Diabetes, Obesity & Metabolism Research in the Early 21st Century* (*from the NIH Point of View)

December, 2004

Maren R. Laughlin, Ph.D.Senior Advisor for Integrative

MetabolismNational Institute of Diabetes & Digestive and Kidney Diseases

National Institutes of Health

Three Major Areas of Interest Diabetes & Metabolic Disease

NIDDK, NHLBI, NIA, NICHD, NIAID, NCI, NIBIB, etc.

ObesityTrans-NIH

http://www.obesityresearch.nih.gov/

http://www.niddk.nih.gov/welcome/org/OD/OOR/OOR.htm

NIH RoadmapTrans-NIH

www.nihroadmap.nih.gov

Diabetes & Metabolic Disease* (*from the NIH Point of View)Type 2 Diabetes Incidence: ~18M Americans Healthcare burden: $132B in 2002 Recently found in children and young people as well as older

adults Major focus of NIDDK research efforts

Type 1 DiabetesSpecial Statutory Funding Program for Type 1 Diabetes Research http://www.niddk.nih.gov/fund/diabetesspecialfunds/funding.htm

$1.14 billion for FY 1998 - FY 2008

Diabetic Complications Common to type 1 and type 2 diabetes Heart disease/atherosclerosis, microvascular disease /

neuropathy, retinopathy, nephropathy

Multi-pronged Approach to Diabetes Research

Investigator Initiated Grants Treatment and Prevention Trials Epidemiology Genetics studies Requests for Applications: NIH Initiated Grants Resources, such as

Animal models Tissue sources Standards Reagents and technologies

Community Organization (consortia, collaberations, workshops, etc)

Training

Type 2 Diabetes Resources

Diabetes Centers: DERCs and DTRCsProvides core resources to foster interdisciplinary research in diabetes and related areas

International Type 2 Diabetes Linkage Analysis Consortium

Mouse Metabolic Phenotyping Centers (MMPC)

Mice are shipped to a Center for in-depth phenotyping

Nuclear Receptor Signaling Atlasto gather and organize information relating to key aspects of

orphan nuclear receptor biology

Type 1 Diabetes Resources cont’d.

Islet Cell Resource Centers (ICR) Human Pancreatic Islets Available for Non-Clinical Research ($0.10 / islet)

Availability of pancreas-specific microarraysMouse PancChip 5.0 and Human PancChip 1.0

Beta Cell Biology ConsortiumReagents for study of islet development & cell replacement therapies

Type 1 Diabetes Resources

Collaborative Projects on Proteomics & Metabolomics For Type 1 Diabetes & its ComplicationsClearinghouse for tissue samples for proteomics/metabolomics analysis www.niddk.nih.gov/fund/diabetesspecialfunds/proteomics/

Access to samples from major clinical trials (DCCT, DPP)

Type 1 Diabetes-Rapid Access to Intervention Development (T1D-RAID)Resources to aid in pre-clinical development of new drugs

Type 1 Diabetes Mouse Repository at the Jax Labs

Animal Models of Diabetic Complications ConsortiumMice and pig models

Growth in Basic Biology Programs

Beta cell developmental biology:

(stem cells and transcription factors, toward cell therapy)

Islet transplantation and engineering

Imaging the pancreatic beta cell

Adipocyte as endocrine organ

Immunology of diabetes

Mechanisms of insulin resistance

Neurobiology of energy balance

Proteomics and metabolomics of diabetes:

Biomarkers of disease

Diabetic Complications

Hypoglycemia unawareness

Molecular mechanisms

Current & Future Diabetes Initiatives

Current:RFA-DK-04-022 receipt: March 17, 2005Collaborative Studies on Angiogenesis and Diabetic

Complications

RFA-DK-05-001 receipt: February 24, 2005 Preventing Mitochondrial Oxidative Stress in Diabetes and

Obesity

Coming Soon: Beta Cell Regeneration for Diabetes Therapy (RFA) Pilot and Feasibility Program in Human Islet Biology (RFA) Mouse Metabolic Phenotyping Centers (RFA)

