frost Young Investigator Awardees. There are plans to advertise and distribute a summary of the workshop, partly using Web-based resources and through publication in BoneKEy. This Workshop is relevant to public health concerns because it brings a multi-disciplinary group of senior and junior scientists together to discuss the pathogenesis and treatment of inflammatory disease such as rheumatoid arthritis, as well as mechanisms of cartilage and bone repair, the latter including fracture healing. Other sessions involve cellular signaling mechanisms that are important to prevention of bone and cartilage disease. It provides vertically-oriented information, from the basic science to clinical pathology, to practitioners and scientists who may not be completely familiar with all aspects of these diseases of public health concern
Keywords: ing; Advertising; African American; Area; arthropathies; Award; Basic Science; Biology; Biomechanics; bone; Bone Diseases; Bone Regeneration; Cartilage Diseases; cartilage repair; Cheese; Cities; Clinical; Clinical Investigator; Clinical Pathology; cost; Cost Sharing; Discipline; Disease; Eating; Educational workshop; Electronic Mail; Faculty; Fellowship; Flying body movement; Fracture Healing; Funding; Goals; Hispanics; Hour; Idaho; improved; Inflammatory; innovation; Institutes; interdisciplinary collaboration; Interdisciplinary Communication; interest; International; lectures; Link; Location; Marketing; meetings; Minerals; Molecular; multidisciplinary; Online Systems; Paper; Participant; Pathogenesis; posters; pressure; Prevention; Process; programs; public health medicine (field); Publications; Published Comment; repaired; Request for Applications; Research Personnel; Resort; Resources; response; Rheumatoid Arthritis; Scientist; Senior Scientist; Signal Transduction; skeletal; skeletal disorder; skeletal tissue; Sleep; Societies; Sodium Chloride; Structure; Students; symposium; The Sun; Time; Tissues; Training; Transportation; Travel; Underrepresented Minority; United States National Institutes of Health; Universities; Walking; web site; Wine; Work
Relevance: This Workshop is relevant to public health concerns because it brings a multi-disciplinary group of senior and junior scientists together to discuss the pathogenesis and treatment of inflammatory disease such as rheumatoid arthritis, as well as mechanisms of cartilage and bone repair, the latter including fracture healing. Other sessions involve cellular signaling mechanisms that are important to prevention of bone and cartilage disease. It provides vertically-oriented information, from the basic science to clinical pathology, to practitioners and scientists who may not be completely familiar with all aspects of these diseases of public health concern
Project start date: 2011-07-11
Project end date: 2012-06-30
Budget start date: 11-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-10-071
1R13AR061926-01 (2011): $20000
SPEECH PERCEPTION AND SPOKEN WORD RECOGNITION
B David, Adjunct Professor
Indiana University Bloomingtoncity: Bloomington country: United States (us)
Grant 2R01DC000111-34 from National Institute On Deafness And Other Communication Disorders
Abstract: This application requests support for a program of basic and clinical research on speech perception and spoken word recognition. The primary objective of this project is to understand how spoken words are recognized and how acoustic-phonetic and indexical information in the speech signal interact with other knowledge sources to support robust spoken language understanding. The proposed research will involve behavioral studies of speech perception and spoken word recognition as well as computational analyses of the sound patterns of word-forms in the mental lexicon to study global organization and connectivity patterns of spoken words. Four specific aims will be studied (1) lexical knowledge and organization, (2) perceptual learning and adaptation, (3) speech perception under adverse listening conditions, and (4) individual differences in working memory dynamics (capacity and speed) in hearing-impaired listeners with cochlear implants (CIs). The research findings will provide a much stronger conceptual and theoretical basis for explaining the core underlying factors that are responsible for the variability and individual differences observed in speech and language processing in normal-hearing typical-developing listeners. The results from this project will also have important direct clinical implications for understanding individual differences in speech and language outcomes in hearing-impaired children and adults who use CIs. The objective of this research project is to understand how spoken words are recognized and how acoustic- phonetic and indexical information encoded in the speech signal interact with other knowledge sources to support robust spoken language processing. The proposed research will involve behavioral studies of speech perception and spoken word recognition as well as computational analyses of the sound patterns of word- forms in the mental lexicon. The results will have direct clinical implications for understanding and explaining the enormous individual differences in speech and language outcomes in hearing-impaired children and adults who use CIs, especially deaf children who may be at high risk for poor outcomes following implantation
Keywords: Acoustics; Adult; Attention; Auditory; base; Basic Science; Behavioral; Child; Clinical; Clinical Research; clinically relevant; Cochlear Implants; Code; Complex; computerized data processing; Computing Methodologies; design; Disease; Environment; executive function; Graph; Hearing; Hearing Impaired Persons; high risk; Human; implantation; Individual Differences; Knowledge; Language; Language Development; language processing; lexical; Linguistics; Link; Measures; Memory; Methods; Nature; Nervous system structure; Neurocognitive; Outcome; Pattern; Perception; Perceptual learning; Phonetics; phonology; Process; processing speed; Production; programs; Property; Protocols documentation; Psyche structure; Request for Applications; Request for Proposals; Research; Research Project Grants; Role; Sensory; Short-Term Memory; Signal Transduction; Simulate; sound; Source; Specificity; Speech; Speech Development; Speech Perception; speech processing; Speed (motion); Staging; Stimulus; Stream; Testing; theories; Time; Training; Voice; Work
Relevance: The objective of this research project is to understand how spoken words are recognized and how acoustic- phonetic and indexical information encoded in the speech signal interact with other knowledge sources to support robust spoken language processing. The proposed research will involve behavioral studies of speech perception and spoken word recognition as well as computational analyses of the sound patterns of word- forms in the mental lexicon. The results will have direct clinical implications for understanding and explaining the enormous individual differences in speech and language outcomes in hearing-impaired children and adults who use CIs, especially deaf children who may be at high risk for poor outcomes following implantation
Project start date: 1975-06-01
Project end date: 2016-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-10-067
2R01DC000111-34 (2011): $646189
DEVELOPMENT OF A UNIVERSAL INFLUENZA SEASONAL VACCINE
B David, Professor A
University Of Pennsylvaniacity: Philadelphia country: United States (us)
Grant 5R01AI092843-02 from Office Of The Director, National Institutes Of Health
Abstract: There is a great need to develop new vaccination approaches for influenza. The current strategy based on waiting to identify each seasons new strains and then building a matching vaccine based mostly on egg production is not ideal. Because of this requirement to match strains and the limits on egg based production, the US is forced to under vaccinate our population due to limitations in supply and the impossible task of vaccinating the entire US population each year. This application proposes a new vaccine approach that if successful can result in a transformative shift in the development of seasonal influenza vaccines. We propose to develop a synthetic collection of HAs encoding a focused set of consensus H1, H3 & HB immunogens as a cocktail that together produce broad HI and uNeutralization against seasonal and pandemic H1, H3 and HB viruses. We use an improved DNA technology which eliminates virus culture entirely. We have assembled an outstanding team of investigators who together have helped to produce the technology and the advances that underpin this important application. There are four specific aims that make up this application. Aim 1 To test the hypothesis that we can create a synthetic H1HA immunogen which generates broad HI antibody responses against all four H1 pandemic strains as well against the last 20 years seasonal H1 viruses in mice and ferret models. Aim 2 To test the hypothesis that we can create a synthetic H3HA as well as HBHA which will each generate broad HI responses against seasonal variants of H3 and HB viruses in mice and ferret models. Aim 3 To test the hypothesis that we can develop a combination immunization strategy for H1, H3 and HB immunogens resulting in broad HI activity at protective levels (greater than 1/40 HI titers in an indicator animal species - Ferrets). Studies in ferrets will include challenge with pandemic as well as seasonal strains. We will confirm the immune potency of this combination vaccine in the Rhesus Macaque model which will provide further evidence of the immune potency of the optimized enhanced delivery DNA platform. Aim 4 To test the hypothesis that we can safely induce, using a well tolerated platform, protective HI levels in humans in a pilot safety and immunogenicity study using the combination H1, H3, HB universal DNA vaccine when delivered to healthy volunteers. Together these aims represent transformational shifts for the development of vaccines to influenza as well as for the DNA vaccine field as a whole. A novel, synthetic, DNA-based vaccine against seasonal influenza comprising immunologically relevant, highly conserved viral components would be more cost-effective than purifying vaccine from viral culture in chicken eggs and potentially more broadly effective than the traditional methodology
Keywords: Animals; Antibody Formation; Antigens; base; Chickens; Collection; Combined Vaccines; Consensus; cost effective; Development; DNA; DNA delivery; DNA Vaccines; egg; Ferrets; healthy volunteer; Human; Immune; Immunization; immunogenicity; improved; Influenza; Influenza virus vaccine; Macaca mulatta; Methodology; Modeling; Mus; novel; novel vaccines; pandemic disease; Population; Production; public health relevance; Research Personnel; response; Safety; seasonal influenza; Seasons; synthetic construct; Technology; Testing; Vaccinated; Vaccination; vaccine development; Vaccines; Variant; Viral; Viral Vaccines; Virus; virus culture
Relevance: A novel, synthetic, DNA-based vaccine against seasonal influenza comprising immunologically relevant, highly conserved viral components would be more cost-effective than purifying vaccine from viral culture in chicken eggs and potentially more broadly effective than the traditional methodology
Project start date: 2010-09-15
Project end date: 2015-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-RM-09-022
5R01AI092843-02 (2011): $428533
UCLA OLDER AMERICANS INDEPENDENCE CENTER
B David
University Of California Los Angelescity: Los Angeles country: United States (us)
Grant 2P30AG028748-06 from National Institute On Aging
Abstract: The UCLA Claude Pepper Older Americans Independence Center (OAIC) is designed to promote research aimed at maintaining and restoring the independence of older persons. Through its theme of Translational Research to Maintain Independence, the UCLA OAlC´s research extends across the full spectrum from T1 to T2 translational research. Within this theme, an important focus of the UCLA OAIC is on developing and understanding interventions that reduce inflammation. To accomplish its goals, the UCLA OAIC has established 4 Research Cores (Recruitment and Retention, Research Operations, Analysis and Cost Effectiveness, and Inflammatory Biology) and a new Information Dissemination Core that will facilitate OAlC-related research at every step (recruitment, measurement, data management, analysis, interpretation, and adoption of findings). Research cores provide support at 4 levels Consultation (e.g., providing up to several hours of advice, reading a paper or a proposal) Short-term (e.g., up to a couple days of consultation, performing assays) Ongoing or long-term support (e.g., ongoing, part of the project team) Partnership on new proposals In addition, the UCLA OAIC Pilot and Exploratory Studies Core and Research Career Development Core stimulate new research via a pipeline of junior investigators and pilot awards and recruit successful investigators into OAlC-related research. A specific goal of the Center is to create teams of translational researchers and to train junior faculty in the principles of conducting research that bridges basic, clinical, and health services/dissemination research. The Leadership/Administrative Core ensures that these specific activities are accomplished and the goals of the UCLA OAIC are optimally achieved. By focusing efforts and resources through the OAIC, the timeline for research to develop, test, and disseminate promising innovations to maintain independence can be accelerated. At the end ofthe 5-year cycle, the UCLA OAIC will be a model program for translational research extending from basic science to clinical practice and policy and will have created a generation of new researchers who can begin to assume leadership in this theme
Relevance: Preventing chronic diseases or reducing their effects requires research on the aging process, on diseases and disorders affecting older persons, on lifestyle modifications, on what treatments work best for whom, and on how best to deliver health care. By focusing efforts and resources through the UCLA OAIC, the timeline for research to develop, test, and disseminate promising innovations to maintain independence can be accelerated
Project start date: 2006-07-01
Project end date: 2013-06-30
Budget start date: 1-SEP-2011
Budget end date: 30-JUN-2012
PFA/PA: RFA-AG-11-002
2P30AG028748-06 (2011): $544865
Sponsored Links Excellgen http://Excellgen.com
IMPACT OF ADOLESCENT SUICIDE ATTEMPTS ON PARENTS
B David, Associate Professor
Duke Universitycity: Durham country: United States (us)
Grant 5R01MH081947-03 from National Institute Of Mental Health
Abstract: The suicidal behavior of teenagers can be associated with considerable distress for parents, raising issues about the possibility of their unaddressed mental health needs. Parents´ level of distress and their potentially higher risk for anxiety and depressive disorders may effect interactions with adolescents, parenting practices, and follow-through with treatment recommendations for youths or involvement with treatment. theless, little is known about which parents have the most difficulties following their teenager´s suicidal behaviors, the nature of these difficulties, or how quickly these reactions resolve. This application is a proposal to address these issues, in response to the NIH Program Announcement 07-079, Research on the Reduction and Prevention of Suicidality. This program announcement invites applications that address the burden, and specifically, "the immediate and long-term mental health needs of family survivors who have experiences suicide attempts and/or deaths in the family." In this study, parents of 180 hospitalized teenagers who have made suicide attempts and 180 hospitalized teenagers who have not made attempts will be examined at 1,3, 6, and 12 months following a suicide attempt. The first specific aim of this project is to examine the distress and risk for anxiety and depressive disorders among mothers of suicidal teens relative to the mothers of other hospitalized youths, the diversity of these reactions, and the amount of time for resolution of these reactions. Using latent class trajectory methods, we will identify groups of parents with different patterns of symptoms over time following adolescents´ hospitalization. The second Specific Aim of this proposal is examine child and maternal factors that are predictive of maternal emotional symptoms following adolescent suicidal behavior including high medical lethality of the attempt, number of prior attempts, family history of suicidal behavior, and past psychiatric treatment history. The third Specific Aim is to examine the association between material symptoms and anxiety/depressive disorders following adolescent suicidal behavior on parenting practices, mental health specialty service use, length of treatment and follow-through with the treatment recommendations. This project will help us to understand the mental health and treatment needs of mothers of adolescents who have attempted suicide. The results of this study will help shed light on the best strategies for meeting parental needs following adolescent suicide attempts, and involving parents in their son´s and daughter´s treatment
