Robert Stanley Sherwin - US grants

The proposed project is designed to examine the role of anti-insulin hormone actions and interactions in the pathogenesis of stress-induced changes in glucose and protein regulation in normal man and diabetic ketoacidosis. Recent studies from our laboratory have demonstrated that physiologic increments in glucagon, epinephrine and cortisol interact synergistically in the normal dog so as to produce marked hyperglycemia. The synergistic nature of the hormone interactions suggests that stress hyperglycemia cannot be ascribed to a single hormone, but is a consequence of the combined elevations of several hormones. In this project we will extend these observations by examining whether hormonal synergism can account for: 1) stress-hyperglycemia in normal man; 2) excessive protein wasting and gluconeogenesis in severe illness; 3) counterregulation of insulin hypoglycemia and 4) decompensation of glucose and ketone regulation in diabetes mellitus. Intravenous infusion of anti-insulin hormones (glucagon, epinephrine, cortisol and growth hormone) will be administered in doses designed to stimulate changes observed in severe stress or diabetic ketoacidosis. A radioactive glucose tracer will be infused to quantitate hepatic glucose production and glucose production and glucose uptake by peripheral tissues (e.g. muscle). The metabolic response to individual hormones will be compared to those observed when these hormones are given in combination. The influence of diabetes and insulin treatment (short and long-term) on the action of anti-insulin hormones will be determined. In additional studies we will examine the factors influencing the hepatic response to glucagon and epinephrine, the effect of small changes in blood epinephrine concentration on glucose tolerance, the effect of cortisol on gluconeogenesis, the insulin antagonistic effects of epinephrine on peripheral tissues, and the effect of somatostatin on hepatic sensitivity to glucagon and on protein absorption. This project will thus provide data regarding the hormonal basis of stress- and diabetes-induced alterations in glucose, fat and protein metabolsim. Such data of particular importance in the treatment of diabetes and protein-wasting conditions.

The Yale Diabetes Endocrinology Research Center was established in the Spring of 1993 with the goal of promoting research in diabetes and related metabolic and endocrine disorders at the University. The Center brings together a multidisciplinary group of nearly 100 independent member scientists as well as professional supporting staff, new investigators and research trainees from the Departments of Internal Medicine, Pediatrics, Immunobiology, Biology, Cell Biology, Molecular Biophysics and Biochemistry, Genetics, Molecular and Cellular Physiology, Pharmacology, Surgery, Orthopedics, Neurosurgery, Neurology, Dermatology, Obstetrics and Gynecology, Diagnostic Radiology and from the Schools of Public Health and Nursing. The Scope of the research activities of the membership is very broad, ranging from basic molecular biology to whole body clinical physiology in diabetic patients. The members, however, share a common interest in research that is related to diabetes or is fundamental to understanding its pathogenesis or for the development of new treatment strategies. The design of the Yale DERC is aimed at developing an infrastructure that could serve as a catalyst to stimulate innovate research. The cornerstone of the Center is its six Research Cores that provide funded basic and clinical investigators with the opportunity to more efficiently utilize resources and expand the scope of their research programs. The Clinical Metabolism Core facilitates metabolic research in patients, whereas the Molecular, Transgenic, Animal Genetics, Animal Physiology and Cell Biology Cores that comprise the Animal Resource Program offer investigators the tools to create and test novel animal models starting from the molecule and ending with the biological outcomes. The Administrative Core oversees the operation of the Center, its Pilot/Feasibility Project and Enrichment Programs, and helps to coordinate patient-based research in diabetes. The goals of the DERC are to: 1) stimulate multidisciplinary interactions, particularly between basic and clinical scientists: 2) efficiently organize time consuming and/or costly techniques through core facilities the enhance the productivity of investigators conducting research in diabetes related areas; 3) promote new research program through pilot feasibility projects; 4) enhance the quality of research training, and 5) create an institutional environment that amplifies and expands research efforts in diabetes or related metabolic and endocrine disorders.

The Yale Diabetes Endocrinology Research Center brings together a multidisciplinary group of independent principal investigators as well as professional supporting staff, young investigators and research trainees from the Departments of Internal Medicine, Pediatrics, Immunobiology, Cell Biology, Molecular Biophysics and Biochemistry, Genetics, Pharmacology, Physiology, Pathology, Surgery, Obstetrics and Gynecology, Biology, Neurology, Neurosurgery, Psychology and from the Schools of Nursing and Public Health. The research activities of the Center members are broad and range from basic cellular and molecular biology to whole body clinical physiology in diabetic patients. The members are, however, linked by their common interest and active participation in research dealing with diabetes mellitus or related metabolic and endocrine disorders. The cornerstone of the Center is its Research Cores that provide funded scientists with the opportunity to more efficiently utilize resources and to expand the scope of their programs. The Cores focus on three major themes: 1) Molecular Biology; 2) Cell Biology and Immunobiology, and 3) Clinical Metabolism. An Administrative Core oversees the operation of the Center and its Pilot and Feasibility Project Program and helps to coordinate patient-based diabetes research throughout the institution. The principal goals of the Center are to: 1) stimulate multidisciplinary interactions, particularly between basic and clinical scientists; 2) efficiently organize time consuming and/or costly techniques through Core facilities to enhance the productivity of investigators conducting research in diabetes or in related areas; 3) promote new research programs through pilot/feasibility projects; 4) enhance the quality of research training, and 5) create an institutional environment that amplifies and expands research efforts in diabetes or related metabolic and endocrine disorders.