Special Emphasis Program Announcements PA-04-092 Long-Term Weight Maintenance: Basic and Clinical Studies

PA-04-088 Non-Invasive Methods for Diagnosis and Progression of Diabetes, Kidney, Urological, Hematological , and Digestive Diseases

PA-04-081 Proteomics: Diabetes, Obesity, and Endocrine, Digestive, Kidney, Urologic, and Hematologic Diseases

PAR-04-078 Ancillary Studies to Major Ongoing NIDDK Clinical Research Studies PA-04-074 Health Disparities in NIDDK Diseases

PA-04-068 Development Assays for High Throughput Drug Screening

PA 04-033 Diet Composition and Energy Balance

Diabetes Program Announcements

PA 03-052 Proteomics in Diabetes and Other Endocrine and Metabolic Diseases

PA 02-077 Secondary Analyses in Diabetes, Digestive and Kidney Diseases

PA03-0156 Insulin Signaling and Receptor Cross-Talk

PA-04-033 Diet Composition and Energy Balance

PA-04-098 Heterogeneity of Fat Depots: Underlying Basis and Association with Morbidity

PA 03-150 Erythroid Lineage Molecular Toolbox

PA 03-145 Ubiquitin and Ubiquitin-Like Modification Regulating Disease Processes PA 02-161 Development of the Endocrine Pancreas

PA 02-117 Racial & Ethnic Differences in the Etiology of Type 2 Diabetes in United States

PA 01-117 Liver and Pancreatic Disease in HIV Infection

PA 01-112 The Role of Antioxidants in the Prevention of Diabetic Complications

PA 02-100 Complex Formation in Hormonal Regulation of Gene Expression

PA 02-094 Ancillary Studies on Control Groups in Clinical Trials

NIDDK Initiative Concepts for 2006

Development of Biomarkers for Disease

Animal Models of NIDDK-Relevant Diseases

Imaging Fibrosis in Kidney, Liver and Bladder

Potential Therapeutic Agents for Diseases of Protein Misprocessing or Misfolding

Genetic Longitudinal Studies of Obesity-Related Phenotypes

Translation of Invertebrate Obesity Genetics to Mammals

Planning or Implementation of New Clinical Studies of Interest to NIDDK

Obesity Research (from the NIH Point of View)NIH Obesity Taskforce established April, 200325 ICs and offices, co-chaired by the Directors of NIDDK and

NHLBIhttp://www.obesityresearch.nih.gov/

Strategic Plan: Research toward preventing and treating obesity through

lifestyle modification.

Research toward preventing and treating obesity through pharmacologic, surgical, or other medical approaches.

Research toward breaking the link between obesity and its associated health conditions.

Cross-cutting research topics, including health disparities, technology, fostering of interdisciplinary research teams, investigator training, translational research and education/outreach efforts.

NIDDK Office of Obesity Researchhttp://www.niddk.nih.gov/welcome/org/OD/OOR/OOR.htm

“Right hand” of NIH Obesity Task Forcecomprised of NIDDK staff

serves toassist the Director, NIDDK in identifying research opportunities, initiatives, and advances

identify and plan appropriate workshops and conferences

Clinical Trials in Obesity

Action to Control Cardiovascular Disease Risk in Diabetes (ACCORD)test best ways to lower risk of heart disease and stroke in adults with type 2

diabetes

BARI 2Bypass Angioplasty Revascularization Investigation 2 DiabetesDetermine the best therapies for people with type 2 diabetes and heart

disease

Longitudinal Assessment of Bariatric Surgery (LABS)conducting coordinated clinical, epidemiological, and behavioral research in

the field of bariatric surgery

SEARCH for Diabetes in Youth Studydetermine the prevalence of diabetes in children in six areas of the U.S. and

help clarify trends in the development of diabetes in youth

TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth)

identify the best treatment of type 2 diabetes in children and teens

Clinical Samples for Obesity & Diabetes Researchers

NIDDK Central Repositories: Biosamples, Genetics, Data

Established to store biosamples and data collected in designated

NIDDK-funded clinical studies. Purpose is to expand the usefulness of these studies by allowing a

wider research community to access collected materials

RFA-DK-03-022 receipt: July 19, 2005

Ancillary Studies to Obesity-Related Clinical Trials

Current Obesity Research Solicitations

RFA-DK-05-0 receipt: February 24, 2005 Preventing Mitochondrial Oxidative Stress in Diabetes and Obesity