Keywords: 0-11 years old; 21+ years old; Active Follow-up; acute stress; Address; Adolescent; adolescent mother; Adolescent Youth; Adult; adult human (21+); Affect; Anxiety; Anxiety Disorders; Area; base; Behavior; Behavioral; Cessation of life; Child; Child Youth; children; Children (0-21); clinical significance; clinically significant; Communities; Data; Daughter; Death; depressed mother; Depression; Depressive disorder; design; designing; Diagnosis; Discipline; Distress; Drops; Drug Therapy; Emotional; emotional distress; Epidemiology, Family Medical History; Ethnic Origin; Ethnicity; Ethnicity aspects; experience; Family; Family history of; Family Medical History; Family psychotherapy; Family Therapy; feeling distress; Feeling suicidal; feeling upset; follow-up; help seeking; help-seeking behavior; high risk; History; HOSP; Hospitalization; Hospitalized Adolescent; Hostility; Human, Adult; Human, Child; Individual; Insurance Coverage; Insurance Status; Interview; juvenile; juvenile human; Length; Light; maternal depression; Medical; Medical Specialities; medical specialties; meetings; Mental Depression; Mental disorders; Mental Health; Mental health disorders; Mental Health Services; Mental Hygiene; Mental Hygiene Services; mental illness; Methods; Methods and Techniques; Methods, Other; Modeling; Monitor; Morbidity; Morbidity - disease rate; Mothers; Nature; Neuroses, Post-Traumatic; Neuroses, Posttraumatic; Neurosis, Depressive; NIH Program Announcements; non fatal attempt; Parenting; Parenting behavior; Parents; pathway; Pathway interactions; Pattern; Pharmacotherapy; Photoradiation; Positive Reinforcements; Post-Traumatic Stress Disorders; Predictive Factor; premature; prevent; preventing; Prevention of suicide; Program Announcement; psychiatric care; Psychiatric Disease; Psychiatric Disorder; Psychiatric therapeutic procedure; psychiatric therapy; psychiatric treatment; psychological disorder; Psychological Health; PTSD; Reaction; Recommendation; Recording of previous events; Recurrence; Recurrent; Relative; Relative (related person); Research; Resolution; response; Risk; Role; Services; Severities; social role; Social support; social support network; Son; Specialties, Medical; Specialty; Stress Disorders, Post-Traumatic; Stress Disorders, Posttraumatic; suicidal; suicidal adolescent; suicidal attempt; suicidal behavior; suicidal ideation; suicidal morbidity; suicidal thinking; Suicidal thoughts; suicidal youth; Suicide attempt; suicide attempter; suicide behavior; suicide death; suicide ideation; suicide intervention; suicide morbidity; Suicide precaution; Suicide prevention; Supervision; Survivors; Symptoms; Techniques; Teen; teen mom; teen mother; teen years; teenage mom; teenage mother; Teenagers; Teens; thoughts about suicide; Time; traumatic neurosis; Unspecified Mental Disorder; youngster; Youth; Youth 10-21
Relevance: This project will help us to understand the mental health and treatment needs of mothers of adolescents who have attempted suicide. The results of this study will help shed light on the best strategies for meeting parental needs following adolescent suicide attempts, and involving parents in their son´s and daughter´s treatment
Project start date: 2009-02-01
Project end date: 2013-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-079
5R01MH081947-03 (2011): $645363
X-RAY SOURCE UPGRADE FOR MACROMOLECULAR CRYSTALLOGRAPHY
B David, Research Professor
University Of Colorado At Bouldercity: Boulder country: United States (us)
Grant 1S10RR031592-01 from National Center For Research Resources
Abstract: The macromolecular x-ray diffraction facility of the University of Colorado, Boulder proposes to upgrade an X-ray source specifically, a Rigaku RUH2R rotating anode X-ray generator with Osmic "blue" confocal multilayer mirrors will be upgraded to a Rigaku MM007 generator with Varimax HR (="high resolution") confocal mirrors. We are receiving a used MM007 as a gift, and request funds only for the confocal mirrors. The x-ray facility is currently used by three major and seven minor NIH-supported users. Crystallographic projects currently underway include large catalytic RNAs (Cech and Pace) and riboswitches (Batey), RNA- protein and DNA-protein complexes such as those found in the telomerase system (Cech and Wuttke) and specific recognition complexes (McKay), molecular chaperone and integral membrane proteins (Sousa), and several RNAs and proteins involved in specific biological processes (Ahn, Copley, Pardi, Falke). Many of these projects pose significant challenges in their early stages; typically, small preliminary crystals from a large number of constructs and/or crystallization conditions must be screened for diffraction to determine whether they are worth pursuing. Additional challenges often present themselves during screens for cryoprotectants or suitable phasing derivatives. Finally, in many cases, complete datasets are collected in- house, either prior to or as an alternative to synchrotron data collection. The requested upgrade will enhance the brightness of our X-ray source severalfold (approximately sixfold according to Rigaku´s data), thereby enhancing the crystal screening and data collection capability of our in-house facilities. The three-dimensional structures of biologically significant macromolecules provide the foundation for modern molecular medicine and rational drug design. Structural studies at the University of Colorado, Boulder encompass ribozymes (catalytic RNAs), telomerase, membrane protein structure and folding, and bacterial drug resistance, to name a few areas. The shared X-ray crystallography facility, for which instrumentation is requested, provides resources (both instrumental and intellectual) to a broad spectrum of users who pursue structural studies on the campus
Keywords: Anodes; Biological Process; Catalytic RNA; Colorado; Complex; Crystallization; Crystallography; Data; Data Collection; Data Set; DNA; Funding; Gifts; Housing; Humpback Dolphins; Integral Membrane Protein; Minor; Molecular Chaperones; Phase; protein complex; Proteins; Resolution; RNA; Roentgen Rays; Screening procedure; Source; Staging; Synchrotrons; System; Telomerase; United States National Institutes of Health; Universities
Project start date: 2011-09-30
Project end date: 2012-09-29
Budget start date: 30-SEP-2011
Budget end date: 29-SEP-2012
PFA/PA: PAR-10-082
1S10RR031592-01 (2011): $112203
PROTEOMIC PREDICTORS OF CLINICAL OUTCOME OF TARGETED THERAPIES IN PROSTATE CANCER
B David, Dir, Ctr For Applied Mol Med
Stanford Universitycity: Stanford country: United States (us)
Abstract: The lack of biomarkers for assessment of which patients may respond to pathway-targeted therapy creates a profound need for the application of integrated technologies for the discovery and translational validation of such biomarkers. Recent advances in proteomic methods and computational bioinformatics processing have enabled application of integrated proteomic technologies to the discovery of biomarkers. If used by ex vivo nano-sensor devices and in vivo nanoparticle imaging methods such biomarkers may provide effective new tools to cancer therapy development and use. We propose to discover candidate markers by integrating two directed and two comprehensive proteomic technologies a) intracellular-signaling protein chips consisting of a directed analysis method which quantitates known, intracellular signaling proteins; b) living-cell capture sensor arrays which represent a nanosensor approach for directed analysis of the cell-surface and secretory proteomes; c) biotin-capture-based cell-surface profiling methods consisting of a comprehensive analysis method that identifies and quantitates the abundance of cell-surface proteins; d) solid-phase extraction of glycoprotein (SPEG) profiling, which is a comprehensive analysis method for the study of secreted proteins and blood. Biomarker discovery will initially be disease- (prostate cancer) and pathway- (human epidermal growth factor receptor (Her)-kinase axis) focused and will provide a foundation our CCNE-TR Center will use to produce, evaluate and validate nanosensors and nanoparticle-based imaging. We will first define the cell-surface and secretory proteomes of androgen-independent prostate cancer and identify proteins within these and the intracellular proteome that are indicative of the perturbations to the Her-kinase axis. We will analyze these sub-proteomes in primary culture models of androgen-independent prostate cancer by treatment with the Her-kinase targeted therapeutics, 2C4 (a humanized monoclonal antibody that binds epitopes on Her-2 that prevent ligand-mediated Her-2 heterodimerization) and geftinib (a small molecule inhibitor that competes for the ATP binding site on epidermal growth factor receptor). We will additionally stimulate with ligands targeting each of the receptor-dimer partners of this axis. Axis-response-informative proteins will be evaluated for their Her-kinase and prostate cancer specificity, by comparison with a database of gene and protein expression in other cell lines of different tissue origin available to the investigator group. Next we will integrate our in vitro results with information of the protein expression patterns of human xenograft models to identify a panel of markers with utility for predicting and/or for monitoring response. The bank of blood and viable tissue samples developed by the UCLA Prostate SPORE for use in this project represent different pre and post-treatment time points and a diverse collection of androgen-independent xenograft models characterized for sensitivity to the Her-kinase-targeted therapeutics. Lastly we will validate the utility of the biomarkers discovered in Specific Aims 1 and 2 for use with ex vivo nanosensor devices and in vivo nanoparticle imaging by generating affinity reagents for protein candidates; We will also validate the panel´s ability to guiding human therapeutic intervention by using SPORE tissue and serum samples of prostate cancer patients treated with Her-kinase-directed therapies
Keywords: 1H-Thieno(3, 4-d)imidazole-4-pentanoic acid, hexahydro-2-oxo-, (3aS-(3aalpha, 4beta, 6aalpha))-; 2C4; 2C4 Antibody; Affinity; After Care; After-Treatment; Aftercare; androgen independent prostate cancer; Androgenic Agents; Androgenic Compounds; Androgens; Antibodies; anticancer therapy; Antigenic Determinants; aptamer; base; Binding; Binding (Molecular Function); Binding Determinants; Binding Sites; Bio-Informatics; Bioinformatics; biological signal transduction; biomarker; Biotin; Blood Banks; Blood Plasma; Blood Proteins; Blood Serum; Body Tissues; c-erbB-1; c-erbB-1 Protein; Cancer Biology; Cancer of Prostate; Cancer Patient; cancer therapy; Cancer Treatment; Cancer, Oncology; Cancers; candidate marker; Cell Communication and Signaling; Cell Line; Cell Lines, Strains; Cell Signaling; Cell surface; Cell Surface Proteins; CellLine; Cells; Clinical; clinical data repository; clinical data warehouse; Clinical Oncology; coenzyme R; Collection; Combining Site; computational methodology; computational methods; computer methods; Computing Methodologies; cultured cell line; Data Banks; Data Bases; data repository; Databank, Electronic; Databanks; Database, Electronic; Databases; Devices; dimer; Disease; disease/disorder; Disorder; EC 2.7; EGFR; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Epitopes; ERBB Protein; erbB Receptor Family; ErbB Receptor Family Protein; erbB-1; erbB-1 Proto-Oncogene Protein; ERBB1; erbBl; Foundations; gene product; Gene Products, RNA; Gene Proteins; Genital System, Male, Prostate; Germinoblastoma; Glycoproteins; Goals; HER1; Heterodimerization; Human; Human Prostate; Human Prostate Gland; Human, General; humanized monoclonal antibodies; Image; imaging; imaging modality; In Vitro; in vitro Model; in vivo; inhibitor; inhibitor/antagonist; intervention development; intervention therapy; Intracellular Communication and Signaling; Intracellular Signaling Proteins; Investigators; Kinases; Life; Ligands; Lymphoma; Lymphoma (Hodgkin`s and Non-Hodgkin`s); Lymphoma, Malignant; malignancy; Malignant neoplasm of prostate; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant prostatic tumor; Malignant Tumor; Malignant Tumor of the Prostate; Man (Taxonomy); Man, Modern; Mediating; member; Methods; MoAb 2C4; Modeling; Molecular; Molecular Interaction; Monitor; Monoclonal Antibody 2C4; nano imaging; nano particle; nano sensing; nano sensors; nanoimaging; nanoparticle; nanosensing; nanosensors; neoplasm/cancer; oncology; Outcome; pathway; Pathway interactions; Patients; Pattern; PC3 cell line; Phase; Phosphotransferases; Plasma; prevent; preventing; Process; Prostate; Prostate CA; Prostate Cancer; prostate cancer cell line; Prostate Gland; Prostatic Cancer; Prostatic Gland; Protein Biochips; Protein Chips; protein expression; Protein Gene Products; Protein Microarray; Protein Microchips; protein profiling; Proteins; Proteome; Proteomics; proto-oncogene protein c-erbB-1; PTK Receptors; Reactive Site; Reagent; receptor; Receptor Protein; Receptor Protein-Tyrosine Kinases; Receptor, EGF; Receptor, TGF-alpha; Receptor, Urogastrone; Receptors, Epidermal Growth Factor-Urogastrone; relational database; Reproduction spores; Research Personnel; Researchers; response; Reticuloendothelial System, Serum, Plasma; Reticulolymphosarcoma; Ribonucleic Acid; RNA; RNA, Non-Polyadenylated; RTK; Sampling; Sarcoma, Germinoblastic; sensor; Serum; Serum, Plasma; Signal Transduction; Signal Transduction Systems; Signaling; small molecule; Solid; Specificity; Spores; System; System, LOINC Axis 4; Technology; Testing; Therapeutic; Therapeutic Androgen; Therapeutic Intervention; therapeutic target; therapy development; Time; Tissue Sample; Tissues; tool; Transforming Growth Factor alpha Receptor; Transmembrane Receptor Protein Tyrosine Kinase; Transphosphorylases; treatment development; Tyrosine Kinase Growth Factor Receptor; Tyrosine Kinase Linked Receptors; Tyrosine Kinase Receptors; Validation; Vitamin H; Xenograft Model
Budget start date: 1-MAY-2010
Budget end date: 30-APR-2011
PFA/PA: RFA-CA-05-024
5U54CA119367-05_0004 (2010): $1088432
IMMUNOBIOLOGY OF ACUTE ENVIRONMENTAL ASTHMA
B David, Prof Peds Med & Toxicology
University Of North Carolina Chapel Hillcity: Chapel Hill country: United States (us)
Grant 5U19AI077437-04 from National Institute Of Allergy And Infectious Diseases
