This is an application for a K23- Mentored Patient-Oriented Research Career Development Award entitled: Proteomic Studies of MMP Profiles in Stroke Thrombolysis. The candidate proposes to use proteomic technology to investigate the mechanism of matrix metallo-proteinases (MMPs) in thrombolysis outcome of acute cerebral focal ischemia, with the ultimate goal of optimizing patient selection to make acute stroke treatment safer and more utilized. We hypothesize that MMP-9 contributes to tPA-related injuries by triggering important downstream cell-cell and cell-matrix signaling mechanisms. The primary goals of the proposed research are: 1) to investigate MMP-9's potential downstream substrates in human endothelial cell culture over-expressing MMP-9;2) to expand MMP-9 substrate characterization to the more complex but more physiologically-relevant environment of thrombolysed human plasma, thereby identifying additional substrates of MMP-9 and of other important candidate proteases;and 3) to conduct exploratory studies to expand the repertoire of proteases important to thrombolysis outcome, as potential targets for therapy. The candidate seeks training in: 1) proteomic techniques and the basic principles of bioinformatics, to analyze proteomic data in human samples and cell cultures;2) the neurobiology of thrombolysis-related adverse outcome in focal ischemia;3) advanced epidemiological clinical research methods, to further patient-oriented research. The proposed research plan, didactic courses, and tutorial instructions from mentors and advisors will ensure the career development of the candidate into an independent clinician scientist.