RFA-HL-04-022 receipt: February 16, 2005  Bioengineering Approaches to Energy Balance and Obesity(measure energy balance, food intake, activity, etc.)

PA-04-156 receipt:Feb 1, June 1, Oct 1Bioengineering Approaches to Energy Balance and Obesity (SBIR/STTR)

RFA-ES-04-003 receipt: Dec. 17, 2004 Obesity and the Built Environment

RFA-DK-03-018 receipt: March 17, 2005 Genetic Studies of Obesity-Related Traits in Model Organisms (Drosophila, C elegans, zebrafish)

Obesity Program Announcements

Basic Research PA-04-124: Studies of Energy Balance and Cancer in Humans

PA-04-098: Heterogeneity of Fat Depots: Underlying Basis & Association with Morbidity

PA-04-081: Proteomics: Diabetes, Obesity, and Endocrine, Digestive, Kidney, Urologic & Hematologic Diseases

PA-04-033: Diet Composition and Energy Balance

Clinical and Behavior Research

PA-04-092: Long-Term Weight Maintenance: Basic and Clinical Studies

PAR-03-009: Improving Diet and Physical Activity Assessment

PAR-04-082: Small Clinical Grants in Digestive Diseases, Nutrition and Obesity

PA-04-121: Understanding Mechanisms of Health Risk Behavior Change in Children & Adolescents

PAR-03-060: Planning Grants for Translational Research for the Prevention and Control of Diabetes

PA-02-153: Translational Research for the Prevention and Control of Diabetes

PA-02-159: Enhancing Adolescent Health Promotion Across Multiple High Risk Behaviors

PA-05-009: Research on the Economics of Diet, Activity, and Energy Balance

PA-04-145: School-Based Interventions To Prevent Obesity

Obesity Program Announcements

Recent NIH Obesity Workshops

Women and ObesityNovember 4, 2004 1-3 p.m.

Obesity and the Built Environment: Improving Public Health Through Community Design May 24-26, 2004

Lipids and the Pathophysiology of Obesity May 10-11, 2004

From clinical trials to community: The science of translating diabetes and obesity researchJanuary 12-13, 2004

Adipose Tissue Secretory Function and Its Role in Obesity-Associated Co-Morbidities December 11-13, 2003

Phenotyping Obesity for Human Genetic Studies October 28-30, 2003

NIH Roadmap*(*from the NIH Point of View) Theory

NIH institutes working together to serve the unique needs of 21st century American biomedical science

PracticeResearch themes, projects and resources that no one

institute could support because of limited budgets and defined missions

28 initiatives & 171 awards to date Resources

$237M in FY05, projected to ~ $500M by FY09

The NIH Roadmap and ObesityPI: JAY D. HORTON Title: Task force for Obesity Research at UT SouthwesternRFA: Exploratory Centers for Interdisciplinary Research

Goals: Taskforce combines neuroendocrinology, genetics, lipid

metabolism, intermediary metabolism, and clinical epidemiology

Brain regulation of food intake and energy expenditure

Dysregulation of glucose and lipid metabolism in the liver

PI: BARRY M. POPKINProject Title: An Interdisciplinary Strategy for ObesityRFA: Exploratory Centers for Interdisciplinary Research

Goals: Inter-Disciplinary Obesity Center (IDOC)

Nutrition, epidemiology, health behavior, urban planning, health economics, physiology, psychology, genetics, and clinical medicine

