The integrating theme of this project is that three classes of gene products are intimately involved with modulating injury of neurons and glia following hypoxia/ischemia and, more specifically, that altering expression of these gene products can attenuate such hypoxic/ischemic damage. The program aims to define more precisely the roles of SOD, bcl-2 and hsp70 in modifying the detrimental effects of oxidative stress on cerebral neurons/glia and determining the ultimate survival or death (necrotic versus apoptotic) of these cells. The selection of these three genes for intense study reflects their potential therapeutic value, as well as the important information their investigation will yield regarding basic biologic mechanisms of ischemic cell death in central nervous tissue. The experimental results of this project could potentially lead to novel strategies for treating clinical stroke, as well as other traumatic and degenerative neurologic disorders showing a similar pathogenesis. The Program includes three interrelated projects utilizing advanced molecular biology techniques, including gene transfer therapy and transgenic technology in several paradigms of both in vitro and in vivo neuronal and glial injury. The protective potential of the three different genes will be examined using gene transfer in neuronal and glial cultures, and in transgenic and knockout cultures under anoxic and aglycemic conditions (Project 1). The neuroprotective benefit of the same three classes of genes will be studied in several models of ischemia using gene transfer in genetically normal rats (Project 2), as well as investigating protection against ischemia in transgenic or knockout rodents (Project 3). The Vector Core 9Core C) will prepare viral vectors to be used in the gene transfer experiments of Projects 1 and 2. The Transgenic Core (Core B) will produce transgenic mice and rats, as well as knockout mutants to be used in Projects 1 and 3. The Administrative Core (Core A) will provide grant management, financial administration, statistical consultation, centralized purchase, seminar arrangements, clerical assistance, and scientific consultation through Advisory Committees.
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