Abstract: The focus of this U19 project, "Immunobiology of Acute Environmental Asthma", is to conduct mechanistic studies of the role of innate immune processes in mediation of acute environmental asthma. Epidemiological studies have clearly shown that asthma exacerbation linked to air pollutants is a major cause of asthma exacerbation. Endotoxin is a commonly encountered environmental pollutant found in ambient particulate matter and in occupational and domestic settings as well. Endotoxin can induce neutrophilic inflammation at high levels, and at low levels enhance response of asthmatics to airway allergen challenge. We have shown that endotoxin causes changes in airway monocytes and macrophages (increased CD14, CD80, Fc?RI and HLA-DR) which are associated with enhanced response to either innate or acquired immune stimuli. Our team has recently identified novel regulatory molecules of inflammation in the CATERPILLER family, specifically cryopyrin (which upregulates neutrophilic inflammation and monocytic function) and monarch-1, (which downregulates response to innate activation). Cryopyrin is of particular interest as it acts through formation of a Caspase-1 based inflammasome to cleave pro-IL-l? to active IL-1? (with downstream production of IL-6 and other mediators) and IL-18. Furthermore, cryopyrin is activated after ligation of either pathogen associated molecular pattern receptors (including CD14 facilitated binding of endotoxin by TLR4) or the P2X7 receptor by ATP (which is increasingly recognized as an endogenous danger signal released by host cells following non-specific cell injury). These dual activation pathways likely account for the similar actions of a wide variety of inhaled environmental contaminants, and represent novel targets for treatment of acute asthma. We will conduct mechanistic studies of the role of the CATERPILLER family members cryopyrin and monarch-1 (Project 1-J. Ting PI), and the role of NALP-1 and the purinergic receptor P2X7 (Project 2-B. Koller, PI) in rodent models of environmental asthma, in conjunction with a translational project (Project 3-D. Peden, PI) designed to determine the effect of interaction of endotoxin- and allergen-induced inflammation on the airway biology of allergic asthmatics. Human studies will be focused on the biology of airway monocytic cells and the expression of innate immune and the CATERPILLAR family of immune regulators and P2X7 receptors in the airway. In addition to assessment of the role of innate immune processes in regulating airway inflammation, we will examine the relationship of this inflammation on airway physiology, specifically mucociliary clearance. Decreased mucociliary clearance is an understudied process which mediates asthma exacerbation and is a feature of increased asthma severity. PROJECT 1 Novel and innate immune genes in asthma (TING, J) PROJECT 1 We recently discovered the CATERPILLER family which share structural similarities with the NB-LRR (nucleotide-binding, leucine-rich repeat) super-family of disease resistance (R) proteins that constitutes the plant immune system. In the animal kingdom, this family is also known as NOD or NLR. The clinical importance of this family is underscored by the genetic linkage of family members to a number of immunologic disorders. Among the human gene family members, several of these appear to mediate negative regulatory function in controlling an overzealous inflammatory response. Most notable is the Monarch-1 protein which blocks the function of NF-?B inducing kinase (NIK). Inhibition of NIK reduces the expression of an array of chemokines with relevance in asthma. Gene profiling of induced sputum from mildly asthmatic individuals suggests that the Monarch-1 gene is reduced in these individuals relative to controls, supporting the inhibitory role of this gene during inflammation. Another group of family members regulates IL-1 production. Most notable among these is cryopyrin which mediates formation of the inflammasome complex upon stimulation with a number of inducers. The inflammasome complex is required for procaspase 1 processing to mature caspase 1. In turn, caspase-1 is required for the processing of pro-IL-1 and pro-IL-18 to their mature forms. IL-1 and IL-18 are respectively important in inflammation and TH2 skewing. Cryopyrin is also important in mediating macrophage necrosis which exacerbates inflammation. Thus there are compelling reasons to believe that Monarch-1 and cryopyrin have crucial roles in asthma, however there is no in vivo data to indicate that this is the case. Furthermore we have shown that both of these proteins are ATP-binding proteins, and they exhibit ATPase activity, thus providing ways to modulate their function, which might be important leads to drug discovery. The goals of this proposal are (1) To study the relevance of Monarch-1 in three animal models of asthma (OVA-induced, endotoxin, and house dust mite and delineate the biochemical effects of Monarch-1 in vivo and ex vivo. (2) To study the relevance of cryopyrin and a cryopyrin-adaptor (ASC) in asthma. (3) To study and identify factors which modulate the nucleotide-binding properties and ATPase function of Monarch-1 and cryopyrin
Project start date: 2008-03-01
Project end date: 2013-02-28
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: RFA-AI-07-002
5U19AI077437-04 (2011): $1429329
B David, Professor
University Of Alabama At Birminghamcity: Birmingham country: United States (us)
Abstract: The Biostatistics Core is designed to (i) provide a wide array of diverse biostatistical methods and approaches to CFAR investigators, (ii) educate CFAR investigators in the proper use of these technologies, and (iii) conduct cutting edge methodological research germane to the field. In the budget period, the Biostatistics Core has supported 45 independently funded HIV research projects, contributed to over 100 manuscripts, s and presentations, generating over $250,000 of user chargebacks. The Specific Aims of the Biostatistics Core are 1. To provide general statistical services including those involving study design, power analysis, data analysis, consultation on interpretation of results and aid investigators in writing up their results. 2. To develop and manage AIDS-related research databases for CFAR investigators and assist in utilizing these databases to address research questions. 3. To provide training to CFAR investigators in the areas of research design and analysis, epidemiologic methods and bioinformatics. 4. To synergize with CFAR programmatic areas and other Cores to interweave the Biostatistics Core services into those areas, and to utilize the scientific expertise of the Core to meet programmatic aims. 5. To interact across CFARs nationwide to facilitate interchange of research ideas to foster new directions The ´Value added" contributions of the Biostatistics Core to the CFAR Mission are the availability of resources and expertise in the design and analysis of studies ranging from basic science to comparative clinical trials. The CFAR Biostatistics Core is essential to provide access to expertise necessary for the special challenges to research in the prevention, treatment and evaluation of risk factors for HIV/AIDS
Keywords: ing; Acquired Immunodeficiency Syndrome; Address; AIDS/HIV problem; Alabama; Area; Basic Science; Bioinformatics; Biometry; Biostatistical Methods; Biostatistics Core; Budgets; Clinic; Clinical; Clinical Trials; Communities; comparative; Computer software; Consultations; Data; Data Analyses; Data Element; data management; data mining; Databases; design; Development; epidemiologic data; Epidemiologic Methods; Epidemiology; Evaluation of Risk Factors; Faculty; Fostering; Funding; HIV; Housing; Institution; International; Malignant Neoplasms; Manuscripts; meetings; Mission; Outpatients; Patients; Preparation; Prevention and Treatment Evaluation; Quality Control; Research; research and development; Research Design; Research Personnel; Research Project Grants; Research Proposals; Resources; Services; Site; statistical service; Technology; tool; Training; Training and Education; Universities; Update; working group; Writing
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
5P30AI027767-23_7133 (2011): $166573
5P30AI027767-22_7133 (2010): $310956
B David, Prof Peds Med & Toxicology
University Of North Carolina Chapel Hillcity: Chapel Hill country: United States (us)
Abstract: The Administrative Core will serve all Projects and Cores of AADCRC U19 Center Program and will be directed by Dr. David Peden, P.I. for this U19 program. Biostatistical support and advice on data management will be provided through this core by Dr. Haibo Zhou, Director of the Biostatistics Core for the UNC Center for Environmental Medicine, Asthma & Lung Biology (of which Dr. Peden is the Director). Data management support will be provided by this core which is funded by NIH and EPA funds. The Administrative Core will be responsible for the day-to-day administration and program coordination and ongoing evaluation of the U19. The functions of the Administrative Core will include all administrative and financial aspects which will include the timely disbursal of funds, submission of reports, assembling and keeping track of program materials and reports, and scheduling meetings of all leaders of Cores and Projects of the U19. Dr. Peden, as Principal Investigator will participate in Steering Committee meetings and other AADCRC activities. The Administrative Core budget includes travel funds for the Principal Investigator to participate in annual Steering Committee meetings, and for the PI and Core and Project leaders to attend an annual two-day AADCRC scientific meeting to be held in conjunction with the Steering Committee meeting in Bethesda, Maryland. Coordination of clinical relevance of the projects will be overseen by Dr. Peden who will review and assist in development of all clinical research protocols with the IRB, GCRC and EPA. Data from animal studies will inform development of these protocols. Weekly protocol review meetings and lab meetings will be conducted by Dr. Peden and Dr. Ting, who will serve as the Co-Pi of the U19. Dr. Peden will also coordinate access to existing NIH funded Sample Acquisition, Analysis, and Repository Core Facility of the Center for Environmental Medicine, Asthma & Lung Biology (headed by Dr. Alexis). These existing cores will provide support for sample analysis of nucleotides in airway fluids and for soluble protein profiling by flow cytometry of airway and blood cells
Keywords: Acute; animal data; Asthma; Biology; Biostatistics Core; Blood Cells; Bronchial Asthma; Budgets; clinical relevance; Clinical Research Protocols; clinically relevant; Core Facility; Cytofluorometry, Flow; data management; Development; Environmental Medicine; Ethics Committees, Research; Evaluation; Flow Cytofluorometries; Flow Cytometry; flow cytophotometry; Flow Microfluorimetry; fluid; Funding; Head; Immunobiology; Immunophysiology; Institutional Review Boards; IRBs; liquid; Liquid substance; Lung; Maryland; meetings; Microfluorometry, Flow; National Institutes of Health; National Institutes of Health (U.S.); NIH; Nucleotides; Peripheral Blood Cell; Principal Investigator; programs; Programs (PT); Programs [Publication Type]; protein profiling; Protocol; protocol development; Protocols documentation; pulmonary; Reporting; repository; Research Ethics Committees; Respiratory System, Lung; Sampling; SCHED; Schedule; Travel; United States National Institutes of Health
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
5U19AI077437-04_8461 (2011): $147000
B David, Dir, Ctr For Applied Mol Med
University Of Southern Californiacity: Los Angeles country: United States (us)
Abstract: The Administrative Core (AC) will function to manage the CAC and help adminster and support the PSOCMC-SMART. The will help coordinate the CAC twice monthly meetings. The CAC, together with the program manager, will assure that project and core plans progress, postdoctoral fellows are shared, training and outreach efforts are implemented, pilot projects are encouraged and funded, and the ´business´ of the program is accomplished. A key element of the AC will be a full time program manager who will work closely with Drs. Hillis as well the other members of the Center Advisory Committee to help execute all recommendations of the CAC, NCI Project Scientist and the PSC. The AC will assure that all meetinggenerated notes/reports to the CAC and PSC are prepared and disseminated. Additionally, as both integrative education and community outreach are such significant portions of the PSOC-MC-START program, the AC will be managing the PSOC-MC-SMART website and the implementation of the PSOC-MCSTART member lectures/seminars in both the i) newly planned series, and the ii) leveraged series at our collaborating institutions, and professional association meetings, to educate about physical sciences and oncology
Keywords: Advisory Committees; Award; Biological Assay; Biomedical Informatics Research Network; Businesses; cancer Biomedical Informatics Grid; Collaborations; Community Outreach; Complex; Comprehensive Cancer Center; Data; Data Analyses; Data Collection; Databases; Deposition; design; Education and Outreach; Elements; Ensure; Funding; Goals; Guidelines; Human Resources; Institution; interest; lectures; meetings; member; Modeling; Modification; Monitor; oncology; operation; physical science; Pilot Projects; Policies; Postdoctoral Fellow; Preparation; Principal Investigator; programs; Progress Reports; protocol development; Protocols documentation; Publications; Publishing; Quality Control; Recommendation; Reporting; Research; Research Design; Research Personnel; research study; Resources; response; Scientist; Screening procedure; Series; Site Visit; System; Time; TimeLine; tool; web site; Work
Relevance: The administrative core will handle administrative functions to facilitate the execution of the physical science/oncology research proposed in the application
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5U54CA143907-03_8460 (2011): $4802
5U54CA143907-02_8460 (2010): $4967
WHOLE-GENOME SHOTGUN SEQUENCING STRATEGY AND ASSEMBLY
B David, Director Of Computational R&d
Broad Institute, Inc.city: Cambridge country: United States (us)
Grant 2R01HG003474-06A1 from National Human Genome Research Institute
Abstract: The ability to read the DNA sequence of an organism´s genome has revolutionized biology and biomedical research. Accurate assemblies of sequence data are critical because they provide the foundation for all subsequent work. Using capillary-based sequencing technology, high quality drafts were generated for many genomes. Over the past several years, massively parallel sequencing technologies have lowered sequencing cost by 1000-fold, but the reads from these technologies are shorter and less accurate than the capillary reads, hence harder to assemble, particularly for large genomes. We have recently demonstrated assemblies of massively parallel data that begin to approach the quality of those from capillary data. These assemblies were of genomes for which exceptionally high-quality (´finished´) assemblies were already available, and we were thus able not only to rigorously assess the quality of our assemblies, but also to systematically diagnose their defects. Moreover we observe that in almost all cases, defective loci have enough coverage that they could in principle be assembled correctly, provided that the right algorithms were available. On this basis we have proposed a research program to develop computational methods for the creation of assemblies of unprecedented quality In our first aim we propose to develop methods to achieve high quality draft assemblies of new genomes. Here our objective is to reach and exceed the level of quality that had been achieved using capillary sequencing. In our second aim we will develop methods to achieve ultra high quality assemblies of human genomes. To do this we will leverage the existing human reference sequence and reference sequences of other individuals, including those that we would create. In this way we aim to achieve near-finished quality for regions represented in the reference sequences (essentially via ´resequencing´ methods), and at the same time (by de novo methods) capture those regions that are not present in the reference sequences. Our aim is thus to produce the best possible representation of each individual´s genome. We note that as costs drop, this is likely to become ´standard of care´ for patients. In our third aim, we look beyond existing data, to the next generation of sequencing technologies, to assemble very hard regions using very long and ´strobe´ reads. These hard regions include segmental duplications, which are evolutionary hotspots, associated with many diseases, and inaccessible to current methods, except those using very expensive clone-by-clone sequencing. Finally our fourth aim is to make assembly methods accessible to the community. Here our goal is to make it as easy as possible for a range of users (including individual investigators) to match the results achievable by genome assembly experts. In short, through our four aims, we will enable the community to achieve the highest possible assembly quality using the lowest cost data. We thus anticipate that our work will advance a broad range of investigations of importance to biology and human disease. This grant will develop better methods for completely and accurately determining the genome sequence of an organism, in particular producing precise representations of complex and repetitive regions of genomes. This will advance a broad range of investigations in genome evolution, cancer and human genetic disease
Keywords: Achievement; Address; Algorithms; base; Base Sequence; Biology; Biomedical Research; Blood capillaries; cancer genetics; cancer genomics; capillary; Collaborations; Communities; comparative genomics; Complex; Computing Methodologies; cost; Data; Defect; Diagnosis; Disease; DNA Resequencing; DNA Sequence; Drops; Evolution; falls; Foundations; Generations; Genes; Genetic; Genome; genome sequencing; Goals; Grant; Health; Hereditary Disease; Human; human disease; Human Genetics; Human Genome; improved; Individual; Industry; Institutes; Investigation; Island; Knowledge; Laboratories; Letters; mammalian genome; meetings; Methods; Metric; new technology; next generation; Organism; pathogen; Patients; Production; programs; Reading; Repetitive Sequence; Reporting; Research; Research Personnel; Sampling; standard of care; Technology; Time; tool; Uncertainty; Variant; Whole-Genome Shotgun Sequencing; Work
Relevance: This grant will develop better methods for completely and accurately determining the genome sequence of an organism, in particular producing precise representations of complex and repetitive regions of genomes. This will advance a broad range of investigations in genome evolution, cancer and human genetic disease
Project start date: 2004-11-01
Project end date: 2014-06-30
Budget start date: 20-SEP-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-10-067
2R01HG003474-06A1 (2011): $859485
Sponsored Links Excellgen http://Excellgen.com
MODELING OF TRANSIENT OXYGEN DELIVERY IN THE BRAIN
B David, Technical Director
University Of Texas Austincity: Austin country: United States (us)
