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Day 1
Sunday, December 3
5:00-6:00 pm Early Registration
Monday, December 4
7:30am Registration, Poster and Exhibit Setup
8:30 Welcome by Session Chairperson
Looking to the Future
| Visionary Presentations |
8:45
Metabolomics: An Evolutionary View of Its Past, Present, and Future
Chris Beecher, Ph.D., President, Metabolic Analyses Inc.
The current concept of metabolomics has evolved in less than ten years from an off-hand comment to the third most significant goal of the NIH Roadmap. In this brief period, it has proven its merits; a society has been formed, significant governmental funding streams have been established, and is now approaching a "mainstream science" status, as many Universities vie to establish departments. Where did it start? How has this occurred? What can we realistically expect as it continues to mature and as metabolomic datasets become are integrated with other omic datasets? These are exciting times and we will provide an evolutionary perspective in answering these questions.
9:30 Metabolic Profiling and Biomarkers: Opportunities and Challenges in Drug Discovery and Development
Rakesh Dixit, Ph.D., DABT., Senior Director and Head, Toxicology Department, MedImmune Incorporated
Metabolomics (typically MS-based) and Metabonomics (typically NMR-based) are concerned with the quantitative profiling of small molecular weight intermediary metabolites in the metabolome in body fluids and/or tissues. Metabolite profiling is complimentary to genomics and proteomics and can offer an integrated approach to systemic biology-based biomarkers of drug's pharmacology and toxicology, disease susceptibility, and identification of mechanisms. The presentation will provide a general overview and a new vision related to metabolomics and metabonomics and their utility and challenges in drug discovery (e.g., target identification), preclinical and clinical development. |
Application of Metabolic Profiling
to Drug Development
10:15 Selection and Structural Elucidation of Unknowns in Metabolic Profiling
Steve Morrall, Ph.D., Principal Scientist, Corporate Research, Procter and Gamble
In “global” metabolic profiling, the determination of unknown chemical structures is often a critical need. Multi-variate models, HPLC/MS/MS, and NMR are used in combination to elucidate these structures. The overall process is described and the importance of HPLC resolution, mass accuracy and the prospects of using statistical correlation to link orthogonal (MS/NMR) data sets are explored.
10:45 Coffee Break, Poster and Exhibit Viewing
11:00 Defining Nutrition and Metabolic Health through Metabonomics
Dr. Laurent-Bernard Fay, Head Leader Metabonomics & Biomarkers, Bioanalytical Science, Nestle Research Center
Increasingly genomics tools are being used to investigate health at the gene, protein or metabolite level using the corresponding “omics” technologies, namely transcriptomics, proteomics and metabonomics. Nutrigenomics, i.e. comprehensive mapping of changes in gene expression following nutritional interventions is very promising but from nutritional perspective, gene expression represents only a part of the metabolic picture. On the other hand, metabonomics-the holistic measurement of all metabolites is closer to the real outcome of potential changes suggested by genomics and proteomics. Metabonomics is also minimally invasive, and can thus easily be applied to study subtle variations in human metabolic health status and metabolism’s dynamic relationship to environment that includes typical lifestyle pattern including diets. The presentation includes application of the minimally invasive metabonomics approach employing 1H NMR and MS of biological fluids (plasma, urine, saliva) for comprehensive biochemical profiles in general human population to understand the metabolic diffrences due to phenotypic (gender, age etc.) and lifestyle (sports, smoking etc.) specific patterns
11:30 Detection of Metabolic Biomarkers of Acute Renal Toxicity
Richard D. Beger, PhD., Branch Chief, Center for Metabolomics, Division of Systems Toxicology, National Center for Toxicological Research, Food and Drug Administration
Groups of three to four 8- to 10-week-old 129/SV mice were administered a single intraperitoneal injection of cisplatin at a dose of 20 mg/kg body weight. A group of four mice were also pretreated for 7 days with the PPAR? ligand, WY 14,643 (1%wt/wt), and its protective effects were examined in samples
collected 2 days after exposure to cisplatin. Pretreatment with WY prevented the elevation of glucose, fatty acids and triglycerides that were observed in urine, serum and tissue of mice treated with cisplatin alone. Since creatinine, which is the common clinical marker for renal toxicity, is not as sensitive or specific as a group of biomarkers, we propose the development of a specific metabolic spectral footprint of drug-induced nephrotoxicity, which will allow us to predict and reduce the incidences of acute renal failure.
12:00 Biomarkers and Metabolic Profiles for Detection and Prediction of Drug Effects
Götz Schlotterbeck, Ph.D., Scientific Specialist, Metabolic Profiling and Biomarkers, F. Hoffmann-La Roche Inc. Switzerland
Metabolic profiling by NMR and LC-MS relies on three basic properties (i) there is almost no sample preparation; (ii) the spectroscopic methods are extremely reproducible; and (iii) the data reflects the actual physiological phenotype. Applications are presented whereby new tools for data pre-processing support the identification of new biomarkers. Simultaneous regulations of several metabolites within pathways are investigated as well as changes of single biomarkers in their mechanistic background.
