Abstract
The purpose of this research program is to use a multidisciplinary approach to investigate the pathophysiology of spinal cord injury (SCI) with the major goal of developing therapies targeted at both the acute and more chronic injury setting. We are testing the overall hypothesis that high content screening (HCS) of available libraries containing 100's to 1000's of chemicals, small molecules, and small interfering RNA's (siRNA's) will lead to the identification of novel strategies to reduce cell death and improve axonal regeneration following SCI. In this period of funding, we have made significant progress in this overall goal. In Specific Aim Number 1, the identification of molecules from HCS screening that inhibit excitotoxic brain cell death in primary neurons has been conducted. One of these compounds BMP7 has now been translated into a clinically relevant model of SCI and shown beneficial effects in preserving neuronal survival. Other studies have assessed the cell signaling cascades in which BMP7 may influence. In Specific Aim Number 2, a variety of EphA4 dependent receptor functions have been evaluated using a various of approaches. Candidate small molecular drug screening procedures have resulted in several exciting compounds that reduce the amount of EphA4 induced apoptosis. Some of these candidate molecules have now been translated into relevant models including EphA4-mediated cell death in primary oligodendrocytes. In Specific Aim Number 3, the compounds and siRNA's capable of producing mononuclear phagocyte inactivation have been evaluated. An in vitro system to evaluate microglial cell activation has been developed and the BIOMOL compound library which includes more than 400 drugs have been screened. The in vivo testing of one of these agents for therapeutic efficacy is now being conducted in a clinically relevant model of spinal cord injury.
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