Grant 1R21HL108143-01 from National Heart, Lung, And Blood Institute
Abstract: Summary Brief periods of neural activity trigger a vascular response with a complex but stable form. This hemodynamic response function (HRF) is extensively exploited in popular imaging methods such as functional magnetic resonance imaging (fMRI) and reflectance based optical imaging. Proper interpretation and utilization of these imaging techniques requires a detailed understanding the HRF. Moreover, because the brain is continually active, transient responses are likely to be important in normal function of the healthy brain. Better understanding of the HRF will enable research efforts that rely on "resting-state" or "default-mode" activity that is clearly evident in the brain. Finally, cerebrovascular pathology is likely to affect such transient responses, so a more complete understanding of their normal character should enable their investigation as diagnostics of incipient or extant pathology. The physiology and physics of the HRF are not well understood. A standard model has been developed that incorporates a non-linear compliant element (balloon) to explain flow and volume changes. However, some specific predictions of the balloon model have not been confirmed experimentally, and there is now great controversy on the subject. We have developed a new model that combines a linear flow with one-dimensional convection-diffusion oxygen transport. The flow model includes the inertial dynamics of moving blood, which should not be neglected in the larger arterioles that mechanically mediate the flow response. Our full model has provided remarkably accurate fits to tissue oxygen measurements performed with polarographic probes consequent to brief (few second) neural stimulation events. This model also provides an explanation for the neurovascular coupling utilized in resting-state fMRI. We propose further development and testing of our model. Specifically, we want to improve the quality of its intravascular oxygen concentration predictions, and to enable examination of oxygen mass-balance issues. Aim 1 is to expand the model in several ways by adding the dynamics of oxygen dissociation from hemoglobin, and by adding terms to deal with alternative oxygen transport mechanisms such as oxygen consumption by endothelial tissue. Aim 2 is to further test our model by fitting additional tissue oxygen measurements obtained using polarographic probes. Aim 3 is to use two-photon optical imaging to measure flow speeds in small arterioles and capillaries, and how they change consequent to brief neural stimulation. We will test how well these measurements are fit by our linear flow model as well as previous non-linear models. The proposed work will further vet our model, bringing it into the mainstream as a simple but powerful analytic for cerebrovascular hemodynamics. We need a better understanding of oxygen transfer from blood to brain tissue, both during steady-state metabolism and as a consequence of brief neural stimulation. Such understanding is critical to the proper use and interpretation of brain imaging techniques that rely on neurovascular coupling, as well as the diagnosis and treatment of cerebrovascular diseases. We propose further development of a novel model for the transient delivery of oxygen to brain tissue, together with efforts that test the model´s predictions against precise local measurements of tissue oxygen and blood flow changes induced by brief neural stimulation
Keywords: Affect; arteriole; base; Behavior; Blood; Blood capillaries; Blood flow; Blood Vessels; Brain; Brain imaging; Brain region; brain tissue; capillary; Cerebral cortex; cerebrovascular; Cerebrovascular Disorders; Cerebrum; Complex; Consumption; Convection; Coupling; Data Set; density; Development; Diagnosis; Diagnostic; Diffusion; Dissociation; Elements; Equilibrium; Erythrocytes; Event; Felis catus; Forelimb; Fractals; Functional Imaging; Functional Magnetic Resonance Imaging; hemodynamics; Hemoglobin; Image; imaging modality; Imaging Techniques; improved; Individual; Investigation; Lateral Geniculate Body; Mainstreaming (Education); Measurement; Measures; Mediating; Metabolism; Modeling; neglect; neural stimulation; Neurons; Non-linear Models; novel; novel strategies; operation; optic imaging; Oxygen; Oxygen Consumption; oxygen transport; Pathology; Photic Stimulation; Physics; Physiology; relating to nervous system; Research; research study; response; Rest; Rodent; Scanning; Somatosensory Cortex; Spatial Distribution; Speed (motion); Testing; Time; Tissues; two-photon; Variant; Visual Cortex; Work
Relevance: We need a better understanding of oxygen transfer from blood to brain tissue, both during steady-state metabolism and as a consequence of brief neural stimulation. Such understanding is critical to the proper use and interpretation of brain imaging techniques that rely on neurovascular coupling, as well as the diagnosis and treatment of cerebrovascular diseases. We propose further development of a novel model for the transient delivery of oxygen to brain tissue, together with efforts that test the model´s predictions against precise local measurements of tissue oxygen and blood flow changes induced by brief neural stimulation
Project start date: 2011-06-15
Project end date: 2013-03-31
Budget start date: 15-JUN-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-10-069
1R21HL108143-01 (2011): $189650
B David
Cornell University Ithacacity: Ithaca country: United States (us)
Grant 5R01GM077167-06 from National Institute Of General Medical Sciences
Abstract: Project Summary/ Lithium enolates constitute one of he most important classes of reactive intermediate in organic synthesis. The pharmaceutical industry uses these reagents frequently and on very large scales. In this proposal we describe efforts to understand the underlying chemistry of the most important reactions of lithium enolates. With methods to establish solution structures that dominated the first funding period largely developed, structural studies will be more targeted in support of mechanistic studies. In the most general sense, we will examine how solvation and aggregation influence reactivity. The mechanistic investigations will focus on specific classes of reaction-case studies-that include (1) aza-aldol condensations; (2) O-silylations; (3) alkylations; (4) acylations; (5) [2,3]- and [3,3]-sigmatropic rearrangements; and (6) nucleophilic aromatic substitutions (SNAr). A uniquely integrated approach based on a combination of NMR spectroscopy, solution kinetics, and computational chemistry will develop an understanding of the mechanistic principles and how to control reactivity and selectivity. By bringing synthetic organic, physical organic, analytical, and computational chemistry together under one roof, we reveal the consequences of solvation and aggregation with an unprecedented clarity. Lithium enolates are reactive intermediates used by other academic and pharmaceutical process chemistry laboratories on a daily basis around the globe. Our mechanistic studies described herein are designed to understand and improve their efficacy. The project originated from collaboration with Sanofi-Aventis to develop anti-asthmatics. The proposed funding period includes a collaboration with Amgen as part of their program to synthesize treatments for colorectal cancer
Keywords: 3-hydroxybutanal; ing; Acylation; Alkylation; Analytical Chemistry; Anti-Asthmatic Agents; base; Case Study; Chemistry; Collaborations; Colorectal Cancer; computational chemistry; design; DNA Sequence Rearrangement; Drug Industry; Fostering; Funding; Group Processes; improved; Investigation; Kinetics; Laboratories; Lithium; Methods; NMR Spectroscopy; Organic Chemistry; Organic Synthesis; Pharmacologic Substance; Physical condensation; Process; programs; Protocols documentation; public health relevance; Reaction; Reagent; Solutions; Staging; Structure
Project start date: 2006-05-01
Project end date: 2014-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01GM077167-06 (2011): $284640
DEFINING RECOVERY FOR ANOREXIA AND BULIMIA NERVOSA: A 25-YEAR OUTCOME STUDY
B David, Psychiatrist
Massachusetts General Hospitalcity: Boston country: United States (us)
Grant 1R03MH094832-01 from National Institute Of Mental Health
Abstract: Project Summary/ Anorexia nervosa (AN) and bulimia nervosa (BN) are chronic and severe psychiatric illnesses associated with complex physical and emotional sequelae. Long-term studies of eating disorders are few in number and comprehensive understanding of the outcome of these illnesses has been challenged by a lack of an empirically-based definition of recovery. The current application proposes a one-time follow-up investigation of the surviving participants of the Massachusetts General Hospital Longitudinal Study of Anorexia and Bulimia Nervosa 25 years after initial funding for the project by NIMH began in 1987. This study of 246 treatment-seeking women, which included 51 women with AN-restricting subtype, 85 with AN-binge/purge subtype, and 110 with BN, is the only long-term, prospective, naturalistic study of its kind, making it an invaluable resource for promoting our understanding of the natural course of eating disorders. The cohort was interviewed at frequent intervals until 2000 for approximately 10 years of follow-up (median = 9 years, maximum = 12 years). The attrition rate at 10 years of follow-up was 7%. Annual contact has been maintained with the cohort. To date, we have confirmed participation in the proposed follow-up with 155 (67%) of our potentially 230 living participants and we continue our efforts to include an additional 44 subjects (only 31 subjects declined participation). This application proposes to establish an empirically-based definition of long-term eating disorder recovery by examining the predictive validity (comparing the first 10 years of follow-up to year 25) of a series of definitions of recovery that differ on thresholds of symptom severity and duration. The Eating Disorder Longitudinal Interval Follow-up Evaluation (the same interview administered in the initial phase of the study) will be used to gather data on eating disorder symptomatology, comorbid psychiatric disorders, and psychosocial functioning. Cross-sectional validity of recovery definitions will be examined using clinically meaningful indices such as quality of life. Finally, this study will document long-term outcome of eating disorders, including mortality rates, as well as the demographic and clinical predictors of 25-year outcome. The proposed study is uniquely positioned to examine these questions due to the availability of both a detailed dataset documenting the course of eating disorders over 10 years of follow-up as well as a high percentage of participants willing to be interviewed at the 25 year follow-up. Findings from this study will create a framework for the evaluation of current treatment efforts, assist in the design of future treatment studies, inform researchers conducting outcome studies, and provide clinicians, researchers, and patients with important clinical information about the outcome of eating disorders. The proposed study is a 25-year one-time follow-up study of the Massachusetts General Hospital Longitudinal Study of Anorexia Nervosa (AN) and Bulimia Nervosa (BN). This study aims to establish an empirically valid definition of long-term eating disorder recovery. Additionally, we plan to document recovery and mortality and identify demographic and clinical predictors of 25-year eating disorder outcome
Keywords: ing; Age; Alcohol abuse; Anorexia; Anorexia Nervosa; base; Behavioral Symptoms; Bulimia; Cessation of life; Chronic; Chronic Disease; Clinical; cohort; Comorbidity; Complex; Coupled; Data; Data Set; design; Diagnostic; DSM-IV; Eating Disorders; Emotional; Evaluation; experience; follow-up; Funding; Future; General Hospitals; indexing; Intake; Interview; Investigation; Life; Longitudinal Studies; Massachusetts; Medical; meetings; Mental Depression; Mental disorders; Morbidity - disease rate; Mortality Vital Statistics; National Institute of Mental Health (U.S.); Neurobehavioral Manifestations; Outcome; Outcome Study; Participant; Patients; Phase; Positioning Attribute; premature; prospective; psychosocial; purge; Quality of life; Questionnaires; Recovery; Relapse; Research Personnel; Residual state; Resources; Risk; Sampling; Sampling Studies; Series; Severities; Severity of illness; Study Subject; Symptoms; Time; Weight; Woman
Project start date: 2011-06-01
Project end date: 2013-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-10-064
1R03MH094832-01 (2011): $88500
IN VIVO ROLE OF NITRIC OXIDE IN MUSCOSAL INFLAMMATION AND CANCER
B David, Professor
Massachusetts Institute Of Technologycity: Cambridge country: United States (us)
Abstract: Project 4 In order to investigate the mechanisms by which inflammation, oxidative stress, and nitric oxide in particular contribute to cancer risk, we have developed a series of mouse models of colitis and colitis-associated cancer. We will use highly susceptible compound mutant mice deficient for interleukin 10 (IL10) and recombination activating gene 2 (Rag2) on a 129/SvEv background. These 129/SvEv ILIO´^Rag"´" mice develop lesions that resemble inflammatory bowel disease (IBD) and cancer when infected with Helicobacter hepaticus or after adoptive transfer with CD4*CD45RBhigh effector T cells (Teff). We will also use IL10"´" mice on a C57BL/6 background infected with Helicobacter trogontum and wild type C57BL/6 mice infected with Citrobacter rodentium. For all three mouse models, the gpt delta reporter transgene will be used to quantify and characterize somatic mutations that arise in vivo. A novel Fluorescent Yellow Direct Repeat (FYDR) transgene will also be generated in order to quantify recombination events in vivo. We will characterize the role of inducible nitric oxide synthase (iNOS) in 129/SvEv ILIO^´Rag"´" mice infected with H. hepaticus that develops a rapid onset of colitis-associated cancer, C57BL/6 IL10"´" mice infected with H. trogontum that develops IBD, and C57BL/6 mice infected with C. rodentium that develops a self-limiting colitis. This will be accomplished by pharmacologic inhibition of NOS enzymes as well as by crossing our C57BL/6 models with iNOS"´" mice. Depletion experiments will also be carried out to ascertain the role of neutrophils and macrophages in colitis and cancer in these model systems. These experiments will provide specimens for the other Projects in this Program in order to validate computational models, characterize chemical biomarkers, and establish the role of DNA damage and repair in mutagenesis. By establishing the role of nitric oxide produced by inflammatory cells and by epithelial cells in the large intestine, we will gain a better understanding of the mechanistic basis of cancer risk in IBD, and in mucosal inflammation in general. These studies and the interactions with the other Projects in the Program should translate into newstrategies to prevent the initiation or delay the progression of inflammation-associated cancer
Keywords: Adoptive Transfer; Assay; base; Bioassay; Biologic Assays; Biological Assay; Biological Models; biomarker; Blood Neutrophil; Blood Polymorphonuclear Neutrophil; Blood Segmented Neutrophil; C57BL/6 Mouse; Cancer Induction; cancer risk; Cancers; carcinogenesis; Cells; Chemicals; Citrobacter freundii Biotype 4280; Citrobacter rodentium; Colitis; colitis associated cancer; Colon; computational modeling; computational models; computational simulation; computer based models; Computer Simulation; computerized modeling; Computerized Models; computerized simulation; CSIF; CSIF-10; Cytokine formation-inhibiting factor (mouse clone F115 protein moiety reduced); Cytokine Synthesis Inhibitory Factor; Direct Repeats; DNA Damage Repair; DNA Recombination; DNA recombination (naturally occurring); DNA Repair; Endogenous Nitrate Vasodilator; endothelial cell derived relaxing factor; Endothelium-Derived Relaxing Factor; Enzymes; Epithelial Cells; Eragrostis; Event; experiment; experimental research; experimental study; Genes; Genetic Recombination; Genetics-Mutagenesis; Helicobacter; Helicobacter hepaticus; Hepatocyte Nitric Oxide Synthase; Heterophil Granulocyte; homologous recombination; human NOS2A protein; IL-10; IL10; IL10A; in silico; in vivo; Inducible Nitric Oxide Synthase; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Bowel Disorder; Inflammatory Intestinal Disease; Inflammatory Intestinal Disorder; INFLM; INOS; iNOS enzyme; Interleukin 10 Precursor; Interleukin-10; language translation; large bowel; Large Intestine; Lesion; macrophage; Macrophage Nitric Oxide Synthase; malignancy; Malignant Neoplasms; Malignant Tumor; Mammals, Mice; man; man`s; Marrow Neutrophil; Mathematical Model Simulation; Mathematical Models and Simulations; Mice; Mice, Mutant Strains; Model System; Modeling; Models, Biologic; Models, Computer; Molecular Biology, Mutagenesis; Mononitrogen Monoxide; mouse model; mouse mutant; Mucosal Inflammation; Mucositis; Murine; Mus; Mutagenesis; Mutant Strains Mice; neoplasm/cancer; neutrophil; Neutrophilic Granulocyte; Neutrophilic Leukocyte; Nitric Oxide; Nitric Oxide Synthase 2A; nitric oxide synthase, Type II; Nitric Oxide, Endothelium-Derived; Nitrites; Nitrogen Monoxide; Nitrogen oxide; Nitrogen Protoxide; NOS Type II; NOS2; NOS2A; NOS2A protein, human; novel; Oxidative Stress; Polymorph; Polymorphonuclear Cell; Polymorphonuclear Leukocytes; Polymorphonuclear Neutrophils; prevent; preventing; programs; Programs (PT); Programs [Publication Type]; Recombination; Recombination, Genetic; Reporter; Research Specimen; research study; Role; Series; Simulation, Computer based; social role; Somatic Mutation; Specimen; T-Cells; T-Lymphocyte; Teff; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; Transgenes; Translating; Translatings; Unscheduled DNA Synthesis; virtual simulation
