This is an application for a competitive supplement to the three-year Mentored Clinical Scientist Development (K08) Award. The original K08 grant entitled, """"""""The role of zinc in focal ischemic brain injury,"""""""" was awarded on 7/1/00. However, in 12/01 (1.5 years into the grant), the applicant's mentor, Dr. Dennis Choi left the institution, prompting a change in mentors (to Dr. Chung Y. Hsu, with co-mentors, Dr. Mark Goldberg and Dr. David Holtzman) and a change in research direction. For the past 9 months, the applicant has been pursuing this new direction, studying the pathogenesis of spontaneous intracerebral hemorrhage in cerebral amyloid angiopathy (CAA). In particular, he has found that the amyloid beta peptide induces the expression and activity of the extracellular matrix-degrading protease, matrix metalloproteinase-9 (MMP-9), in cultures of cerebral endothelial cells. Furthermore, vascular MMP-9-like immunoreactivity was found in aged mice carrying the double Swedish mutation of the amyloid precursor protein (APPsw, a rodent model of CAA), but not in younger mice. The central hypothesis of this proposal is that amyloid beta, which accumulates in cerebral blood vessels in CAA, induces vascular MMP-9 activity and contributes to the development of spontaneous hemorrhagic stroke. Due to space limitations a complete application detailing the new proposal is not possible; however, Specific Aims, preliminary studies, and a brief outline of research design is included in this proposal. The goal of the applicant during this extension is to pursue the project outlined above and to receive additional training in molecular biology, microscopy and in developing animal models for disease. The additional two years of funding will allow protected time to accumulate data and publications that will put the applicant in a position to apply for independent funding (R21 or R01) and, ultimately, develop into an independent investigator.
