Drug Response - A Tool for Understanding the Systems Biology of Type 2 Diabetes

Event Details

Meeting Objectives

Many recent advances in diabetes research have generated a body of knowledge indicating that diabetes is a heterogeneous disease with a complex genetic component. Environmental factors such as lifestyle and diet also play a major role in the development and progression of diabetes. Although diabetes is defined only by measuring glucose in the blood (or HbA1c as a surrogate), it is apparent that many factors can lead to hyperglycemia, and this single measurement does not accurately describe the cause(s) of the disease. In fact, several biological systems appear to be involved in the progression and development of type 2 diabetes, including several organs/tissues, hormones, as well as several intracellular molecular pathways. The limited understanding of the complexities of these systems and their interactions has been a major barrier in the development of optimal treatments in type 2 diabetes. A systems biology approach potentially could model these complex networks and thus help in characterizing key elements that affect the energy homeostasis. Within this new discipline, data sets obtained by the application of high-throughput technologies such as genomics, proteomics, and metabolomics are integrated to develop models that can be used to explain specific biological or physiological endpoints.

It may seem that at this stage of knowledge creating a model that can capture the complexity of the systems involved in the development of type 2 diabetes might be too difficult. As a result, within this workshop we would like to explore the possibility of focusing systems biology approaches on populations from clinical studies in which a specific agent (e.g., metaformin) is used as a single variable and the molecular profile, genes, and protein networks could be characterized before and after treatment.

More generally, within this workshop we intend to bring together experts in the areas of computational biology, clinical trials, proteomics, metabolomics, genomics, and physiology to identify how systems biology studies could be pursued in the context of diabetes.

Agenda

April 21, 2011

7:30 a.m. - 8:00 a.m.

Registration and Continental Breakfast

8:00 a.m. - 8:15 a.m.

Call To Order and Introduction
Salvatore Sechi, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH)

Welcome
Gregory G. Germino, Deputy Director, NIDDK

8:15 a.m. - 9:00 a.m.

Keynote Opening Lecture

A Multiscale Biology Approach for Linking the Molecular Biology of Disease to Clinical Medicine
Eric Schadt, Pacific Biosciences

Session I: The Clinical and Physiological Perspective

Chair: William Knowler

9:00 a.m. - 9:25 a.m.

Systems Biology and Type 2 Diabetes:  What Do We Hope to Learn?
William Knowler, NIDDK, NIH

9:25 a.m. - 9:50 a.m.

Fatty Liver:  A Marker of Looming Diabetes in Obese Youth
Sonia Caprio, Yale University

9:50 a.m. - 10:15 a.m.

Systems Biology Analysis of Metabolic Dysfunction:  Lessons From the Past and Future Directions
Richard Bergman,  University of Southern California

10:15 a.m. - 10:30 a.m.

Break

10:30 a.m. - 10:55 a.m.

Inflammation in T2D:  Potential Pathophysiological Mediator and Pharmacological Target
Steven Shoelson, Joslin Diabetes Center

10:55 a.m. - 11:20 a.m.

Cellular Mechanisms of Insulin Resistance in Humans
Gerald I. Shulman,  Yale University

11:20 a.m. - 11:45 a.m.

Diabetes Drug Discovery and Development - Where are we now? What do we really need to be successful?
David Moller,  Eli Lilly and Company

Session II: Molecular Profiling - The State of the Art

Chair: Robert Gerszten

11:45 a.m. - 12:10 p.m.

Pharmacogenetics in Type 2 Diabetes
Jose Florez,  Massachusetts General Hospital

12:10 p.m. - 1:15 p.m.

Lunch

1:15 p.m. - 1:40 p.m.

The Role of UCP3 in Exercise Metabolism Studied by Comprehensive Metabolomics
Olivier Fiehn,  University of California, Davis

1:40 p.m. - 2:05 p.m.

Metabolic Profiling for Understanding of Metabolic Disease Mechanisms and Progression
Christopher B. Newgard,  Duke University

2:05 p.m. - 2:30 p.m.

Large-scale Analysis of Metabolite-protein Interactions Reveals Novel Regulatory Mechanisms in Eucaryotes
Mike Snyder, Stanford University

2:30 p.m. - 2:55 p.m.

Metabolite Profiles and the Risk of DM
Robert Gerszten,  Massachusetts General Hospital

2:55 p.m. - 3:20 p.m.

Imaging Mass Spectrometry:  New Views of Biology and Medicine
Richard Caprioli, Vanderbilt University

3:20 p.m. - 3:35 p.m.

Break

3:35 p.m. - 4:00 p.m.

Epigenetics, Imprinting and Metabolism
Anne Ferguson-Smith, University of Cambridge (UK)

Session III: The Animal Models of Diabetes

Chair: C. Ronald Kahn

4:00 p.m. - 4:25 p.m.