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
5P01CA026731-32_7986 (2011): $326440
AIRWAY BIOLOGY OF ACUTE ENVIRONMENTAL ASTHMA IN HUMANS
B David, Prof Peds Med & Toxicology
University Of North Carolina Chapel Hillcity: Chapel Hill country: United States (us)
Abstract: Project 3, "Airway Biology of Acute Environmental Asthma in Humans" will examine the effect of environmental endotoxin on acute exacerbation of asthma. Epidemiological studies have shown that environmental particulate matter (PM) and endotoxin (a component of PM) are associated with increased occurrences of asthma exacerbation and wheeze. Published reports from our group and others demonstrate that endotoxin induce an innate response in the airway characterized by changes in monocyte/macrophage biology and influx of airway neutrophils. We have also shown that these responses correlate well to expression of CD14 on airway macrophages. Low levels of endotoxin prime the airway such that response of allergic asthmatics to allergens is enhanced, and lead to the general hypothesis that priming of the airway by pollutants via innate immune mechanisms to respond to additional pollutants or allergens is a central process by which environmental asthma is initiated. Though it is clear that environmental endotoxin induces asthma exacerbation, there is a significant gap in knowledge regarding the mechanisms which modulate inflammation due to this environmental irritant. Recent preliminary data from our group suggest that IL-1 (3 is an important modulator of endotoxin induced events in the airway. The recently discovered members of the CATERPILLER family of immune regulatory proteins play an important role in regulating IL-1p induced inflammation and we hypothesize that CATERPILLER genes are important in regulating pollutant induced asthma. Signals from pathogen associated molecular patterns entities (such as endotoxin) activate cryopyrin and NALP1, and induce the loss of the negative regulator protein monarch-1. In addition to being activated by PAMPs, cryopyrin is activated by endogenous ligands such as ATP (which is released by inflamed/injured airway cells) after ligation to the P2X7 receptor. Projects 1 and 2 focus on the role that these molecules have in mediating airway responses to LPS, differences in these responses observed between allergen sensitized and naTve mice, and the priming effect of endotoxin on response to allergen. This aims of this project will be to examine the effect of allergen and endotoxin-induced inflammation on expression of CATERPILLAR regulators, P2X7 receptors and other molecules which enhance innate and immune response by airway monocytes, granulocytes and epithelial cells in allergic asthmatics, the modification of response to LPS by allergic inflammation, and the effect of anti-inflammatory therapy on these processes
Keywords: 3-10C; Acidophilic Leukocyte; acquired immunity; Acute; Adenock; Adrenal Cortex Hormones; Air; airway epithelium infalmmation; airway hyper-reactivity; Airway Hyper-responsiveness; airway hyperreactivity; airway hyperresponsiveness; airway inflammation; airway injury; Airway Obstruction; Allergens; Allergic; Allergic asthma; Allergic inflammation; allergic response; Allo-Puren; Allozym; Allural; Aloprim; Aloral; Alositol; AMCF-I; Anoprolin; Anti-Inflammatories; Anti-inflammatory; Anti-Inflammatory Agents; Antigens; Antiinflammatories; Antiinflammatory Agents; Anzief; APS Brand of Allopurinol; Apulonga; Apurin; Apurol; Aspiration, Respiratory; Asthma; ATGN; atopic asthma; Azupharma Brand of Allopurinol; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; b-ENAP; BASF Brand of Allopurinol; BCDF; Biological; biological signal transduction; Biology; Bleminol; Blood Eosinophil; Blood granulocytic cell; Blood monocyte; Blood Neutrophil; Blood Polymorphonuclear Neutrophil; Blood Segmented Neutrophil; Bloxanth; Boehringer Mannheim Brand of Allopurinol; Boots Brand of Allopurinol; Breathing; Bronchial Asthma; Bronchial Constriction; Bronchoconstriction; BSF-2; BSF2; BSF2 (B cell stimulating factor 2); Caplenal; CD14; CD14 gene; Cell Communication and Signaling; Cell Signaling; Cellidrin; Cells; chemoattractant cytokine; chemokine; Closure by Ligation; Corticoids; Corticosteroids; Cosuric; Coupled; CXCL8; Cytofluorometry, Flow; cytokine; Cytokines, Chemotactic; Dabroson; Data; Dendritic Cells; Deposit; Deposition; Development; Differentiation Factor, B-Cell; Disease; disease/disorder; Disorder; Dorsch Brand of Allopurinol; Embarin; Endotoxins; environmental endotoxin; Environmental Irritants; environmental particulate; eosinocyte; eosinophil; Eosinophilic Granulocyte; Eosinophilic Leukocyte; Epidemiologic Research; Epidemiologic Studies; Epidemiological Studies; Epidemiology Research; Epidropal; Epithelial Cells; Event; Exhalation; Exhaling; Expiration, Respiratory; extrinsic allergic asthma; Extrinsic asthma; Family; Flow Cytofluorometries; Flow Cytometry; flow cytophotometry; Flow Microfluorimetry; fluid; Foligan; GCP-1; GCP1; Geapur; Gene Expression; Gene Expression Monitoring; Gene Expression Pattern Analysis; Gene Expression Profiling; gene product; Genes; genetic regulatory protein; gepepharm Brand of Allopurinol; Gichtex; Glaxo Wellcome Brand of Allopurinol; Granular Leukocytes; granulocyte; Granulocytic cell; Hamarin; heavy metal lead; heavy metal Pb; Hennig Brand of Allopurinol; Henning Berlin Brand of Allopurinol; Hepatocyte-Stimulating Factor; Heterophil Granulocyte; Hexanurat; Homologous Chemotactic Cytokines; host response; HPGF; Human; Human Biology; Human Volunteers; Human, General; Hybridoma Growth Factor; IFN-beta 2; IFN-gamma-Inducing Factor; IFNB2; IgE; IGIF; IL-1; IL-1 Gamma; IL-18; IL-1g; IL-6; IL-8; IL1; IL18 Protein; IL1F4; IL6 Protein; IL8; IL8 gene; Immune; Immune response; Immunity; Immunity, Innate; Immunity, Native; Immunity, Natural; Immunity, Non-Specific; Immunobiology; immunogen; Immunoglobulin E; Immunophysiology; immunoresponse; Infection; Inflammation; Inflammatory; INFLM; Inhalation; Inhaling; injured airway; inspiration; Inspiration, Respiratory; Intercrines; interferon beta 2; Interferon-gamma-Inducing Factor; Interleukin 18 (Interferon-Gamma-Inducing Factor); Interleukin 18 Proprotein; Interleukin 6 (Interferon, Beta 2); Interleukin I; Interleukin-1; Interleukin-1 Gamma; Interleukin-18; Interleukin-18 Precursor; Interleukin-6; Intracellular Communication and Signaling; K60; Ketanrift; Ketobun-A; Knowledge; knowledge translation; Label; Lead; LECT; Ledopur; Ligands; Ligation; liquid; Liquid substance; Lopurin; LUCT; Lung; lung function; lymphocyte activating factor; Lymphocyte-Stimulating Hormone; LYNAP; Lysuron; macrophage; Macrophage Cell Factor; Mammals, Mice; Man (Taxonomy); Man, Modern; Marrow Eosinophil; Marrow monocyte; Marrow Neutrophil; MDNCF; Measures; Mediating; Mediator; Mediator of Activation; Mediator of activation protein; member; Merckle Brand of Allopurinol; Messenger RNA; MGC12320; MGI-2; Mice; Microfluorometry, Flow; Miniplanor; Mites; Modeling; Modification; Molecular; MONAP; Monarch; monocyte; mRNA; Mucociliary Clearance; Mucociliary Transport; mucous; Mucous body substance; Mucus; Multipharma Brand of Allopurinol; Murine; Mus; Myeloid Differentiation-Inducing Protein; NAF; Natural Immunity; Nektrohan; Network Analysis; neutrophil; Neutrophilic Granulocyte; Neutrophilic Leukocyte; Nicholas Brand of Allopurinol; novel; novel therapeutic intervention; Pan Quimica; particle; Particulate Matter; pathogen; Pathogenesis; pathway; Pathway Analysis; Pathway interactions; Pattern; Pb element; Peripheral; Phase; Physiology; Plasmacytoma Growth Factor; Play; pollutant; Polymorph; Polymorphonuclear Cell; Polymorphonuclear Leukocytes; Polymorphonuclear Neutrophils; Process; Profilings, Gene Expression; Proteins; Protocol; Protocols documentation; Publishing; pulmonary; purine; Purines; radiolabel; Radiolabeled; radiotracer; receptor; Receptor Protein; Regulation; regulatory gene product; Regulatory Protein; Remid; Reporting; respiratory function; Respiratory physiology; Respiratory System, Lung; response; Rh?`ne-Poulenc Rorer Brand of Allopurinol; Riball; Risk Factors; RNA, Messenger; Roche Brand of Allopurinol; Role; SCYB8; Signal Transduction; Signal Transduction Pathway; Signal Transduction Systems; Signaling; SIS cytokines; social role; Source; Spirometry; Sputum; Stimulus; Suspendol; T Helper Factor; TAD Brand of Allopurinol; Takanarumin; Testing; Therapeutic Corticosteroid; Transcript Expression Analyses; Transcript Expression Analysis; TSG-1; Urbol; Uricemil; Uripurinol; Urosin; Urtias; Veiled Cells; volunteer; Wellcome Brand of Allopurinol; wheeze; Wheezing; Wheezings; Xanturat; Zyloprim; Zyloric
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
5U19AI077437-04_8456 (2011): $385261
NON-CLOTTING MICRO-CATHETER FOR NEWBORNS
B David, President / Cto
Gel-del Technologies, Inc.city: St. Paul country: United States (us)
Grant 5R43RR031306-02 from National Center For Research Resources
Abstract: Pre-mature and critically ill infants often require frequent medication and nutrient administration, necessitating use of peripheral intravenous catheters for prolonged periods. Due to the small diameter of these newborns´ veins, these catheters demonstrate a propensity for clotting, limiting their use and potentially endangering the health of these infants. We plan to develop an ultra-small diameter catheter for this critical application that will greatly improve outcomes. We have successfully developed a small diameter vascular graft using our hemo- compatible, non-clotting, and non-thrombogenic, elastin-collagen material (ECM) through our patented and patent pending novel process and incorporation of heparin. Our 3.75 mm arterial-mimetic graft, VasoGraft", allows blood to flow through it without blood clotting or thrombosis in tests lasting over 6 months. VasoGraft has been the topic of a currently funded NHLBI project (HL072670) for the past 4+ years with demonstrated patency in over 40 subjects tested in a porcine severed femoral artery end-to-end anastomosis model (artery to graft to artery reattachment), out to 200+ days, at the VA Med Ctr, Minneapolis, MN. Since ECM technology is a thermoplastic it can be molded to create ultra-small diameter constructs for use as catheters for long-term implantation. This application seeks funding through the two-year SBIR PHASE 1 grant to generate proof-of- concept studies, with the ultimate goal of developing catheters of sufficiently small diameter (d1mm) for long- term (e 2 weeks) use in newborns, where these catheters remain patent. We will leverage an existing, productive collaboration with MP&E, Inc, an engineering company with extensive experience producing catheters and other tubing medical devices and continue to collaborate with the VA Medical Center. Through these collaborations, ultra-small diameter constructs will be manufactured utilizing embedded reinforcements such as coiled or otherwise shaped tube reinforcement wire, to provide both flexibility and strength, while maintaining hemocompatibility. This ECM material creates an elastic wall structure to the catheter tube that is an insoluble, non-clotting, biocompatible surface to provide its proven non-thrombogenic, hemocompatibility. The specific aims for this project are to 1) Fabricate and manufacture Gel-Del catheter tubing of the appropriate diameter (21-24 gauge, e.g., d1 mm); 2) Test the constructs in vitro for mechanical strength, integrity and consistency using standard catheter bench testing, anti-clotting analyses (standard Lee-White test and surface blood contact tests), and microscopic analyses (light and scanning electron microscopy); and 3) utilize in vivo models of indwelling catheters in a rat model to assess patency for two weeks or longer. We will also plan to assess this catheter´s ability to fight infection due to its ability to allow tissue closure around the catheter surface. Future development will include anti-infection agents into the catheter ECM material for long- term drug delivery. These aims will provide the proof-of-concept studies to allow the extension of our existing small diameter vascular graft technology into development of ultra-small catheter products for use in newborns. The use of peripherally inserted percutaneous central venous catheters (PCVC) is important for providing both medication and nutrition in premature or critically ill infants. However, the materials used to make catheters can present problems associated with both hemocompatibility and infection complications, which limits their use and threatens the treatment of this patient population. The development of a neonatal catheter that uses our non-clotting elastin-collagen material (ECM) technology will greatly reduce the risks of such complications and greatly improve the treatment of critically ill newborns
Keywords: Adult; Anastomosis - action; Antibiotic Therapy; Arteries; Bacterial Infections; base; Binding (Molecular Function); Biochemical; Biocompatible; Blood; Blood Clot; Blood coagulation; Blood Vessels; Caliber; Catheters; Cells; Characteristics; Child; Coagulation Process; Collaborations; Collagen; Complication; Critical Illness; critically ill newborn; dacron; design; Development; Distant; Drug Delivery Systems; Elastin; Embolism; Engineering; experience; Extracellular Matrix; Extravasation; Family suidae; femoral artery; fighting; flexibility; Funding; Future; Gel; Glycosaminoglycans; Goals; Grant; Heparin; implantation; improved; In Vitro; in vivo Model; Indwelling Catheter; Infant; Infant Health; Infection; Infection prevention; Inflammation; Intercellular Fluid; Intravenous; Legal patent; Light; Liquid substance; Mechanics; Medical center; Medical Device; Microscopic; Microscopy, Electron, Scanning; mimetics; Modeling; Molds; National Heart, Lung, and Blood Institute; Nature; Neonatal; Newborn Infant; novel; Nutrient; nutrition; Outcome; Pain; patient population; Peripheral; Pharmaceutical Preparations; Population; premature; Process; Property; Proteins; Psychological reinforcement; public health relevance; Rattus; Reporting; Risk; scaffold; Shapes; Site; Skin; Skin Tissue; Small Business Innovation Research Grant; Structure; Surface; Systemic infection; Technology; Testing; Thrombosis; Thrombus; Time; Tissues; Travel; Tube; Vascular Graft; Veins; Venous; Veterans
Relevance: Narrative: The use of peripherally inserted percutaneous central venous catheters (PCVC) is important for providing both medication and nutrition in premature or critically ill infants. However, the materials used to make catheters can present problems associated with both hemocompatibility and infection complications, which limits their use and threatens the treatment of this patient population. The development of a neonatal catheter that uses our non-clotting elastin-collagen material (ECM) technology will greatly reduce the risks of such complications and greatly improve the treatment of critically ill newborns
Project start date: 2010-08-01
Project end date: 2012-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: RFA-HD-09-017
5R43RR031306-02 (2011): $224997
ARTERIAL-MIMETIC GRAFTS MOLDED FROM PURIFIED PROTEINS
B David, President / Cto
Gel-del Technologies, Inc.city: St. Paul country: United States (us)
Grant 5R44HL072670-06 from National Heart, Lung, And Blood Institute