Find effective interventions for prevention and treatment of obesity

The NIH Roadmap and Obesity

The NIH Roadmap & Metabolic DiseasePI: HENRI BRUNENGRABERTitle: Dynamic Metabolomics via Isotopomer AnalysisRFA: Metabolomics Technologies Development

Goals: Identify, measure and interpret the complex time-related

concentration, activity and flux of endogenous metabolites

instrumentation to increase sensitivity

Carbon-labeled substrates and 2H2O to measure fluxes in metabolic networks via mass isotopomer analysis

Models and multivariate statistics to provide new avenues for understanding metabolic diseases

NIH Roadmap Themes (& 13 Implementation Committees)New Pathways to Discovery

Building Blocks, Biological Pathways, and Networks Molecular Libraries & Molecular Imaging Structural Biology Bioinformatics and Computational Biology Nanomedicine

Research Teams of the FutureHigh-Risk Research Interdisciplinary Research Public-Private Partnerships

Re-engineering the Clinical Research EnterpriseClinical Research Networks/NECTAR Clinical Research Policy Analysis and Coordination Clinical Research Workforce TrainingDynamic Assessment of Patient-Reported Chronic Disease Outcomes Translational Research

New Pathways to Discovery Projects

SMALL MOLECULES Metabolomics Technology Development Projects

tools to measure metabolites and their dynamic fluctuations within cells

Molecular Libraries Screening Center Network (MLSCN) high throughput screening of chemically diverse small molecules (500,000) with the hope of providing new reagents for research (activators / inhibitors / markers)

MOLECULAR IMAGINGtechnologies and reagents for imaging of molecules or molecular events within single cells and whole organisms

PROTEINS National Technology Centers for Networks and Pathways

tools to measure the activity, translocation, and interactions of intracellular protein molecules

Innovation in Membrane Protein ProductionCenters to prepare membrane proteins for structural studies

Research Teams of the Future ProjectsHIGH RISK RESEARCH:

9 Pioneer Awards $500K/yr for 5 yrs to encourage creative, outside-the-box thinkers to pursue exciting and innovative ideas in biomedical research

INTERDISCIPLINARY RESEARCH Exploratory Centers (P20) for Interdisciplinary

Research Large series of training initiatives in IR

TRANSLATIONAL RESEARCHRAID: Rapid Access to Intervention Developmentresources for pre-clinical development of drugs (toxicology, dosing, manufacture, etc.)

2005 RM Initiatives (from 16 total) http://nihroadmap.nih.gov/grants/index.asp

Building Blocks, Biological Pathways RM-04-019 receipt 2/22/05 National Technology Centers for Networks and Pathways

Molecular Libraries

RM-04-027   receipt 3/10/05 Cheminformatics Research Centers

RM-05-011   receipt 2/14/05 Assay Technology Development

RM-05-014 receipt 2/15/05 Pilot-Scale Libraries for High-Throughput Screening

 

Structural Biology RM-04-026 receipt 1/24/05 Membrane Protein Production and Structure Determination

2005 RM Initiatives (cont’d.) http://nihroadmap.nih.gov/grants/index.asp

Interdisciplinary ResearchRM-04-008 receipt 2/11/05 Short Programs for Interdisciplinary Research Training

RM-05-010 receipt 2/11/05  Interdisciplinary Health Research Training: Behavior, Environment and Biology

High Risk ResearchNIH Director's Pioneer Awards

Other Funding Mechanisms for Partnerships BRP Bioengineering Research Partnerships

http://grants2.nih.gov/grants/guide/pa-files/PAR-04-023.html

R24 Interactive Partnerships NIGMS or NIDDK Grantees, Collaboration between funded investigators $300K/yr for 4 yrs, non-renewable For consortium activities http://grants2.nih.gov/grants/guide/pa-files/PA-

03-127.html

Contact Information

Maren R. Laughlin, Ph.D.Senior Advisor for Integrative MetabolismNIDDK, NIH6707 Democracy Blvd., MSC 5460Bethesda, MD 20892

301-594-8802Maren.laughlin@nih.gov

www.nih.gov & www.niddk.nih.gov