The study involves the novel use of microdialysis in human skeletal muscle and adipose tissue.

Two patients were referred to the GCRC this year to determine whether they had diabetes and were insulin resistant. They were ruled out for both.

A central hypothesis of this proposal is that insulin-dependent diabetes (IDDM) begins with a beta cell targeted attack that unmasks a variety of beta cell antigens leading to the recruitment of distinct population of T-cells that either perpetuate the destructor process or protect against the immune response. According to this view, it is the balance between these opposing influences that determines whether or not IDDM is expressed. The overall goal is to elucidate the molecular mechanisms used by an insulin-reactive cloned CD4T cell line that presents the development of diabetes in NOD mice. this clone, designed 2H6, CD4 produces INFgamma, TNFalpha, as well as TGF beta, but not IL-4, IL-10 or Il-2 i.e., it is a unique "Th1-like" cell. Labeling experiments show that this protective clone trafficks to the islets where it blocks the accumulation of diabetogenic splenocytes with the islet. In vitro experiments indicate that the protective clone or supernatant derived from it inhibits proliferation and the release of IL-2 by a variety of NOD-derived T cells. The specific aims of this proposal are: 1. To examine the mechanisms used by the protective insulin-reactive T cell clone to inhibit the function of diabetogenic T cells. In vitro studies will examine the specificity and nature of the inhibitory activity and its effect on T cell function. The contribution of TGFbeta to the clone's immunoregulatory activity will be examined. In vivo studies will examine the mechanisms used by the protective cells to target the islet, the importance of islet targeting for disease protection, and the capacity of the clone to alter the expression of a variety of cytokines, constimulatory and adhesion molecules after adoptive transfer of (a) diabetogenic splenocytes or () GAD-reactive or insulin-reactive diabetogenic T cells into NOD/SCID mice. We will test the hypothesis that the insulin specific TCR allows the clone to target the islet where it locally releases immunoregulatory factors, specifically TGFbeta that blocks the islet entry and/or activation of diabetogenic T cell. 2. To develop a TCR transgenic NOD mouse derived from the insulin-reactive protective clone and study the natural history of disease expression as well as the biological function of T cells derived from such mice. Alterations in T cell function will be evaluated after the mice are immunized with insulin B chain peptide using a variety of antigenic routes and doses. We will explore modes of activation that promote the appearance of a protective phenotype. These studies should offer insights into the mechanisms for the diabetes protective effects of insulin therapy and could aid in development of a vaccine against the disease.

The purpose of the study is to determine in subjects with Type 1 & 2 diabetes mellitus currently receiving insulin therapy: 1) whether glycemic control can be achieved at least as effectively with an insulin regimen involving pre-meal inhaled insulin plus a single bedtime Ultralente injection as with a conventional subcutaneous insulin regimen involving 2-3 injections per day; and 2) the toleration and safety of inhaled insulin therapy and its effects, if any, on measures of pulmonary function.

Immune responses in peripheral blood of newly diagnosed patients with Type I diabetes will be studied. The goal of the study is to isolate potentially pathogenic T cells from peripheral blood of newly diagnosed diabetic patients and to examine their characteristics in vivo.

physiology; diabetes mellitus; biomedical facility; glucose clamp technique; animal breeding; genetically modified animals; glucose tolerance test; fluorescent dye /probe; serology /serodiagnosis; surgery;

hypothalamic pituitary adrenal axis; corticotropin releasing factor; autonomic disorder; hypoglycemia; pathologic process; hormone regulation /control mechanism; norepinephrine; cortisol; endocrine pharmacology; epinephrine; patient oriented research; laboratory rat; human subject; clinical research;

neurophysiology; diabetes mellitus; hypoglycemia; brain; oxygen transport; insulin dependent diabetes mellitus; brain metabolism; patient oriented research; human subject; functional magnetic resonance imaging; clinical research;

glucose metabolism; blood glucose; epilepsy; brain metabolism; neurotransmitter metabolism; neurotransmitters; lactates; hippocampus; frontal lobe /cortex; glutamates; glucose; patient oriented research; human subject; clinical research; microdialysis;

DESCRIPTION (provided by applicant): Hypoglycemia is the major factor limiting the use of effective insulin treatment regimens in type I diabetes (T1DM). In some patients the severity as well as the inability to detect hypoglycemia (hypoglycemia unawareness) has sufficient clinical impact to warrant consideration for islet transplantation, the primary indication for the procedure. Little is known about the CNS adaptations that influence brain metabolism and cognitive function in response to hypoglycemia in unaware patients. This proposal is a multicenter, multidisciplinary clinical trial that brings together a group of clinical and basic scientists at Yale with a strong track record of research in the area of hypoglycemia and brain metabolism and a group of the most experienced islet transplant surgeons in North America. The primary goal is to better define the impact of recurrent hypoglycemia and hypoglycemia unawareness on CNS function and metabolism in T1DM patients with severe hypoglycemia unawareness being considered for islet transplantation. For this purpose, we will apply state-of-the-art MRS techniques to study patients selected to undergo islet cell transplantation because of a history of severe hypoglycemia and hypoglycemia unawareness at the University of Alberta, Edmonton, the University of Miami, and the University of Minnesota. We will test the hypothesis, based on our preliminary data in intensively treated T1DM patients and rodent models, that these patients show upregulation of monocarboxylic acid transport which serves to protect basic brain functions, but may be inadequate for optimal cognitive performance during acute hypoglycemia. The specific aims are: 1) To determine the long-term effect of severe recurrent hypoglycemia and hypoglycemia unawareness in patients with T1DM on: a) brain metabolism, including monocarboxylic acid transport, brain glucose levels and TCA cycle activity; b) cognitive function, and c) counterregulatory hormone secretion and symptoms during acute hypoglycemia. These data will provide new insights into changes in brain metabolism in T1DM patients with hypoglycemia unawareness, and would set the stage for future studies designed to assess the impact of restoring normoglycemia (via islet transplantation) on these.