Abstract: Peripheral artery disease and trauma are leading causes of morbidity and amputation in the United States. Recent advances in biomaterials provide for potential development of small diameter vascular grafts as a life-saving treatment. Development of a life-long graft (< 6 mm id) requires a construct that will not cause significant blood clotting/thrombosis and allow biologic integration to sustain life-long performance. Gel-Del Technologies has developed and tested prototypes using a patented fabrication process with purified proteins, water, and other biochemicals to produce biomimetic vascular constructs (Gel-Del(R) VasoGraft"). Collagen and elastin proteins, along with the anti-clotting factor, heparin, are processed together with a scaffolding material to create a tubular construct (VasoGraft"). VasoGraft testing and recent SBIR Phase I and II studies demonstrate excellent bio- and hemocompatibility, including non-thrombosis, host tissue integration and in vivo patency, in tests continuing out past 150 days using a porcine femoral artery model. While the graft´s lumen remains non-thrombogenic, significant intimal hyperplasia occurs in native artery anastomosis sites, an expected adverse response to surgical arterial transection. Because the graft functions well, it was hypothesized here that reduction of intimal hyperplasia allows long-term function and patency. Therefore, we have developed an additional component of the VasoGraft system, which incorporates drug (rapamycin) to inhibit smooth muscle cell proliferation in the native artery. In vitro drug elution profiles have been characterized, and incorporation of this drug-eluting component has led to increased length of graft patency in a porcine femoral artery model. This proposal will pursue the necessary steps to gain IDE approval to commence clinical trials with the VasoGraft System, including additional long-term porcine efficacy studies, biocompatibility and safety studies according to ISO 10993, and manufacturing scale-up. These studies will be executed as follows Aim 1 Assess optimal dose of rapamycin within drug-eluting threads for reducing stenosis, and test this within the VasoGraft System under GLP conditions using the porcine femoral artery end-to-end anastomosis model out to 450 days. VasoGraft System will be made with scaleable manufacturing procedures. Aim 2 Complete manufacturing scale up, and perform biocompatibility/safety/stability testing required for IDE submission. Aim 3 Final preparation of IDE and submission to FDA. These aims will generate the necessary information to submit an IDE application for approval to test the VasoGraft in a clinical trial, designed to include 30 patients with a 6-month follow-up to address any safety issues. Peripheral vascular disease and trauma is a prevalent cause of amputation for military personnel and general population in the United States. Current blood vessel graft replacements are inadequate, often leading to occlusion and graft failure. The development of a novel blood vessel graft, which can also be utilized at trauma and battlefield sites, will greatly enhance the lives of people suffering from PAD or trauma
Keywords: acronyms; Address; Amputation; Anastomosis - action; Arteries; Biochemical; Biocompatible; Biocompatible Materials; biomaterial compatibility; Biomimetic Materials; Biomimetics; Blood capillaries; Blood Clot; Blood coagulation; Blood Coagulation Factor; Blood Vessels; Caliber; capillary; Carbohydrates; Carotid Arteries; Cell Proliferation; Clinical; clinical application; Clinical Trials; Clinical Trials Design; Coagulation Process; Collagen; Collagen Type I; Coronary artery; dacron; Data; Dermal; Dermis; design; Development; Disease; Dose; Drug Delivery Systems; Elastin; Endothelial Cells; Face; Family suidae; femoral artery; Fibroblasts; follow-up; Funding; Future; Gel; General Population; Goals; graft failure; graft function; Growth; Guidelines; Healed; healing; Health; Heparin; Human; Hyperplasia; improved; In Vitro; in vivo; inhibitor/antagonist; Intervention; Legal patent; Length; Life; Limb structure; manufacturing scale-up; Mechanics; Military Personnel; mimetics; Modeling; Molds; Morbidity - disease rate; novel; Operative Surgical Procedures; Particulate; Patients; Performance; Peripheral; Peripheral arterial disease; Peripheral Vascular Diseases; Pharmaceutical Preparations; Phase; Physiological; Preparation; prevent; Procedures; Process; Production; Proteins; prototype; reconstruction; regenerative; repaired; response; Safety; safety study; Salts; scaffold; scale up; Shapes; Simulate; Sirolimus; Site; Skin; Small Business Innovation Research Grant; Smooth Muscle Myocytes; Sodium Chloride; stability testing; Staging; Stenosis; Structure; success; Surgical sutures; System; Techniques; Technology; Testing; Therapeutic; Thrombosis; Time; Tissues; Transplanted tissue; Trauma; Tubular formation; United States; Vascular Graft; Water
Relevance: Peripheral vascular disease and trauma is a prevalent cause of amputation for military personnel and general population in the United States. Current blood vessel graft replacements are inadequate, often leading to occlusion and graft failure. The development of a novel blood vessel graft, which can also be utilized at trauma and battlefield sites, will greatly enhance the lives of people suffering from PAD or trauma
Project start date: 2003-01-03
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-08-050
5R44HL072670-06 (2011): $1395176
SUSTAINABILITY OF THE GO SUN SMART PROGRAM IN A RECREATION INDUSTRY
B David
Klein Buendel, Inc.city: Golden country: United States (us)
Grant 1R01CA159840-01 from National Cancer Institute
Abstract: Outdoor workers are at increased risk for skin cancer because of occupational exposure to ultraviolet radiation in sunlight. Our research team has developed Go Sun Smart (GSS), an occupational sun protection program for outdoor workers, and demonstrated its effectiveness. We also evaluated successful theory-based strategies for disseminating GSS to the entire North American ski industry. The proposed study is designed to examine the sustainability of GSS dissemination and provide a final assessment in a comprehensive decade-long examination of the development, effectiveness, dissemination, and sustainability of a workplace sun protection program. Sustainability of health intervention programs is essential to achieve long-term health behavior change; however, only limited research exists on the sustainability of evidence-based prevention programs. Sustainability of GSS will be assessed by observing continued use of GSS at the ski areas that participated in the GSS II dissemination trial. Specific aims of the sustainability assessment are to 1) evaluate the continued use of GSS by the workplaces enrolled in the GSS II dissemination trial; 2) examine whether continued use of GSS was affect by dissemination strategy (Basic v. Enhanced); 3) explore continued theoretical fidelity of the occupational sun protection principles in GSS; and 4) determine whether sustained use of GSS, if present, influences employees´ sun protection. We expect that 61 of the original 68 ski areas in the GSS II dissemination trial will agree to participate in this 2-year project on GSS sustainability. Trained research staff will return to each ski area and observe use of GSS and non-GSS messages and actions intended to improve occupational sun safety. We will use the on-site observations, a modified version of the survey of managers from the GSS II dissemination trial, and a new pilot-tested protocol for performing semi-structured interviews with senior managers to measure continued use of GSS, theoretical fidelity of occupational sun protection principles, and the integration of GSS and sun protection into organizational culture at the ski areas. Intercept surveys with employees using a shortened version of the employee survey from the GSS II dissemination trial will be conducted to assess continued influence of GSS on employees´ sun safety (i.e., exposure to sun safety messages, reduced prevalence of sunburn, and increased frequency of sun protection practices). The proposed project is significant and innovative because it will a) help to fill a gap in the understanding of the sustainability of prevention programs in general and occupational sun protection in particular; b) explore whether strategies used to disseminate a program affects its sustainability; c) identify organizational characteristics that affect program sustainability; d) determine whether workplaces implement changes that promote occupational sun protection principles even if they do not utilize GSS; and e) test whether GSS continues to improve sun safety by employees. Outdoor workers are at increased risk for skin cancer and our team developed an effective occupational sun protection program, Go Sun Smart. In a previous study, strategies for disseminating this program to the entire North American ski industry were evaluated and researchers will return to the workplaces participating in that study and perform a final assessment of whether they continue to use Go Sun Smart. Sustainability of prevention programs is a major concern for public health because sustained intervention is essential to achieve long-term improvements in health
Keywords: Adopted; Affect; American; Area; Attention; base; Behavior; Canada; Cessation of life; Characteristics; Chronic Disease; Colorado; County; Coupled; Data; Data Collection; design; Development; Diagnosis; dissemination trial; Effectiveness; effectiveness trial; Employee; Enrollment; Evaluation; evidence base; Evidence based program; Exposure to; falls; Frequencies (time pattern); Funding; Future; Goals; Health; Health behavior change; improved; Industry; innovation; Intercept; Intervention; intervention program; Interview; Investigation; Kentucky; Life Style; Measurement; Measures; melanoma; Nature; North America; Occupational; Occupational Exposure; Occupations; Organizational Culture; Populations at Risk; Prevalence; Prevention program; Program Sustainability; programs; Protocols documentation; public health medicine (field); public health relevance; Randomized; Recreation; Research; Research Personnel; Research Training; Resources; Risk; Safety; safety practice; Site; Skiing; Skin Cancer; skin cancer prevention; Skin Carcinoma; Squamous cell carcinoma; Structure; success; Sun Exposure; sun protection; Sunburn; Sunlight; Surveys; Testing; The Sun; theories; Time; TimeLine; Translating; Ultraviolet Rays; United States; UV Radiation Exposure; Vendor; Visit; Work; Workplace
Project start date: 2011-05-01
Project end date: 2013-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-10-067
1R01CA159840-01 (2011): $619415
REMODELING SUPPRESSION: COLLAGEN EFFECTS ON FRACTURE ENERGY
B David
Indiana Univ-purdue Univ At Indianapoliscity: Indianapolis country: United States (us)
Grant 5R01AR047838-09 from National Institute Of Arthritis And Musculoskeletal And Skin Diseases
Abstract: Our objective is to determine the role that collagen cross-linking (both enzymatic- and non- enzymatically-mediated), collagen maturity (alpha/beta CTX), and the accumulation of advanced glycation end-products (AGE´s) play in bone´s structural and material energy absorption capacity. Aim 1 will determine whether there is a significant accumulation of AGE´s in bone following 2 or 3 years treatment with doses of bisphosphonate currently used to treat postmenopausal osteoporosis, or those used to treat Paget´s disease. AGE accumulation will be correlated to toughness and normalized energy to failure. This Aim uses dogs that have already been treated and sacrificed, but proposes material property measurements as well as analysis of collagen cross-linking and maturation that were not proposed in our original application. Aim 2 will determine whether diabetic rats, known to accumulate AGE´s in bone, show changes in toughness and normalized energy to failure consistent with our hypothesis that AGE accumulation is associated with reduced energy to failure at the tissue and structural levels. Use of two different AGE inhibitors will establish cause and effect, and may provide information about the mechanism of AGE accumulation, as the inhibitors act at different points of the reaction cycle. Aim 3 will allow us to establish the relationship between AGE accumulation and altered mechanical properties in an estrogen-deficient animal model (ovariectomized rats), an established model for post-menopausal osteoporosis. Use of an AGE inhibitor will establish cause and effect between AGE accumulation and bone´s material properties (toughness and normalized energy to failure) that may be more relevant to the post-menopausal situation than intact dogs. Acquisition of a new Skyscan 1172 micro-CT as part of an NIH infrastructure grant will allow us to assess changes in trabecular architecture to better characterize trabecular bone properties. It will also allow us to normalize the mechanical data by the plane of smallest BV/TV to prevent weighting by regions of bone with higher density that do not fail. Our work could help to explain the reason for the reduced toughness and normalized energy to failure found with bisphosphonate treatment, and to determine whether it is possible to prevent these changes in patients who are being treated with bisphosphonates. PUBLIC HEALTH NARRATIVE The objective of this proposal is to determine the role that collagen, and the accumulation of advanced glycation end-products, play in the mechanical properties of bone. This has relevance in understanding the fragility of bone that occurs in post-menopausal osteoporosis, and in Type II diabetes
Keywords: absorption; Adult; Advanced Glycosylation End Products; Alendronate; Animal Model; Animals; Architecture; bisphosphonate; bone; Bone Density; Bone Matrix; Bone Tissue; Canis familiaris; Clinical; clinically relevant; Collagen; Control Animal; crosslink; Cyclophosphamide; Data; density; deoxypyridinoline; Diabetes Mellitus; diabetic; diabetic rat; Diaphyses; Distal; Dose; Estrogens; Failure (biologic function); Femur; Fracture; Gender; Grant; Health; High Pressure Liquid Chromatography; inhibitor/antagonist; Measurement; Measures; Mechanics; Mediating; mineralization; Modeling; non-diabetic; Non-Insulin-Dependent Diabetes Mellitus; Paget`s Disease; Patients; Play; Postmenopausal Osteoporosis; Postmenopause; prevent; Property; pyridinoline; Pyridoxamine; Rattus; Reaction; Research Infrastructure; research study; Role; Site; skeletal; Sorbitol; spine bone structure; substantia spongiosa; sugar; Testing; Time; Tissues; treatment duration; United States National Institutes of Health; vertebra body; Weight; Work
Project start date: 2001-07-01
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5R01AR047838-09 (2011): $315723
MOLECULAR GENETIC ANALYSIS OF HUMAN OBESITY
B David, Professor Of Pediatrics & Medicine
Columbia University Health Sciencescity: New York country: United States (us)
Grant 5R01DK052431-18 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Our goal is to understand the molecular bases for the control of body weight by using molecular genetic and molecular physiological approaches in humans and rodents. There is growing evidence that multiple genes - each with relatively modest effect on relevant phenotypes such as food intake, energy expenditure, hedonic responses to food - interact with each other, intrauterine and early neonatal development, and the environment, to determine an individual´s susceptibility to become obese within a specific environment. Deployment of reciprocal molecular genetic approaches in humans and mice provides a powerful platform by which to identify and characterize these genes. The feasibility of genome-wide association studies (GWAS) utilizing large numbers of subjects (ultimately >100,000), availability of low cost/high throughput sequencing techniques, and access to sophisticated computational approaches, will create a deluge of genes with strong statistical but virtually no physiological insight into the mechanism(s) of action with regard to obesity. Mice - that can be manipulated and studied with a wide repertoire of transgenic, neurophysiologic and bioenergetic techniques - are an optimal resource for delineating the mechanism of action of such genes. We have used these approaches fruitfully in the past, and propose to continue to do so. This proposal has 2 major Aims 1. To identify new genes mediating the control of body weight in humans; 2. To identify the molecular bases for the effects of these genes. Aim 1 will make use of our access to large collections of human subjects (New York Health Project, Yup´ik Eskimos, DNA samples selected from extremes of BMI in the NHANES, and the international GIANT consortium); a prospective study of the effects on body weight with use of second generation antipsychotic medications; and individuals with syndromic and severe, early onset obesities. Using a range of strategies, we will identify new genes for human obesity. Aim 2 will use mice to address the molecular physiology of a recently discovered pair of adjacent genes (FTO/FTM) - and a related transcription factor, CUTL1 - strongly implicated in obesity by three GWAS; and a gene (MGRN1=mahoganoid) recently cloned by us and another group which acts in the MC4R signaling pathway by unknown mechanisms. This Aim will also provide for creation and study of transgenic animals segregating for "designer" alleles of genes identified in the first specific aim. Obesity is arguably the major health issue - in terms of medical morbidity and costs - now confronting developed and developing nations. Body weight and degree of fatness (adiposity) reflect the interactions of an individual´s genes with developmental and environmental factors. This grant is designed to identify the genes responsible for susceptibility to obesity in humans. Success in this endeavor will impact diagnosis, treatment and prevention of obesity and its associated co-morbidities such as diabetes and heart disease
