We have found that reactive microglia and invading macrophages exacerbate many neuropathic conditions including stroke and trauma. Moreover, drug inhibition of mononuclear phagocytes reduces neuronal loss and improves neurologic function. In order to understand and control inflammatory responses after acute CNS injury, we will study fundamental issues of microglial biology by comparing microglia with other classes of mononuclear phagocytes, by identifying activators and inhibitors of microglia function, and by delineating microglia-astroglia and microglia-neuron interactions. Bulk isolation of highly enriched populations of microglia will provide material needed to develop cell specific monoclonal antibodies. These reagents will then be used to monitor subclasses of mononuclear phagocytes after brain injury. Transplantation of prelabeled microglia will allow investigation of the functional capacities and fates of brain mononuclear phagocytes in vivo. Biochemical studies will include structural analysis of a brain-derived microglial mitogen as well as study of cytotoxic and neuro-excitant factors. In vitro and in vivo models will be used to explore the action of cytokines upon microglial cells and to screen immunosuppressive drug effects upon brain inflammation. We believe that these proposed experiments will uncover new and important roles for brain mononuclear phagocytes and, thus, provide new and important insights concerning immunologic events that regulate the structure and function of the CNS.
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