12:30pm Lunch (on your own) or
Technology Workshop (Sponsorship Available)
Metabolomics in the Clinic
1:45 Comments by Session Chairperson
1:50 Rapid Classification of Lung Diseases by Ion Mobility Spectrometry Using Biomarker Data Analysis
Wolfgang Vautz, Director, Ph.D., Institute for Analytical Sciences (ISAS)
Metabolic profiling of human exhaled breath will be considered with respect to bronchial carcinoma, chronic obstructive pulmonary disease (COPD), bronchiectasis, airway infections, bacteria, and antibiotics.
2:20 Metabolic Profiling for Defining Diabetes and Obesity Mechanisms
Christopher B. Newgard, Ph.D., Director, Sarah W. Stedman Nutrition and Metabolism Center, W. David and Sarah W. Stedman Distinguished Professor, Duke University Medical Center
The team at the Sarah W. Stedman Nutrition and Metabolism Center seeks to gain insights into metabolic mechanisms underlying diabetes and obesity via application of a suite of metabolic analysis methods. These include targeted mass spectrometry for quantitative measurement of metabolites in multiple chemical classes, “unbiased” metabolic profiling to deduce broad metabolic changes, and NMR-based analysis of metabolic flux. Through application of these and genetic engineering approaches, our group has gained some fresh insights into mechanisms of glucose-stimulated insulin secretion from the pancreas and its impairment in diabetes, as well as metabolic mechanisms of insulin resistance in obesity and diabetes in animal models and humans. Key examples of these advances will be presented.
2:50 1H-NMR Based Metabolomics: Translational Applications to Transplantation
Natalie J. Serkova, Ph.D., Department of Anesthesiology, Clinical Research and Development, MRI/MRS Cancer Center Core, University of Colorado Health Sciences Center
This presentation addresses 1H-NMR based metabolomics principles and potential applications in transplantation, with special emphasis on translational research. Validated biomarkers in blood and urine can early predict graft dysfunctions, ischemia/reperfusion injury and immunosuppressant toxicity in animal models and then be translated into clinical trials.
3:20 Utility and Limitation of Biomarkers in Metabolic Disease Target Validation: A Case Study with c-Jun N-terminal Kinase Inhibitors
Gang Liu, Ph.D., Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories
c-Jun N-terminal kinases (JNK1, 2,3) are members of the mitogen activated protein kinase (MAP kinase) family of enzymes which are activated in responses to cellular stresses and cytokines. JNK inhibitors have been proposed to be potentially useful for the treatment of diabetes, obesity, autoimmune diseases, and neurodegenerative diseases. A series of structurally novel pan-JNK inhibitors was discovered in our laboratories and several lead compounds were studied in details in several diabetes/obesity rodent models. The utility and limitation of several biomarkers in confirming the mechanism of action of these compounds in insulin responsive tissues will be discussed. Comparison of our in vivo results to the phenotypes observed from JNK1 genetic depletion model will also be presented.
3:50 Refreshment Break, Poster and Exhibit Viewing
| 4:20 Problem-Solving Roundtables
Table 1
Overcoming Challenges in Taking Biomarkers to the Clinic
Facilitator: Joerg Ingo Baumbach, Ph.D., Director, Department of Metabolomics, Institute for Analytical Sciences
(ISAS)
• Correlating Animal Models
• Monitoring Clinical Trials
Table 2
Data Integration Strategies
Facilitator: TBA
• Finding the right mining tool
• Determining the desired data points
Table 3
Application of Metabolic Markers to Disease Process Understanding
Facilitators: Christopher B. Newgard, Ph.D., Director, Sarah W. Stedman Nutrition and Metabolism Center, W. David and Sarah W. Stedman Distinguished Professor, Duke University Medical Center
Table 4
Intermediary Metabolites Profiling
Facilitator: Rakesh Dixit, Ph.D., DABT., Senior Director and Head, Toxicology Department, MedImmune Incorporated
• Quantitation using Metabolomics versus Metabonomics
• Correlation with other “omics” profiling
• Target, efficacy, mechanism of action, and safety assessment
• Limitations and opportunities
Table 5
Mass Spectrometry for Identification of Unknown Metabolites
Facilitator: Dr. Liang Li, Professor of Chemistry and Canada Research Chair in Analytical Chemistry, Department of Chemistry, University of Alberta, Edmonton
• Complementary techniques used for metabolite identification:
NMR,
MS, and others
• Metabolite identification based on molecular mass and fragment
ion
spectra
• Challenges and opportunities in developing new MS methods for
metabolite identification
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5:30 Networking Reception, Poster and Exhibit Viewing
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