ROLE OF HSP 25 IN THE ASTROCYTE RESPONSE AND RECOVERY FROM SPINAL CORD INJURY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Spinal cord injury (SCI) and subsequent secondary cell death partially involves an ischemic component. Oligodendrocytes and astrocytes survival is critical to maintain cellular interactions in the white matter and limit secondary injury damage. The purpose of this proposal is to study heat shock proteins (hsps) induction and interactions in hypoxia/ischemia-exposed oligodendrocytes and astrocytes and identify molecules and signaling pathways associated with higher tolerance to ischemia. Hsps induced by various stresses are involved in protein refolding and repair, and have been implicated in cellular ischemic tolerance in brain and in spinal cord. We will test the hypothesis that after SCI, induction of hsp expression modulates glial cell survival signaling pathways to preserve oligodendrocyte / astrocyte integrity and interactions with neurons. The specific aims of this proposal are: 1. To examine the expression profile of heat shock proteins induced in hypoxic/ischemic oligodendrocytes and astrocytes in culture, and in contused spinal cord. 2. To determine the effect of hsp on oligodendrocytes and astrocytes survival to hypoxia/ ischemic injury and after SCI. 3. To determine the mechanism(s) of hsp-related cell protection and the role of hsp binding proteins in hypoxia/ ischemia survival pathways and in cell death after SCI. Using embryonic oligodendrocyte precursors (OPCs) differentiated to either oligodendrocytes or astrocytes and exposed to hypoxia/ischemia, we will assess heat shock proteins expression in a cellular model and correlate the levels of hsp expression with cell survival. In addition, we will characterize the profile of hsps induced by SCI in rodent spinal cord. The effect of hsp gene overexpression or silencing on oligodendrocytes/astrocytes survival to cellular hypoxia/ ischemia and on SCI-induced delayed injury will be determined, as well as the effect of experimental hsp induction in the whole animal on secondary injury-induced damage after SCI. Finally, we will use proteomic approaches to identify protein-protein interactions with hsps induced by hypoxia/ischemia in oligodendro- cytes and in astrocytes, and in differentially damaged areas of the spinal cord after SCI. Thus, we will characterize signaling pathways underlying cellular differential sensitivity to hypoxia/ischemia and identify potential intervention targets in SCI. These studies will identify novel therapeutic approaches to preserve oligodendroglial support in injured spinal cord, inhibit apoptosis, and reduce delayed white matter injury.