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Oxidant stress is a pervasive characteristic of cardiovascular diseases and has been implicated in the etiology and progression of coronary artery disease, hypertension, diabetes mellitus, sickle cell disease, and cardiac failure. The clinical investigators of the Boston University Cardiovascular Proteomics Center have funded research programs focused on oxidant stress in cellular and mouse models, patient groups, and the cohort of the Framingham Heart Study who have been diagnosed as having one (or more) of these cardiovascular diseases. Of the multiple phenotypic markers of oxidant stress noted in all these studies, impaired endothelial cell function and altered antioxidant systems are key. Our preliminary studies demonstrate that oxidative protein modifications in endothelial nitric oxide synthase, manganese superoxide dismutase, and sarcoplasmic calcium ATPase, for example, not only serve as markers of oxidant stress, but also account for physiological dysfunction. In addition, deficiencies in antioxidant systems including glutathione peroxidase, glucose-6-phosphate dehydrogenase, and superoxide dismutase promote ischemia, proliferation, apoptosis, atherosclerosis, and cardiac failure. We propose a Cardiovascular Proteomics Center with innovative technology development to accomplish the characterization of oxidant stress in cardiovascular disease. These technologies consist of:

1. A matrix-assisted laser desorption/ionization (MALDI) cryogenic Fourier transform ion cyclotron resonance mass spectrometer to enable rapid automated sample analysis with increased sensitivity and resolution, and data-dependent targeting of protein modifications
2. Protein separation methodology based entirely on capillary HPLC, eliminating the time required for 2D gels, and
3. A highly integrated bioinformatics approach developed by Beyond Genomics which has proven capable of acquiring and analyzing the proteome of a mouse model

Using these technologies, we propose to:

1. Screen for alterations in protein abundance in cell and mouse models, select patient groups, and populations with evidence of oxidant stress and cardiovascular disease,
2. Investigate in greater structural detail the proteins already and to be identified as being oxidatively modified in order to facilitate development of screens for similarly modified unknown proteins,
3. Elucidate the nature of novel protein modifications that may be found in association with oxidative stress, and
4. Use and develop several bioinformatics approaches capable not only of handling the large amounts of data required, but also of identifying key nodes within protein networks important for understanding both the cellular response and how to modify the effects of oxidant stress.

The capabilities of this program are unique because of: the breadth of ongoing studies on oxidant stress in cardiovascular disease which will enable rapid dissemination of data to many levels of cardiovascular investigation, the proposed development of new technologies to increase our capacity for proteomic analyses, and the innovative bioinformatics approaches capable of deriving new insights into the causes and improved treatments of cardiovascular disease.

Catherine E. Costello, PhD