Astrocyte-Microglia communication and function in response to ischemic stroke

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DESCRIPTION (provided by applicant): Stroke is responsible for 1 out of every 18 deaths in the US with ischemic stroke, by far, the most common stroke etiology (87%). Mortality and morbidity, for those that survive ischemic stroke, result from cerebral injury caused by severely reduced blood flow to localized brain areas (cerebral ischemia) and accompanied pro- inflammatory responses that occur when blood flow returns to the ischemic tissue (reperfusion injury). Cerebral injury caused by ischemic stroke and reperfusion correlates with immune cell and pro-inflammatory responses, with clear evidence identifying microglia, the resident brain immune cell, as a dominate early responder in stroke. In response to injury and disease, microglia cell morphology changes from resting (small cell body with long active processes) to various stages of activation (enlarging cell bodies and retracting/thickening processes) to reflect their physiologic and pathologic environments. Functionally, microglia have two divergent responses to injury, producing (1) pro-inflammatory and (2) pro-survival/neurotrophic factors. Our objective, presented in this project, is to link microglia morphology to microglia function and to determine whether astrocyte-microglia interactions contribute to microglia morphologic changes after ischemic stroke and reperfusion. Our central hypothesis is that measures of activated microglia morphology and pro-inflammatory function will positively correlate to areas of increased cerebral injury in a spatial and temporal manner and that astrocyte-microglia interactions contributes to increased microglia activation after ischemic stroke and reperfusion. We will use, in a mouse model of ischemic stroke and reperfusion, immunohistochemical and novel image analysis methods in fixed brain tissue as well as, in live brain slices, high speed confocal imaging techniques to address two main issues. In Aim 1 we will identify activated microglia morphology and function in a spatial and temporal relationship to cerebral injury after ischemic stroke and reperfusion. In Aim 2 we will determine how astrocyte-microglia communication alters microglia morphology after ischemic stroke and reperfusion. This study will increase our understanding of microglia actions and function after ischemic stroke and reperfusion as well as elucidating microglia-astrocyte interactions that alter microglia activation after ischemic stroke. Such an understanding of the contribution of localized immune responses and glia-to-glia interactions to cerebral injury after ischemic stroke and reperfusion will direct he development of future novel stroke therapies.