Defining Causal Factors in Diabetes Prone vs. Diabetes Resistant Mice Using a Systems Biology Approach
C. Ronald Kahn,  Joslin Diabetes Center

4:25 p.m. - 4:50 p.m.

Genetics of Diabetes in Mice:  New Pathways of Diabetes Susceptibility
Alan Attie,  University of Wisconsin

4:50 p.m. - 5:15 p.m.

MAP Kinases and the Metabolic Stress Response
Roger Davis,  University of Massachusetts Medical School

5:15 p.m. - 5:40 p.m.

Nonhuman Primates in Translational Metabolic Studies: Importance of Chronomics
Barbara Hansen, University of South Florida

5:40 p.m. - 6:05 p.m.

Profiling Obesity Phenotypes in Adipose Tissue
Dorothy D. Sears, University of California, San Diego

Session IV: Modeling a Complex Disease

Chair: Albert-László Barabasi

6:05 p.m. - 6:30 p.m.

Network Medicine:  From Cellular Networks to Human Diseases
Albert-Laszlo Barabasi,  Northeastern University

6:30 p.m.

Adjournment

April 22, 2011

7:30 a.m. - 8:00 a.m.

Registration and Continental Breakfast

Session IV: Modeling a Complex Disease (continued)

8:00 a.m. - 8:25 a.m.

Systems Macro-Biology:  From Genes and Genomes to Network Signatures of Disease
Simon Kasif,  Boston University

8:25 a.m. - 8:50 a.m.

Systems Biology of Type 2 Diabetes:  The Road Ahead
Pierre DeMeyts, Novo-Nordisk

8:50 a.m. - 9:15 a.m.

Systems Pharmacology and Adverse Event Predictions
Ravi Iyengar, Mount Sinai School of Medicine

Discussion Panels

9:15 a.m. - 10:30 a.m.

(1-hour parallel discussions that specifically answer the questions posed for each of the above four sessions) Key Questions for "The Clinical and Physiological Perspective" Session:
Moderators: Peter Savage and William Knowler

• What patient population and type of samples might be available for initiating systems biology studies?
• Is the "drug treatment" concept a reasonable entry point for systems biology studies in humans, or are there better models that we could start with?
• How should we apply systems biology approach for better understanding the meachanism of action of insulin sensitizers (e.g., metformin) in human?
• How can we best use drug response and systems biology for understanding type 2 diabetes and potentially improve its treatment and diagnosis?
• How should the NIDDK further promote the application of systems biology approaches?

Key Questions for the "Molecular Profiling - The State of the Art" Session:
Moderators: Olivier Blondel and Robert Gerszten

• What samples are needed?
• What data already are available?
• What is the state of the art in molecular profiling?
• How well can we apply high-throughput approaches to large cohorts?
• What could be an ideal clinical study, and what type of samples could be analyzed?
• Can we characterize the molecular phenotypes of different stages in diabetes pathogenesis?
• How should we apply systems biology approach for better understanding the meachanism of action of insulin sensitizers (e.g., metformin) in human?
• How can we best use drug response and systems biology for understanding type 2 diabetes and potentially improve its treatment and diagnosis?
• How should the NIDDK further promote the application of systems biology approaches?

Key Questions for "The Animal Models of Diabetes" Session:
Moderators: Saul Malozowsky and C. Ronald Kahn

• How have animal models contributed to advance this field, and what are their relevance to humans?
• To what extent should we focus on animal models and on humans?
• How should we apply systems biology approach for better understanding the meachanism of action of insulin sensitizers (e.g., metformin) in human?
• How can we best use drug response and systems biology for understanding type 2 diabetes and potentially improve its treatment?
• How should the NIDDK further promote the application of systems biology approaches?

Key Questions for the "Modeling Complex Disease" Session:
Moderators: Salvatore Sechi and Albert-Laszlo Barabasi

• To what extent has computational modeling been used successfully in complex diseases for describing molecular networks?
• What type of data are needed and can be integrated for generating systems biology models of diabetes in humans?
• How should we apply systems biology approach for better understanding the meachanism of action of insulin sensitizers (e.g., metformin) in human?
• How can we best use drug response and systems biology for understanding type 2 diabetes and potentially improve its treatment and diagnosis?
• How should the NIDDK further promote the application of systems biology approaches?

10:30 a.m. - 10:45 a.m.

Break

10:45 a.m. - 11:30 a.m.

Reports From Working Groups
(One speaker from each group - 10 minutes per speaker)

11:30 a.m. - 12:15 p.m.

Keynote Closing Lecture
FDA:  A Perspective on Personalized Medicine
Janet Woodcock, U.S. Food and Drug Administration (FDA)

12:15 p.m.

Adjournment