The aim of this proposal is to test the hypothesis that viability of differentiated (brain) cells is to a large extent regulated by the activity of protein kinase C (PKC) isozymes. As shown by several investigators, this family of enzymes plays a key role in cell-surface signal transduction and regulation of cytoskeletal and cell membrane elements, e.g. ionic channels and receptors, in a variety of cells including neurons. Pathologically altered brain tissues are also known to undergo severe alterations in intracellular architecture. PKC also plays a role in neuronal activity as shown by the potentiation of synaptic transmission by phorbol esters in the hippocampus. It is also accepted by cytoskeletal elements undergo sequences of assembly and disassembly in response to cycles of phosphorylation and dephosphorylation through the interactions of calcineurin, clamodulin and various protein kinases. We thus postulate that the loss of viability of neuronal cells may result from long-term inactivation of """"""""membrane-anchored"""""""" PKC isozyme(s) whose role is to maintain the differentiated state and functionality of the membrane in these cells. We further suggest that endocrine influences (e.g. from gonadal hormones) extend from the induction of sex differentiation during brain development, to modulation of autonomous programs of gene expression, re-initiation of proliferation, and the triggering of cell death. It is thus crucial to determine whether there is a reciprocal relationship between steroid content and the activity of PKC of pathologically altered brain tissue samples from experimental animals and human patients. We propose to determine whether there is a significant change in the activity of specific PKC isozymes in brain tissue samples obtained by the rapid autopsy protocol. If this is the case we will initiate enzymatic and molecular/immunological studies to fully identify and characterize the specific PKC isozymes that undergo changes in parallel to the loss of neuronal viability and function.

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Duke University
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