The PI is continuing studies on the regulation and function of aB- crystallin, a major component of the vertebrate lens and a member of the small """"""""heat shock"""""""" protein family. AB-crystallin accumulates in CNS glia and neurons in a variety of neurological disorders, in some cases actually forming inclusions in glial cells, such as the Rosenthal fibers of Alexander disease. The gene is upregulated in response to physiological stresse and the protein serves to protect cells from the adverse consequences of those stresses, but the modes of regulation and the mechanisms of protection are not fully understood. Over the previous grant period, the laboratory has begun to characterize two different transcription controlpathways through which aB-crystallin expression is regulated in astrocytes subjected to physiological stresses, one through a heat shock factor pathway and one through a heat shock-independent pathway. The PI has also begun to explore how this protein confers protection upon cells. He proposes a set of interrelated specific aims for the next grant period to examine further the transcriptional regulation of the aB-crystalling gene and the function of the protein in protecting CNS cells from physiological stress. Specifically, he plans to: 1. continue our studies todefine the transcriptional regulation of the aB-crystallin gene during phsiological stress. 2. further define how aB-crystallinprotects cells from hypertonic and other stresses, 3. explore mechanisms of Rosenthal Fiber production.
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