Keywords: Accounting; Address; adipose; Adipose tissue; adiposity; adult onset diabetes; Affect; Allele Frequency; Alleles; allelic frequency; allelic variant; Allelomorphs; Antipsychotic Agents; Antipsychotic Drugs; Antipsychotics; Attention; attractin; attractin protein; Autoregulation; base; Binding; Binding (Molecular Function); Binding Sites; Bioenergetic; Bioenergetics; Biological; BMI percentile; BMI z-score; Body Composition; Body mass index; Body Weight; body weight gain; body weight increase; Brain; caloric dietary content; Caloric Intake; Candidate Disease Gene; Candidate Gene; Cardiac Diseases; Cardiac Disorders; cell biology; Cell Nucleus; Cells; Cellular biology; Collection; Color; Combining Site; Comorbidity; Computational Technique; corpulence; corpulency; corpulentia; cost; Data; Deoxyribonucleic Acid; design; designing; Development; diabetes; Diabetes Mellitus; Diabetes Mellitus, Adult-Onset; Diabetes Mellitus, Ketosis-Resistant; Diabetes Mellitus, Non-Insulin-Dependent; Diabetes Mellitus, Noninsulin Dependent; Diabetes Mellitus, Slow-Onset; Diabetes Mellitus, Stable; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type II; Diagnosis; DNA; DNA Resequencing; drug/agent; Drugs; E3 Ligase; E3 Ubiquitin Ligase; Eating; Encephalon; Encephalons; Energy Expenditure; Energy Intake; Energy Metabolism; Environment; Environmental Factor; environmental risk; Environmental Risk Factor; Epistasis; Epistasis, Genetic; Epistatic Deviation; Eskimo; Eskimo Population; fasted; Fasting; fasts; Fatty Tissue; Food; Food Intake; Future; Gene Duplication; Gene Expression; Gene Frequency; Gene variant; gene x gene interaction; Generations; Genes; Genetic Alteration; Genetic analyses; genetic analysis; Genetic Change; Genetic defect; Genetic Diversity; genetic epistases; Genetic Epistasis; genetic variant; Genetic Variation; genome mutation; genome wide association scan; genome wide association studies; genome wide association study; genome-wide scan; genomewide association scan; genomewide association studies; genomewide association study; genomewide scan; Genotype; Goals; Grant; GWAS; Health; Heart Diseases; heart disorder; hedonic; Homeostasis; Human; Human body; Human Figure; Human Genetics; Human Resources; human subject; Human, General; hypothalamic; Hypothalamic structure; Hypothalamus; In Vitro; in vivo; Individual; insight; Interaction Deviation; interest; International; Intervening Sequences; Intervention; Intervention Strategies; interventional strategy; Introns; ketosis resistant diabetes; LEPR; LEPR gene; Literature; Major Tranquilizers; Mammals, Mice; Mammals, Rodents; Man (Taxonomy); Man, Modern; Manpower; maturity onset diabetes; Maturity-Onset Diabetes Mellitus; MC4 Receptor; Mediating; Medical; Medication; Melanocortin 4 Receptor; Methods and Techniques; Methods, Other; Mice; MODY; Molecular; Molecular Genetic; Molecular Genetics; Molecular Interaction; Morbid Obesity; Morbidity; Morbidity - disease rate; Murine; Mus; Mutation; National Health and Nutrition Examination Survey; Neonatal; Nervous System, Brain; Neurochemistry; neurochemistry; Neuroleptic Agents; Neuroleptic Drugs; Neuroleptics; New York; NHANES; NIDDM; Non-Insulin Dependent Diabetes; Non-Insulin-Dependent Diabetes Mellitus; novel; Nucleus; obese; obese people; obese person; obese population; Obesity; obesity prevention; obesity, extreme; Obesity, Morbid; OBR; Patients; personnel; Pharmaceutic Preparations; Pharmaceutical Preparations; Phenotype; Physiologic; Physiological; Physiological Homeostasis; Physiology; Play; Population; Predisposition; Prospective Studies; Quetelet index; Reactive Site; receptor; Receptor Protein; Receptor Signaling; Receptor, Melanocortin, Type 4; Research Resources; Resequencing; Resources; response; Rodent; Rodentia; Rodentias; Role; Sampling; Science of neurochemistry; severe early onset obesity; Severe obesity; Signal Pathway; social role; Structure; success; Susceptibility; T2D; T2DM; Techniques; Tranquilizing Agents, Major; transcription factor; Transcription Regulation; Transcriptional Control; Transcriptional Regulation; transgenic; Transgenic Animals; Transgenic Organisms; Type 2 diabetes; Type II diabetes; ubiquitin-protein ligase; Ubiquitin-Protein Ligase E3; Variant; Variation; Variation (Genetics); Viral Vector; Weight Gain; Weight Increase; white adipose tissue; whole genome association studies; whole genome association study; wt gain; yellow adipose tissue; Yup`ik
Relevance: Obesity is arguably the major health issue - in terms of medical morbidity and costs - now confronting developed and developing nations. Body weight and degree of fatness (adiposity) reflect the interactions of an individual´s genes with developmental and environmental factors. This grant is designed to identify the genes responsible for susceptibility to obesity in humans. Success in this endeavor will impact diagnosis, treatment and prevention of obesity and its associated co-morbidities such as diabetes and heart disease
Project start date: 1996-07-15
Project end date: 2013-11-30
Budget start date: 1-DEC-2010
Budget end date: 30-NOV-2011
PFA/PA: PA-07-070
5R01DK052431-18 (2011): $526978
Sponsored Links Excellgen http://Excellgen.com
DESIGN ISSUES IN OBESITY RCTS: BUILDING AN EVIDENCE BASE
B David, Professor
University Of Alabama At Birminghamcity: Birmingham country: United States (us)
Grant 5R01DK078826-03 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Obesity is estimated to affect over 50 million Americans and its resulting morbidities remain significant problems for many individuals. Current treatments are only modestly effective and no treatment works for all individuals. Thus, it is critical to identify and evaluate new strategies for both efficacy and safety. Yet, several important questions about how to best design, interpret, and analyze randomized clinical trials for obesity treatments remain unanswered and in some cases completely unaddressed. Tens of millions of dollars are spent on obesity treatment studies annually by government and industry. Such studies could be better designed and more efficiently executed if they could draw on a well established body of empirical evidence regarding factors such as the effects of using run-in periods, expected drop-out rates, factors affecting drop-out rates, and the relation between population treatment effect and the expected degree of weight loss in a control condition. Information about all of these factors is critical for optimally designing studies, yet no rigorously established comprehensive body of knowledge about these factors exists. Thus, the purpose of the proposed research is to use meta-analytic methodology to develop this knowledge. Three specific aims are proposed. Aim 1. Comprehensively investigate of the effect of run-in periods on (a) subject drop-out rates (DORs); and (b) weight loss (WL). Aim 2. Comprehensively characterize DORs and patterns in obesity RCTs and how such rates and patterns vary as a function of RCT and patient characteristics using meta-regression of published summary statistics AND analysis of multiple raw datasets from large RCTs. Aim 3. Use a novel hierarchical meta-regression method to estimate the association between the true population (not sample) treatment effect and the true population (not sample) mean weight loss of the control group. This is important because it influences decisions about how vigorous the lifestyle modification interventions provided to control groups in RCTs of pharmaceuticals, surgery, and extra-lifestyle interventions should be. To accomplish these aims, we have assembled an experienced team of obesity researchers and statisticians. This research should give valuable answers and critical information for more evidence-based decisions about the design, analysis, and interpretation of obesity RCTs. The purpose of the research is to use meta-analytic methodology to develop this knowledge that would inform the design of randomized clinical trials for obesity treatment and prevention. It will entail comprehensively investigating the effect of run-in periods on subject drop-out rates (DORs) and weight loss; determining predictors of DORs, and estimating the association between the true population (not sample) treatment effect and the true population (not sample) mean weight loss of the control group. This research should give valuable answers and critical information for more evidence-based decisions about the design, analysis, and interpretation of obesity RCTs
Keywords: Abbreviations; Address; Advisory Committees; Advocate; Affect; alternative treatment; American; Behavior Therapy; Body mass index; Body Weight decreased; Cardiovascular Diseases; Characteristics; Choices and Control; Clinical Trials; clinically significant; Code; complement C2b; Conduct Clinical Trials; Control Groups; Controlled Study; Data; data acquisition; Data Set; design; Drops; European; evidence base; expectation; experience; Future; Government; Health; human subject; improved; Individual; Industry; Intervention; Investigation; Investments; Knowledge; lifestyle intervention; Literature; Longevity; Malignant Neoplasms; Methodology; Methods; Morbidity - disease rate; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; novel; Obesity; obesity prevention; obesity treatment; Operative Surgical Procedures; Outcome; Patients; Pattern; Pharmacologic Substance; placebo controlled study; Population; Prevalence; Prevention; Principal Investigator; Publishing; Randomized; Randomized Clinical Trials; randomized trial; Research; Research Design; Research Personnel; Resource Sharing; Retrieval; Running; Safety; Sampling; Serious Adverse Event; Solutions; Specialist; statistics; stroke; Testing; TimeLine; treatment effect; Vertebrates; Work
Relevance: Principal Investigator: Allison, David B. The purpose of the research is to use meta-analytic methodology to develop this knowledge that would inform the design of randomized clinical trials for obesity treatment and prevention. It will entail comprehensively investigating the effect of run-in periods on subject drop-out rates (DORs) and weight loss; determining predictors of DORs, and estimating the association between the true population (not sample) treatment effect and the true population (not sample) mean weight loss of the control group. This research should give valuable answers and critical information for more evidence-based decisions about the design, analysis, and interpretation of obesity RCTs. Page: 1
Project start date: 2009-03-01
Project end date: 2012-02-28
Budget start date: 1-MAR-2011
Budget end date: 28-FEB-2012
PFA/PA: PA-07-070
5R01DK078826-03 (2011): $247279
5R01DK078826-02 (2010): $241164
UAB PRE-DOCTORAL TRAINING PROGRAM IN OBESITY-RELATED RESEARCH
B David, Professor
University Of Alabama At Birminghamcity: Birmingham country: United States (us)
Grant 5T32HL105349-02 from National Heart, Lung, And Blood Institute
Abstract: Obesity is a major source of morbidity and mortality and of heart, lung, and blood related morbidity and mortality in particular. This application for an interdisciplinary pre-doctoral training program offers coordinated mentorship, didactic training, career development activities, and supervised research experiences to prepare PhD students for careers as independent investigators. The proposed pre-doctoral program will build on the momentum of a highly successful pilot implementation and will also complement and interface with our existing NIH-funded T32 program for post-doctoral training in obesity research. Students entering their 2nd year of PhD training will enroll in a formal integrated program tailored to individual interests. Trainees participate in the investigative programs of UAB´s NIH-funded Nutrition Obesity Research Center, one of only 12 such centers nation-wide. Each trainee will have an individual mentoring team consisting of a primary mentor and two co-mentors with one mentor from each of three major disciplinary domains (Biomedical; Behavioral/Social; Quantitative/Physical). The faculty´s multidisciplinary nature (physicists, physicians, psychologists, statisticians, physiologists, geneticists, epidemiologists, etc) and strong collaborative ties facilitates multidisciplinary training. Students from any UAB department may apply, but must have a mentoring team from this program´s approved faculty, if selected, participate in all activities and coursework specialized for this program. Individuals will be recruited from the large pool of eligible 1st year PhD students on campus and selected via formal application and committee review, based on graduate school performance, faculty recommendations, and consideration of the degree to which their interests fit with those of the faculty and ongoing research programs. All trainees must have as a future plan an investigative career in obesity-related research. The program promotes an approach to investigation that is scientifically and ethically rigorous. Regular reviews of individual trainees with the program directors insure that adequate progress toward an independent research career is made
Keywords: Obesity; pre-doctoral; Research; Training Programs
Relevance: Obesity is a highly prevalent condition that exacts a high price in suffering for afflicted individuals and economically for society. Causes are complex, manifold, and only partially understood and available treatments are only modest in efficacy. New scientific insights are badly needed and training a new generation of multidisciplinary obesity researchers is essential to meet that objective
Project start date: 2010-09-22
Project end date: 2015-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-10-036
5T32HL105349-02 (2011): $154757
1T32HL105349-01 (2010): $76471
B David, Professor
University Of Alabama At Birminghamcity: Birmingham country: United States (us)
Grant 5R01DK076771-03 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Obesity decreases longevity. Some new data involving body mass index (BMI; kg/m2) and mortality rate (MR) tentatively support three suppositions 1) the number of annual deaths attributable to obesity is roughly 1/3 of that previously estimated; 2) overweight (as opposed to obesity) does not result in an increased MR and may even confer a survival advantage; and 3) the deleterious effect of overweight and obesity on MR has declined over calendar time, and obesity and overweight are less harmful than they once were. Other data and much recent discussion highlights that we may be mischaracterizing the impact of obesity by reliance on BMI as opposed to measures of total or regional fat mass. Each of the three suppositions listed above is important. The first helps place the magnitude of society´s obesity problem in perspective. Regarding the second point, the extent to which overweight influences MR has important implications on how severe a health problem overweight is and how we should respond to it. The third point is quite novel and, if true, has the important implication that continuing to develop better treatments for the negative sequelae of obesity might dramatically lessen the need to directly address obesity per se. Yet, there are reasons to question each of these propositions and we propose to thoroughly evaluate them. We also aim to bring more direct measures of adiposity to bear on such questions. In Specific Aim 1, we will separately analyze (i.e., not pool) raw data from multiple well-characterized US datasets, each with a sufficiently long follow-up, to test whether the effect of obesity on MR has changed over calendar time within studies. We will then conduct a comprehensive meta-analysis to address this same question across studies. By using both approaches to address Specific Aim 1 we counterbalance the different strengths and limitations of these approaches, thereby allowing us to rigorously address this important question. In Specific Aim 2 we will use the bio-impedance analysis measurements of body fat and waist and hip measurements in NHANES III to estimate deaths attributable to obesity, years of life lost because of obesity, and mortality hazard ratios. Measuring obesity as body fatness and fat distribution instead of just using BMI should provide a more solid basis for public health and clinical recommendations by focusing on the more relevant variables of body fatness