bioengineering /biomedical engineering; community; university

This subproject represents an estimate of the percentage of the CTSA funding that is being utilized for a broad area of research (AIDS research, pediatric research, or clinical trials). The Total Cost listed is only an estimate of the amount of CTSA infrastructure going towards this area of research, not direct funding provided by the NCRR grant to the subproject or subproject staff. DESCRIPTION (provided by applicant): The Yale Center for Clinical Investigation (YCCI) was created to provide a "home" for training the next generation of clinical investigators. Key programmatic goals are to 1) attract highly talented students and junior faculty across medicine, nursing, public health, biological sciences and biomedical engineering;and train them in the use of state-of-the-art research tools;give them the skills to work within complex research teams;and support their professional development;and 2) foster the translation of disease-related discoveries from the laboratory into the clinic and then the community by: stimulating the creation of interdisciplinary teams;making available state-of-the-art core facilities and expanded biostatistical and bioinformatics resources;establishing organizational and regulatory infrastructure for clinical studies;and forging new partnerships that will integrate community leaders, physicians, and health centers and encourage participation in research. Participating institutions include the Schools of Medicine, Nursing, and Public Health, the department of Biomedical Engineering and the Graduate Programs in Biological and Biomedical Sciences. The Junior Faculty Scholars award program and the Investigative Medicine program (IMP) are central to YCCI's education and training efforts. IMP is a unique doctoral program that offers Ph.D. degrees in Health Sciences Research to highly qualified M.D. fellows embarking on careers in translational or clinical research and the junior faculty scholars program is a career development program. YCCI has also created a Society of Mentors who participates actively in the training and nurturing of the YCCI Scholars. Pilot and feasibility (P&F) grants will be awarded for: 1) interdisciplinary translational team research;2) development of novel methodologies;3) Use of Core (incl imaging) technologies;and 4) community-based research. YCCI will cluster research cores around common themes, including: imaging;genomics and proteomics;cell and tissue based tech;Integrated metabolics;cognition and biobehavior;and animal models. The Office of Research Services will provide robust facilities and resources for regulatory, biostatistical, bioinformatics, recruitment and other support services. YCCI will have an office to coordinate the University's efforts to address health issues facing our community and our national community. PUBLIC HEALTH RELEVANCE (provided by applicant): This research has direct relevance to public health in that its goals are to facilitate clinical research, including by training the next generation of clinical researchers that will lead to better treatments for human disease and better health outcomes.

Infrastructure; Research; Research Infrastructure

The Yale Center for Clinical Investigation (YCCI) was created to provide a "home" for training the next[unreadable] generation of clinical investigators. Key programmatic goals are to 1) attract highly talented students and[unreadable] junior faculty across medicine, nursing, public health, biological sciences and biomedical engineering; and[unreadable] train them in the use of state-of-the-art research tools; give them the skills to work within complex research[unreadable] teams; and support their professional development; and 2) foster the translation of disease-related[unreadable] discoveries from the laboratory into the community by: stimulating the creation of interdisciplinary teams;[unreadable] making available state-of-the-art core facilities and expanded biostatistical and bioinformatics resources;[unreadable] establishing organizational and regulatory infrastructure for clinical studies; and forging a dynamic new[unreadable] partnership that will integrate community leaders, physicians, and health centers. Participating institutions[unreadable] include the Schools of Medicine, Nursing, Public Health, the Department of Biomedical Engineering and[unreadable] Graduate Programs in Biological and Biomedical Sciences. The Investigative Medicine program (IMP) is[unreadable] central to YCCI's education and training efforts. It is a unique doctoral program that offers Ph.D. degrees in[unreadable] Health Sciences Research to highly qualified M.D. fellows embarking on careers in translational or clinical[unreadable] research. IMP will be expanded with CTSA support to include nursing, public health, biological sciences,[unreadable] and MD-PhD students. YCCI has also created a Society of YCCI Faculty Mentors who will participate[unreadable] actively in the training and nurturing of the students and junior faculty members identified as YCCI Clinical[unreadable] Scholars. Pilot and feasibility (P&F) grants will be awarded for 1) junior faculty; 2) interdisciplinary[unreadable] translational teams; 3) new technologies; and 4) community-based projects. YCCI will cluster research[unreadable] cores around common themes.including: imaging; specimen analysis; physiology; cognition and behavior;[unreadable] drug development; and cell therapy. A new Office of Research Services will provide facilities for "one-stop"[unreadable] shopping for regulatory, biostatistical, bioinformatics, recruitment and other support services. YCCI will have[unreadable] an office to coordinate the University's efforts to address health issues facing our community. The[unreadable] University's decision to immediately provide substantial support to establish the YCCI reflects its strong[unreadable] commitment to an innovative redesign of our clinical and translational research activities.

