Understanding the mechanisms underlying the phenomenon of ISCHEMIC TOLERANCE in brain, in which brief preconditioning ischemia confers potent neuroprotection against subsequent ischemic injury, may yield powerful insight into both the control of cell death in brain and therapeutic strategies with which to treat cerebrovascular disease. BCL-2 FAMILY PROTEINS have pivotal roles in the control of both necrosis and apoptosis, and are strongly implicated in the response of the brain to ischemia. Their role in the mechanism of tolerance remains unexplored and therefore the aim and objective of this proposal is to characterize the response, mechanism of action and therapeutic potential for modulation of bcl-2 family genes in ischemic tolerance, for which we now have exciting preliminary data. The hypotheses to be tested are: (a) Preconditioning ischemia induces changes in the expression of pro- and antiapoptotic bcl-2 family genes congruent with the temporal and regional profile of tolerance induction; (b) preconditioning ischemia may also induce dimerization and translocation of bcl-2 family gene products that confer protection; (c) modification of bcl-2 gene expression may replicate the effects of preconditioning ischemia; (d) the cellular basis for ischemic tolerance resides with both neurons and glia.
The Specific Aims for this project are to: (1) Identify the temporal, regional and cellular profile of bcl-2 family gene expression in brain made tolerant to ischemia by ischemic preconditioning. (2) Investigate the DIMERIZATION and TRANSLOCATION characteristics of bcl-2 family gene products in that portion of brain made tolerant to ischemia. (3) Reproduce or obviate the effects of preconditioning by modifying bcl-2 family gene expression in vivo by overexpression with ADENO-ASSOCIATED VIRAL VECTORS or inhibition by ANTISENSE techniques. (4) Determine the effects of ischemic tolerance on neurons and glia in vitro, and their relative contribution to the underlying mechanism of tolerance. Endogenous stress responses, of which tolerance is one, are evolutionarily highly conserved, and may reveal particularly relevant protective neurobiological mechanisms. Therefore, understanding the role of bcl-2 family gene products in the mechanism underlying ischemic tolerance has the potential to yield further insight into stroke-induced brain damage, and offers novel therapeutic targets based on the means by which the brain's endogenous protective capacity functions.
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