Mark R. Chance, Ph.D.

Faculty Appointments School of Medicine Vice Dean for Research Center for Proteomics and Bioinformatics: Director Charles W. and Iona A. Mathias Professor of Cancer Research Department of General Medical Sciences: Professor (Primary) Department of Genetics and Genome Science: Professor (Secondary)

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The research in my laboratory is focused in the important areas of structural and cellular proteomics. High throughput methods are revolutionizing structural biology through structural genomics initiatives. We are using these advances to identify the structure and function of large macromolecular complexes in areas relevant to iron transport, mis-match repair, and actin filament assembly. New technologies in mass spectrometry are also allowing protein expression, localization, and interactions to be studied in increasing detail and on a genome wide scale. Our expertise in quantitative mass spectrometry and 2-D gel technologies are being applied to identify biomarkers and regulatory pathways in colon cancer, diabetes, radiation exposure, and HIV infection.

In structural biology, structural genomics has as its goal the provision of structural models for all possible open reading frame sequences. This will be accomplished by solving the structures of 5,000-10,000 carefully selected target proteins, each one a member of a distinct protein family. The remainder of the structures will be solved by comparative modeling. Our experience in the New York Structural GenomiX Research Consortium with the 200 structures that have been solved so far is that we can model over 500 additional open reading frame sequences for each solved structure.

Although structural genomics is rapidly progressing, our progress to date clearly identifies the next biological hurdle. High-throughput structural biology is optimized to examine the structure of small soluble protein domains, while critical functions of biology are controlled by larger multi-protein complexes. The availability of high resolution domain structures is critical to understanding the assemblies, the domains must "dock" with each other in a functionally relevant fashion. The long term structural goals of my laboratory are focused on understanding the structure and dynamics of these assemblies. We are using biochemical approaches, mass spectrometry, crystallography, cryo-EM, cross-linking, footprinting, and molecular modeling to understand the physiologically relevant functional states.

In our expression proteomics studies, examining the post-translational modifications, amounts, and interactions of proteins are combined in integrated studies to understand the pathology of human disease. Working with investigators across the Case campus and across NE Ohio, we are developing new biomarkers to direct therapeutic approaches for patients, probing fundamental regulatory mechanisms of disease, and comparing these markers and regulatory mechanisms to those seen in normal development and normal physiology.

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