The Yale Diabetes Research Center (DRC) was established in 1993 with the goal of promoting research in diabetes and related metabolic and endocrine disorders at the University. The DRC brings together a multidisciplinary group of over 100 member and associate member scientists as well as professional supporting staff, new investigators and research trainees from in 16 departments and 4 colleges or schools at Yale University The scope of the research activities ofthe membership is very broad, ranging from basic molecular biology to whole body physiology and the treatment of diabetic patients. The members, however, share a common interest in research that is related to diabetes and metabolism or is fundamental to understanding its pathogenesis or for the development of new treatment strategies. The design of the Yale DRC is aimed at developing an infrastructure that could serve as a catalyst to stimulate innovative diabetes-related research. The cornerstone of the DRC is its five Research Cores that provide funded basic and clinical investigators with the opportunity to more efficiently utilize resources and expand the scope of their research programs. The Clinical Metabolism and the Diabetes Translational Cores facilitate metabolic research in patients, whereas the Molecular Genetic Mouse Core, Physiology and Cell Biology Cores that comprise the more basic science focus of the Center offer investigators the tools to create and test novel animal models starting from the molecule and ending with biological outcomes. The Administrative Core oversees the operation of the Center, its Pilot/Feasibility Project and Enrichment Programs, and helps to coordinate patient-based research in diabetes. The goals of the DRC are to: 1) stimulate multidisciplinary interactions, particulariy between basic and clinical scientists; 2) encourage established investigators not presently working in diabetes-related areas, to bring their expertise to bear on problems relevant to diabetes; 3) efficiently organize time consuming and/or costly techniques through Core facilities to enhance the productivity of investigators conducting research in diabetes related areas; 4) promote new research programs through pilot feasibility projects; 5) enhance the quality of research training, and 6) create a stimulating institutional environment that enhances research efforts by its members to develop new strategies to prevent and treat diabetes and related metabolic disorders at the local and national level.

DESCRIPTION (provided by applicant): In the recent Clinical Translational Science Award strategic planning process and in meetings with representatives for various NIH Institutes, the enhancement and improvement in clinical research management at all stages has been identified as a key goal of the program and for the national research agenda. In this application we are proposing a series of annual conference workshops that will serve as a critical resource in facilitating and advancing interdisciplinary and translational clinical research nationally through promotion of scientific exchange among investigators, regulatory professionals and regulators, IRB administrators, industry, and NIH. The task of planning for and reporting on the workshops will be delegated to the national CTSA Clinical Research Management (CRM) Taskforce and its planning committee. The overall mission of the CRM is to: Make recommendations regarding standard metrics for the CTSA consortium;Develop methodology and specific, practical interventions for implementation at the CTSA sites;Create networks of partners and mentor-mentee relationships;Develop objective evidence of improvement;and Publish information to enable broad application of lessons learned in the scientific community. The conference workshops are geared towards 1) identifying issues which impede the clinical research development process;2) developing innovative strategies for addressing problems encountered;and 3) modifying, implementing and sharing best practices nationally. This information exchange will promote improved methodology for process control, implementation of revised systems for protocol processing, and enterprise-wide use of metrics and information exchange that will allow the CTSA centers to serve as model for reducing regulatory burdens both within sites and between collaborating sites. The 2009 conference will be held on the NIH Campus at the Natcher Building, which includes a 1,000-seat auditorium, and a state-of- the-art multiuse Conference Center with nine conference rooms, and will include networking opportunities, use of posters to provide individual site data and processes and lessons learned, and podium lectures to demonstrate the use of expert advice in re-structuring protocol processing and clinical trials management. The PI, Dr. Robert Sherwin, M.D., will oversee the activities, with overall administration and planning directed by committee Chairs, Dr. Michael Joyner and Ms. Tesheia Johnson who will have responsibilities of chairing the planning meeting, setting milestones to achieve conference timelines, and reporting after the conference. Dr. Daniel Rosenblum, NCRR, and the CTSA coordinating center will provide critical organization infrastructure with responsibilities for scheduling and arranging the conference, circulating agendas and meeting materials, and overall administrative support to the group. PUBLIC HEALTH RELEVANCE: The NIH is dedicated to improving public health by conducting and funding medical research. The information exchange at this conference will promote improved methodology for process control, implementation of revised systems for protocol processing, and enterprise-wide use of metrics with the overall goal of reducing regulatory burdens that hinder Medical research.

This subproject represents an estimate of the percentage of the CTSA funding that is being utilized for a broad area of research (AIDS research, pediatric research, or clinical trials). The Total Cost listed is only an estimate of the amount of CTSA infrastructure going towards this area of research, not direct funding provided by the NCRR grant to the subproject or subproject staff. Membership on CTSA Consortium Management Group