Keywords: Abbreviations; Address; Adult; Attention; Attitude; attributable mortality; base; Body fat; Body mass index; Calendar; Categories; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Confidence Intervals; Data; Data Set; density; Educational workshop; electric impedance; Fatty acid glycerol esters; follow-up; Future; General Population; hazard; Health; Health Personnel; Height; Hip region structure; indexing; Institute of Medicine (U.S.); Investigation; Least-Squares Analysis; Life Style; Literature; Longevity; Measurement; Measures; Meta-Analysis; Methods; Modeling; Mortality Vital Statistics; National Health Interview Survey; NHANES; novel; Obesity; Overweight; Paper; Patient Self-Report; Population; Principal Investigator; Probability; public health medicine (field); Public Policy; Publishing; Recommendation; Relative (related person); Relative Risks; Reliance; Reporting; Research; Research Methodology; Research Personnel; Sampling; Science; Scientist; Series; Societies; Solid; Solutions; sound; Staging; statistics; Survival Analysis; Testing; Time; TimeLine; Ursidae Family; waist circumference; Waist-Hip Ratio; Weight; Work; years of life lost
Project start date: 2007-08-15
Project end date: 2011-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2011
5R01DK076771-03 (2009): $229986
DIFFUSING SUN SAFE POLICIES AND ENVIRONMENTS TO SCHOOLS
B David, Research Director
Klein Buendel, Inc.city: Golden country: United States (us)
Grant 5R01CA100285-06 from National Cancer Institute
Abstract: New strategies in the U.S. are needed to combat the rising rates of skin cancers, such as methods to promote the adoption of sun protection policies and environmental features by school. In this revised application we propose to create a program to promote sun protection policies and environments to public school districts and to evaluate its effectiveness at producing district-level changes and implementation of changes in schools. The project will test predictions from diffusion of innovations theory (DIT) about the adoption process and program effects on sun protection policy and environment changes, as well as about secular trends in policy and environmental changes in control districts. DIT, national and local advisory board, and formative assessments of school districts by project staff (analysis of structure and in-depth interviews with administrators) will inform methods for communicating with with district personnel. Program features will be pretested for information design and usability and program implementation procedures will be piloted tested. The Los Angeles Metropolitan Dermatological Society will implement the program in 10 counties in Southern California with on-site assistance from Cooper Institute and University of Southern California staff. Eligible districts will have 40% or more white non-Hispanic students. Districts will be randomized to receive either the CDC national guidelines on school sun safety (control) or in-person, telephone and email contacts with school district administrators, printed materials (policy guidebook, fact sheets, sun protection products catalogue, and employee training), and a Web site (intervention). The program will be evaluated in a group-randomized pretest-posttest two-group trial with 140 districts as the unit of analysis. District policies on sun protection of students and employees will be obtained at pretest and posttest and coded to create composite policy scores. Samples of 980 adminstrators will be surveyed by telephone at pretest and posttest to measure secondary policy and environment outcomes, theoretical mediators and moderators, and district policy-making process. Also, 980 school principals will be pretested and posttested to determine whether policy and environment changes are communicated to and implemented at schools, and how policies are enforced. On-site observations of sun protection policies, environmental features, and employee clothing will validate principal reports
Keywords: Actinic Rays; Active Follow-up; Administrator; Adopted; Adoption; Behavior; behavior change; California; Cancer Cause; Cancer Etiology; Cataloging; Catalogs; CDC; Centers for Disease Control; Centers for Disease Control (U.S.); Centers for Disease Control and Prevention; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child Behavior; Childhood; Clothing; Clothings; Code; Coding System; Communication; Communities; Complex; cost; County; Death; Deep; Depth; design; designing; Development; Diagnosis; Diffuse; Diffusion of Innovation; E-Mail; Education; Educational aspects; Effectiveness; Electronic Mail; Email; Employee; Environment; environmental change; Environmental Policy; experience; follow-up; guidebooks; Guidebooks; Guidebooks (PT); Guidebooks [Publication Type]; Guidelines; Health; Health Campaign; Health Promotion; Human Resources; Incidence; Individual; Individual Differences; innovate; innovation; innovative; Institutes; Internet; Intervention; Intervention Strategies; interventional strategy; Interview; Literature; Los Angeles; Malignant Melanoma; Malignant Skin Neoplasm; Malignant Tumor of the Skin; Manpower; Measures; Mediating; Mediator; Mediator of Activation; Mediator of activation protein; melanoma; Melanoma and Non-Melanoma Skin Cancer; Methods; metropolitan; Non-Hispanic; nonmelanoma skin cancer; Not Hispanic or Latino; Numbers; Organizational Change; Organizational Innovation; Outcome; pediatric; personnel; Persons; Phone; Physicians; Policies; Policy Making; prevent; Prevent skin cancer; preventing; Prevention; Prevention of Skin Cancer; Prevention strategy; Preventive strategy; Printing; Procedures; Process; Program Effectiveness; programs; Programs (PT); Programs [Publication Type]; Public Health; public health medicine (field); randomisation; randomization; Randomized; randomly assigned; Rate; Reporting; Research Resources; Resources; Risk; Safety; Salutogenesis; Sampling; Schools; Score; Site; Skin Cancer; skin cancer prevention; Skin Cancer, Including Melanoma; Skin Cancer, Non-Melanoma; Skin Carcinoma; Societies; solar exposure; Structure; Students; Sun Exposure; sun protection policies; sun safe policies; Sun/Ultra-Violet Rays; Sunlight; Survey Instrument; Surveys; System; System, LOINC Axis 4; Telephone; Testing; theories; Training; trend; ultraviolet light; ultraviolet radiation; Ultraviolet Rays; United States Centers for Disease Control; United States Centers for Disease Control and Prevention; Universities; usability; UV radiation; web; world wide web; WWW
Project start date: 2004-09-30
Project end date: 2011-06-30
Budget start date: 1-JUL-2008
Budget end date: 30-JUN-2011
5R01CA100285-06 (2008): $755068
ACCOMMODATION AND THE DEVELOPMENT OF REFRACTIVE STATE
B David
State College Of Optometrycity: New York country: United States (us)
Grant 5R01EY011228-15 from National Eye Institute
Abstract: Myopia (nearsightedness) is on the rise around the world and in the United States. It affects tens-of-millions of Americans and, in progressive forms, is a leading cause of blindness. Earlier research with humans and experimental animal models has shown that the postnatal development of the eye and its refractive state involves a combination of genetic and visual factors. The rising incidence of myopia in humans has been associated with increases in literacy and levels of education, although the nature of the relationship is unclear and predicting who will become myopic is difficult. Research using animal models has established that visual stimuli related to retinal defocus are used to regulate eye growth and refractive state. The principal aim of this proposal is to explore the spatial and temporal integration of the visual signal that drives eye growth. We will examine how eye shape, the optical quality of the eye, and accommodation interact and may affect that signal. An additional line of investigation will examine how visual acuity is affected by experimental manipulations that alter eye growth and refractive state. The specific aims and questions being asked in this proposal are the following Aim 1. Characterize changes in eye shape, peripheral refraction, and off-axis optics during experimentally-induced refractive errors. Do differences in eye shape, and the peripheral refractive states associated with them, make the eye more susceptible to developing a refractive error? How, in turn, is eye shape affected by the development of refractive errors? Aim 2. Examine the spatial integration of peripheral retinal defocus for the regulation of eye size and refractive state. Is refractive state in the retinal periphery important for the visual control of eye growth and the development of refractive error? Is there local eye growth in the primate, and can it influence axial length and refractive state on-axis? Aim 3. Examine the effects of brief periods of controlled focus on the regulation of eye size and refractive state. How does the primate eye temporally integrate visual defocus signals that affect eye growth? How does emmetropization function given that accommodation alters retinal defocus from moment-to-moment and potentially removes hyperopic defocus cues? Aim 4. Correlate changes in visual acuity with induced changes in eye growth and refractive state. Do lens-induced refractive changes affect visual acuity in marmosets? Can compensation for visually induced defocus take place without changes in visual acuity?
Keywords: Address; Adverse effects; Affect; American; Ametropias; Animal Model; Animals; Blindness; Callithrix; Clinical; Cues; design; Development; Educational Background; emmetropization; experience; Experimental Animal Model; Eye; Eye Development; Financial compensation; Genetic; Growth; Growth and Development function; Human; Image; Incidence; Investigation; Length; lens; literacy; Magnetic Resonance Imaging; Measures; Modeling; Myopia; Nature; Optics; Peripheral; postnatal; prevent; Primates; programs; Refractive Errors; Regulation; Reporting; Research; Research Personnel; research study; response; Retina; Retinal; Risk Factors; Scanning; Shapes; Signal Transduction; spatial integration; United States; Visual; Visual Accommodation; Visual Acuity; visual control; visual process; visual processing; visual stimulus
Project start date: 1995-07-01
Project end date: 2012-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5R01EY011228-15 (2011): $346643
LYMPHAGIOGENESIS AND LYMPHATIC METASTASIS IN PROSTATE CANCER
B David, Dir, Ctr For Applied Mol Med
University Of California Los Angelescity: Los Angeles country: United States (us)
Abstract: Metastasis is the main cause of prostate cancer mortality. The support of prostate cancer SPORE Developmental Program in the past two years has enabled us to investigate the contribution of lymphangiogenesis to prostate cancer metastasis. We discovered that elevated pro-lymphangiogenic factor (VEGF-C) in the prostate tumors induces the growth of lymphatic vessels, which in turn facilitates tumor cell dissemination to regional lymph nodes. Moreover, the lymphatic dissemination process also greatly impacts metastasis to distal organs, such as lung and liver. Hence, our current working hypothesis suggests that lymphatic circulation is a preferred route of dissemination and that regional lymph nodes provide a reservoir from which subsequent dissemination to distal sites occurs. This proposal will investigate this hypothesis further. In particular, we will examine in detail the connection between lymphangiogenic pathways and metastasis in prostate cancer patients, focusing our molecular and histological analyses on the patients with node positive and recurrent disease. Using many relevant preclinical models developed at our institution, our efforts will be directed towards addressing two areas of great need, i.e. therapeutic intervention and diagnostic imaging of nodal metastasis. We will investigate therapeutic effects of blockading the lymphangiogenic tyrosine kinase receptor by specific VEGFR3 antibody, and Sorafenib, a multi-kinase inhibitor known to target both VEGFR3. Molecular imaging technologies will be applied to monitor the impact of these interventions on the metastatic process. We will also evaluate the ability of a prostate-specific imaging adenoviral vector to specifically detect nodal metastases in preclinical models. In addition, we will develop and assess potential circulating surrogate markers for the lymphangiogenic pathways. The lack of such markers has halted progress in anti-metastatic treatment. The prostate cancer SPORE program at University of Washington is initiating a phase II neoadjuvant clinical trial of Sorafenib in patients with high- risk localized prostate cancer. In a collaborative effort with this study, we will obtain blood and tissue samples from the patients to analyze the molecular activity of Sorafenib against the VEGFR3 pathway and tumor lymphangiogenesis axis. The myriad of approaches taken in this proposal is directed towards improving the clinical management of metastasis stage of prostate cancer in the future
Keywords: Address; Adenovirus Vector; angiogenesis; Animals; Antibodies; antibody inhibitor; Area; autocrine; base; BAY 54-9085; Biological Assay; Blood Circulation; Blood specimen; Blood Vessels; Cancer Patient; Clinic; Clinical Management; Clinical Research; Clinical Trials; clinically relevant; Complex; density; Development; Diagnostic Imaging; Disease; Disease Progression; Distal; Evaluation; Extracapsular; Functional Imaging; Future; Gleason Grade for Prostate Cancer; Growth; Hand; high risk; Human; Image; imaging modality; Imaging technology; Immune system; improved; inhibitor/antagonist; Institution; interest; Intervention; Investigation; kinase inhibitor; Life; Liver; Lung; lymph nodes; Lymphangiogenesis; Lymphatic; lymphatic circulation; Lymphatic Metastasis; Lymphatic vessel; macrophage; Malignant neoplasm of prostate; metastatic process; Metastatic Prostate Cancer; Modality; Modeling; Molecular; molecular imaging; molecular marker; Monitor; Mortality Vital Statistics; Mus; Neoadjuvant Therapy; Neoplasm Metastasis; neoplastic cell; Nodal; novel; Organ; Palpable; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phosphotransferases; Positive Lymph Node; Positron-Emission Tomography; Pre-Clinical Model; Process; prognostic indicator; programs; Prostate; Prostatectomy; Prostatic Neoplasms; Receptor Protein-Tyrosine Kinases; Recurrence; Recurrent disease; Reporter Genes; Reporting; Research Personnel; research study; Route; Sampling; Seminal Vesicles; Sentinel Lymph Node; Signal Transduction; Site; Source; Staging; Surrogate Markers; System; Testing; Therapeutic Effect; Therapeutic Intervention; Time; Tissue Microarray; Tissue Sample; tumor; Tumor Angiogenesis; tumor progression; Universities; Use Effectiveness; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factors; vector; Washington; Work; Xenograft Model
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5P50CA092131-10_0003 (2011): $239188
5P50CA092131-09_0003 (2010): $239188
THE CHEMISTRY OF LITHIUM AMIDES
B David
Cornell University Ithacacity: Ithaca country: United States (us)
Grant 5R37GM039764-23 from National Institute Of General Medical Sciences
Abstract: Lithium amides are some of the most important reagents in organic synthesis. The pharmaceutical industry uses these reagents frequently and on very large scales. In this proposal we describe efforts to understand the underlying chemistry of the most important reactions of lithium amides with the goal of improve existing synthetic methods and developing new ones. We continue to focus on the three most important amides lithium hexamethyldisilazide, lithium diisopropyiamide, and lithium tetramethylpiperidide. The case studies to be investigated include (1) ketone and ester enolizations; (2) imine lithiations;(3) epoxide eliminations; (4) ortholithiations; (5) N-alkylations; (6) N-arylations; and (7) N-acylations. These case studies touch on the preponderance of the chemistry of lithium amides. Each poses unique questions and offers unique opportunities. Through an understanding of the mechanistic principleswe learn to control reactivity and selectivity. We use a uniquely integrated approach allows a combination of NMR spectroscopy, solution kinetics, and computational chemistry are brought to bear on the problems. By bringing synthetic organic, physical organic, analytical, and computational chemistry together under one roof, we reveal the consequences of soIvation and aggregation with an unprecedented clarity
Keywords: Academia; Acetals; Acids; Age; Alkylation; Amides; Analytical Chemistry; Back; base; Case Study; Chemistry; Clinical Trials; Complex; computational chemistry; Data; Development; drug candidate; drug development; Drug Industry; drug synthesis; Epoxy Compounds; Esters; Event; Feedback; Fostering; Glean; Goals; Imines; improved; In Situ; Investigation; ketal; Ketones; Kilogram; Kinetics; Learning; Ligands; Lithium; lithium diisopropylamide; lithium hexamethyldisilazide; Methods; Modeling; N acylation; NMR Spectroscopy; Organic Chemistry; Organic Synthesis; Pathway interactions; Pharmacologic Substance; Play; Process; Property; Reaction; Reagent; Relative (related person); Renaissance; Role; Solutions; Solvents; Staging; Structure; Techniques; Time; Touch sensation; Ursidae Family
Project start date: 1989-04-01
Project end date: 2014-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5R37GM039764-23 (2011): $325839
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