DESCRIPTION (provided by applicant): Adolescent obesity is fueling the increase in the prevalence of T2DM in youth. Obese adolescents on their path to developing prediabetes/T2DM present with severe peripheral insulin resistance, marked hyperinsulinemia and relatively low leptin levels. These abnormal adiposity related signals may not only favor the development of peripheral but also central insulin resistance, thereby promoting the perpetuation of obesity and its associated metabolic complications. Dr. Caprio's research is mainly in peripheral insulin and glucose metabolism in obese adolescents. However, there are a number of basic, clinical, physicist and neurobehavioral scientists at Yale actively working in the field of Central Regulation of Energy Metabolism. Our goal is to bring together these various Yale-based investigators to explore whether obese adolescents with insulin resistance and relative low leptin levels exhibit functional alterations of the neuronal circuits involved in the regulation of energy metabolism and food seeking behaviors. We here propose a series of hypotheses-driven studies which will be performed by a multidisciplinary team of investigators from Internal Medicine, Diagnostic Radiology, Psychiatry and Pediatrics, using an integrated team approach. The hypotheses are: 1- The hypothalamic fMRI signal after the ingestion of glucose is attenuated in obese adolescents with insulin resistance, relative low levels of leptin and marked hyperinsulinemia compared to age, gender and puberty matched obese sensitive and lean adolescents. 2- Fructose consumption has differential effects when compared to glucose on the functional connections between the hypothalamus and other brain regions implicated in feeding behavior and that these differential effects are magnified in obese adolescents. 3- Functional connectivity between brain regions of the reward system implicated in the response to specific food cues are altered in the obese adolescents and this is related to hyperinsulinemia/insulin resistance. The team will use functional connectivity fMRI mapping to examine the connections between specific appetitive regions such as the dorsal striatum and caudate nucleus and the hypothalamus. In particular, we will examine how connectivity within these networks changes as a function of brain fuel, and we will look for differential network responses to the fuels between lean and obese adolescents with extreme ends of the insulin resistance spectrum. Understanding the differential response of centers regulating the homeostatic and non-homeostatic neuronal circuits to common highly palatable foods (glucose) in obese adolescents may translate into the development of more effective weight gain and diabetes prevention program in youth.

DESCRIPTION (provided by applicant): The Norepinephrine Transporter: A Novel Target for Imaging Brown Adipose tissue Abstract Obesity, and more specifically insulin resistance is characterized by impaired energy expenditure associated adaptive thermogenesis. Adaptive thermogenesis in animals involves activation of brown adipose tissue (BAT), a tissue previously thought to completely regress in adult humans. Biopsy-confirmed BAT in adult humans has revived interest in discovering whether dysfunction in regulation and/or activity of BAT contributes to the pathogenesis of obesity. New methodologies are needed to increase our knowledge of BAT in humans. The purpose of this application is to test a new, mechanistically driven approach using positron emission tomography (PET) imaging of BAT in humans. BAT is strongly innervated and regulated by the sympathetic nervous system. We propose to use a structural feature of the sympathetic nervous system, and image the norepinephrine recycling component, designated the norepinephrine transporter (NET). For this purpose, we will utilize a recently developed, highly selective NET ligand for PET imaging, ((S,S)-[11C]O-methylreboxetine) ([11C]MRB). PET imaging NET has the advantage over [18F]-2-fluoro-deoxy-D-glucose ([18F]FDG) currently in use, because unlike [18F]FDG, it is more specific, and should allow detection of non-stimulated BAT. Our general hypothesis is that the [11C]MRB PET imaging approach will provide a non-stimulated target for BAT that is proportional to BAT mass, but also demonstrates up-regulation with activation of adaptive thermogenesis due to environmental cold exposure. Our aims are divided into both animal, and human experiments. The animal work will directly compare the [11C]MRB and [18F]FDG tracers in awake rats under room temperature and mild cold (40C) conditions for their relationship to interscapular BAT dimensions, mass, and intensity of label. Moreover, we will examine interscapular BAT during in vivo PET imaging after both environmental conditions for [11C]MRB labeling kinetics. Human work will both validate the [11C]MRB PET strategy against the current gold standard of [18F]FDG labeling, using both room temperature and mild cold exposure, as well as provide a preliminary gender comparison of BAT, also using the [11C]MRB PET strategy with room temperature and mild cold exposures. By targeting a primary regulatory system component of BAT, NET, we are establishing a basis for future mechanistic studies of BAT function/dysfunction in obesity and diabetes, as well as for therapeutic approaches for these disorders. PUBLIC HEALTH RELEVANCE: The purpose of this application is to test a new, mechanistically driven approach to image brown adipose tissue (BAT) by targeting its primary regulatory system, the norepinephrine recycling component, designated the norepinephrine transporter (NET). The results from the validation study of NET-PET against FDG-PET will establish a basis for future mechanistic studies of BAT function/dysfunction in obesity and diabetes, as well as for therapeutic approaches for these disorders.

The Yale Center for Clinical Investigation (YCCI) was created to provide a home for training the next generation of clinical investigators. Key programmatic goals are to 1) attract highly talented students and junior faculty across medicine, nursing, public health, biological sciences and biomedical engineering; and train them in the use of state-of-the-art research tools; give them the skills to work within complex research teams; and support their professional development; and 2) foster the translation of disease-related discoveries from the laboratory into the clinic and then the community by: stimulating the creation of interdisciplinary teams; making available state-of-the-art core facilities and expanded biostatistical and bioinformatics resources; establishing organizational and regulatory infrastructure for clinical studies; and forging new partnerships that will integrate community leaders, physicians, and health centers and encourage participation in research. Participating institutions include the Schools of Medicine, Nursing, and Public Health, the department of Biomedical Engineering and the Graduate Programs in Biological and Biomedical Sciences. The Junior Faculty Scholars award program and the Investigative Medicine program (IMP) are central to YCCI's education and training efforts. IMP is a unique doctoral program that offers Ph.D. degrees in Health Sciences Research to highly qualified M.D. fellows embarking on careers in translational or clinical research and the junior faculty scholars program is a career development program. YCCI has also created a Society of Mentors who participate actively in the training and nurturing of the YCCI Scholars. Pilot and feasibility (P&F) grants will be awarded for: 1) interdisciplinary translational team research; 2) development of novel methodologies; 3) Use of Core (ind imaging) technologies; and 4) community-based research. YCCI will cluster research cores around common themes, including: imaging; genomics and proteomics; cell and tissue based tech; Integrated metabolics; cognition and biobehavior; and animal models. The Office of Research Services will provide robust facilities and resources for regulatory, biostatistical, bioinformatics, recruitment and other support services. YCCI will have an office to coordinate the University's efforts to address health issues facing our community and our national community.

DESCRIPTION (provided by applicant): In the recent Clinical Translational Science Award strategic planning process and in meetings with representatives for various NIH Institutes, the enhancement and improvement in clinical research management at all stages has been identified as a key goal of the program and for the national research agenda. In this application we are proposing a series of annual conference workshops that will serve as a critical resource in facilitating and advancing interdisciplinary and translational clinical research nationally through promotion of scientific exchange among investigators, regulatory professionals and regulators, IRB administrators, industry, and NIH. The task of planning for and reporting on the workshops will be delegated to the national CTSA Clinical Research Management (CRM) Taskforce and its planning committee. The overall mission of the CRM is to: Make recommendations regarding standard metrics for the CTSA consortium; Develop methodology and specific, practical interventions for implementation at the CTSA sites; Create networks of partners and mentor-mentee relationships; Develop objective evidence of improvement; and Publish information to enable broad application of lessons learned in the scientific community. The conference workshops are geared towards 1) identifying issues which impede the clinical research development process; 2) developing innovative strategies for addressing problems encountered; and 3) modifying, implementing and sharing best practices nationally. This information exchange will promote improved methodology for process control, implementation of revised systems for protocol processing, and enterprise-wide use of metrics and information exchange that will allow the CTSA centers to serve as model for reducing regulatory burdens both within sites and between collaborating sites. The 2009 conference will be held on the NIH Campus at the Natcher Building, which includes a 1,000-seat auditorium, and a state-of- the-art multiuse Conference Center with nine conference rooms, and will include networking opportunities, use of posters to provide individual site data and processes and lessons learned, and podium lectures to demonstrate the use of expert advice in re-structuring protocol processing and clinical trials management. The PI, Dr. Robert Sherwin, M.D., will oversee the activities, with overall administration and planning directed by committee Chairs, Dr. Michael Joyner and Ms. Tesheia Johnson who will have responsibilities of chairing the planning meeting, setting milestones to achieve conference timelines, and reporting after the conference. Dr. Daniel Rosenblum, NCRR, and the CTSA coordinating center will provide critical organization infrastructure with responsibilities for scheduling and arranging the conference, circulating agendas and meeting materials, and overall administrative support to the group.

PROJECT SUMMARY (See instructions); The Yale Diabetes Research Center (DRC) was established in 1993 with the goal of promoting research in diabetes and related metabolic and endocrine disorders at the University. The DRC brings together a multidisciplinary group of over 100 member and associate member scientists as well as professional supporting staff, new Investigators and research trainees from in 16 departments and 4 colleges or schools at Yale University The scope ofthe research activities ofthe membership is very broad, ranging from basic molecular biology to whole body physiology and the treatment of diabetic patients. The members, however, share a common interest in research that is related to diabetes and metabolism or is fundamental to understanding its pathogenesis or for the development of new treatment strategies. The design of the Yale DRC is aimed at developing an Infrastructure that could serve as a catalyst to stimulate innovative diabetes-related research. The cornerstone of the DRC is its five Research Cores that provide funded basic and clinical investigators with the opportunity to more efficiently utilize resources and expand the scope of their research programs. The Clinical Metabolism and the Diabetes Translational Cores facilitate metabolic research in patients, whereas the Molecular Genetic Mouse Core, Physiology and Cell Biology Cores that comprise the more basic science focus of the Center offer investigators the tools to create and test novel animal models starting from the molecule and ending with biological outcomes. The Administrative Core oversees the operation ofthe Center, Its Pilot/Feasibility Project and Enrichment Programs, and helps to coordinate patient-based research in diabetes. The goals ofthe DRC are to: 1) stimulate multldisciplinary Interactions, particularly between basic and clinical scientists; 2) encourage established Investigators not presently working in diabetes-related areas, to bring their expertise to bear on problems relevant to diabetes; 3) efficiently organize time consuming and/or costly techniques through Core facilities to enhance the productivity of investigators conducting research in diabetes related areas; 4) promote new research programs through pilot feasibility projects; 5) enhance the quality of research training, and 6) create a stimulating institutional environment that enhances research efforts by its members to develop new strategies to prevent and treat diabetes and related metabolic disorders at the local and national level.

Contact PD/PI: Sherwin, Robert S. 1. Overall Project Summary- The Yale Center for Clinical Investigation (YCCI) was created in 2005 to strengthen Yale's infrastructure for clinical and translational research, based on the recommendation of a Medical School strategic planning committee. Soon afterwards, when NIH launched its new program of Clinical & Translational Science Awards, YCCI applied and became the home of the Yale CTSA. Since then, one of its major priorities has been to support the education and career development of the next generation of clinical and translational investigators. As described in the present application, this initiative has met with great success, underscored by the fact that graduates of YCCI's K-Scholar program have received 47 individual NIH K Awards, 43 NIH RO1 awards, and 65 Foundation grants, published >1,800 papers, and obtained >$240 million in independent research funding. Remarkably, 98% of the program's graduates have stayed in academic medicine or pursued research careers in the biotech or pharmaceutical industries. YCCI has also made substantial progress in its push to accelerate the translation of disease-related discoveries into the clinic. As will be described, it provides Yale investigators with key assistance in areas including biostatistics and bioinformatics, study design, protocol development, regulatory approval, patient recruitment, access to inpatient and outpatient research facilities, and budgeting support, and gives them ready access to pilot grants and state-of-the-art research cores. The result has been a significant upsurge in the number and scope of clinical research projects throughout the Medical Center. In the next grant cycle, YCCI will build upon these achievements with an emphasis on team-based T1 to T4 research, including studies across the lifespan. YCCI will also pursue new partnerships with the Yale School of Engineering & Applied Science to develop an innovative technology transfer program called the Center for Biological and Innovative Technology (CBIT) and with the School of Organization & Management to offer a novel program of leadership training for clinicians and physician-scientists. In addition, YCCI will take active advantage of the recent expansion of clinical services by Yale-New Haven Hospital (YNHH), which now has 1,540 beds and more than 1 million outpatients visits per year, and the growth of the Yale Medical Group (YMG), which has a network of >1,200 practicing physicians in >100 clinical specialties. The resulting clinical volume (~4 million patient records) gives Yale researchers access to a large, diverse patient base for outcomes studies and clinical trials. Overall, YCCI will leverage Yale's outstanding scientific and clinical environment and work with other CTSA hubs to foster the growth of multidisciplinary team science, to develop innovative strategies for disease prevention, diagnostics, and therapeutics, and to implement results for the benefit of the health care system and the population as a whole. Project Summary/Abstract Page 220 Contact PD/PI: Sherwin, Robert S. Program Narrative Yale Center for Clinical Investigation (YCCI) is a leader in team-based T1 to T4 research, including studies across the lifespan. YCCI will leverage Yale University's outstanding scientific and clinical environment and work with other CTSA hubs to foster the growth of multidisciplinary team science, to develop innovative strategies for disease prevention, diagnostics, and therapeutics, and to implement results for the benefit of the health care system and the population as a whole.

Contact PD/PI: Sherwin, Robert S. 1. Overall Project Summary- The Yale Center for Clinical Investigation (YCCI) was created in 2005 to strengthen Yale's infrastructure for clinical and translational research, based on the recommendation of a Medical School strategic planning committee. Soon afterwards, when NIH launched its new program of Clinical & Translational Science Awards, YCCI applied and became the home of the Yale CTSA. Since then, one of its major priorities has been to support the education and career development of the next generation of clinical and translational investigators. As described in the present application, this initiative has met with great success, underscored by the fact that graduates of YCCI's K-Scholar program have received 47 individual NIH K Awards, 43 NIH RO1 awards, and 65 Foundation grants, published >1,800 papers, and obtained >$240 million in independent research funding. Remarkably, 98% of the program's graduates have stayed in academic medicine or pursued research careers in the biotech or pharmaceutical industries. YCCI has also made substantial progress in its push to accelerate the translation of disease-related discoveries into the clinic. As will be described, it provides Yale investigators with key assistance in areas including biostatistics and bioinformatics, study design, protocol development, regulatory approval, patient recruitment, access to inpatient and outpatient research facilities, and budgeting support, and gives them ready access to pilot grants and state-of-the-art research cores. The result has been a significant upsurge in the number and scope of clinical research projects throughout the Medical Center. In the next grant cycle, YCCI will build upon these achievements with an emphasis on team-based T1 to T4 research, including studies across the lifespan. YCCI will also pursue new partnerships with the Yale School of Engineering & Applied Science to develop an innovative technology transfer program called the Center for Biological and Innovative Technology (CBIT) and with the School of Organization & Management to offer a novel program of leadership training for clinicians and physician-scientists. In addition, YCCI will take active advantage of the recent expansion of clinical services by Yale-New Haven Hospital (YNHH), which now has 1,540 beds and more than 1 million outpatients visits per year, and the growth of the Yale Medical Group (YMG), which has a network of >1,200 practicing physicians in >100 clinical specialties. The resulting clinical volume (~4 million patient records) gives Yale researchers access to a large, diverse patient base for outcomes studies and clinical trials. Overall, YCCI will leverage Yale's outstanding scientific and clinical environment and work with other CTSA hubs to foster the growth of multidisciplinary team science, to develop innovative strategies for disease prevention, diagnostics, and therapeutics, and to implement results for the benefit of the health care system and the population as a whole. Project Summary/Abstract Page 220 Contact PD/PI: Sherwin, Robert S. Program Narrative Yale Center for Clinical Investigation (YCCI) is a leader in team-based T1 to T4 research, including studies across the lifespan. YCCI will leverage Yale University's outstanding scientific and clinical environment and work with other CTSA hubs to foster the growth of multidisciplinary team science, to develop innovative strategies for disease prevention, diagnostics, and therapeutics, and to implement results for the benefit of the health care system and the population as a whole.

Contact PD/PI: Sherwin, Robert S. 1. Overall Project Summary- The Yale Center for Clinical Investigation (YCCI) was created in 2005 to strengthen Yale's infrastructure for clinical and translational research, based on the recommendation of a Medical School strategic planning committee. Soon afterwards, when NIH launched its new program of Clinical & Translational Science Awards, YCCI applied and became the home of the Yale CTSA. Since then, one of its major priorities has been to support the education and career development of the next generation of clinical and translational investigators. As described in the present application, this initiative has met with great success, underscored by the fact that graduates of YCCI's K-Scholar program have received 47 individual NIH K Awards, 43 NIH RO1 awards, and 65 Foundation grants, published >1,800 papers, and obtained >$240 million in independent research funding. Remarkably, 98% of the program's graduates have stayed in academic medicine or pursued research careers in the biotech or pharmaceutical industries. YCCI has also made substantial progress in its push to accelerate the translation of disease-related discoveries into the clinic. As will be described, it provides Yale investigators with key assistance in areas including biostatistics and bioinformatics, study design, protocol development, regulatory approval, patient recruitment, access to inpatient and outpatient research facilities, and budgeting support, and gives them ready access to pilot grants and state-of-the-art research cores. The result has been a significant upsurge in the number and scope of clinical research projects throughout the Medical Center. In the next grant cycle, YCCI will build upon these achievements with an emphasis on team-based T1 to T4 research, including studies across the lifespan. YCCI will also pursue new partnerships with the Yale School of Engineering & Applied Science to develop an innovative technology transfer program called the Center for Biological and Innovative Technology (CBIT) and with the School of Organization & Management to offer a novel program of leadership training for clinicians and physician-scientists. In addition, YCCI will take active advantage of the recent expansion of clinical services by Yale-New Haven Hospital (YNHH), which now has 1,540 beds and more than 1 million outpatients visits per year, and the growth of the Yale Medical Group (YMG), which has a network of >1,200 practicing physicians in >100 clinical specialties. The resulting clinical volume (~4 million patient records) gives Yale researchers access to a large, diverse patient base for outcomes studies and clinical trials. Overall, YCCI will leverage Yale's outstanding scientific and clinical environment and work with other CTSA hubs to foster the growth of multidisciplinary team science, to develop innovative strategies for disease prevention, diagnostics, and therapeutics, and to implement results for the benefit of the health care system and the population as a whole. Project Summary/Abstract Page 220 Contact PD/PI: Sherwin, Robert S. Program Narrative Yale Center for Clinical Investigation (YCCI) is a leader in team-based T1 to T4 research, including studies across the lifespan. YCCI will leverage Yale University's outstanding scientific and clinical environment and work with other CTSA hubs to foster the growth of multidisciplinary team science, to develop innovative strategies for disease prevention, diagnostics, and therapeutics, and to implement results for the benefit of the health care system and the population as a whole.

Contact PD/PI: Sherwin, Robert S. 1. Overall Project Summary- The Yale Center for Clinical Investigation (YCCI) was created in 2005 to strengthen Yale's infrastructure for clinical and translational research, based on the recommendation of a Medical School strategic planning committee. Soon afterwards, when NIH launched its new program of Clinical & Translational Science Awards, YCCI applied and became the home of the Yale CTSA. Since then, one of its major priorities has been to support the education and career development of the next generation of clinical and translational investigators. As described in the present application, this initiative has met with great success, underscored by the fact that graduates of YCCI's K-Scholar program have received 47 individual NIH K Awards, 43 NIH RO1 awards, and 65 Foundation grants, published >1,800 papers, and obtained >$240 million in independent research funding. Remarkably, 98% of the program's graduates have stayed in academic medicine or pursued research careers in the biotech or pharmaceutical industries. YCCI has also made substantial progress in its push to accelerate the translation of disease-related discoveries into the clinic. As will be described, it provides Yale investigators with key assistance in areas including biostatistics and bioinformatics, study design, protocol development, regulatory approval, patient recruitment, access to inpatient and outpatient research facilities, and budgeting support, and gives them ready access to pilot grants and state-of-the-art research cores. The result has been a significant upsurge in the number and scope of clinical research projects throughout the Medical Center. In the next grant cycle, YCCI will build upon these achievements with an emphasis on team-based T1 to T4 research, including studies across the lifespan. YCCI will also pursue new partnerships with the Yale School of Engineering & Applied Science to develop an innovative technology transfer program called the Center for Biological and Innovative Technology (CBIT) and with the School of Organization & Management to offer a novel program of leadership training for clinicians and physician-scientists. In addition, YCCI will take active advantage of the recent expansion of clinical services by Yale-New Haven Hospital (YNHH), which now has 1,540 beds and more than 1 million outpatients visits per year, and the growth of the Yale Medical Group (YMG), which has a network of >1,200 practicing physicians in >100 clinical specialties. The resulting clinical volume (~4 million patient records) gives Yale researchers access to a large, diverse patient base for outcomes studies and clinical trials. Overall, YCCI will leverage Yale's outstanding scientific and clinical environment and work with other CTSA hubs to foster the growth of multidisciplinary team science, to develop innovative strategies for disease prevention, diagnostics, and therapeutics, and to implement results for the benefit of the health care system and the population as a whole. Project Summary/Abstract Page 220 Contact PD/PI: Sherwin, Robert S. Program Narrative Yale Center for Clinical Investigation (YCCI) is a leader in team-based T1 to T4 research, including studies across the lifespan. YCCI will leverage Yale University's outstanding scientific and clinical environment and work with other CTSA hubs to foster the growth of multidisciplinary team science, to develop innovative strategies for disease prevention, diagnostics, and therapeutics, and to implement results for the benefit of the health care system and the population as a whole.