Astrocyte-Microglia communication and function in response to ischemic stroke

描述（由申请人提供）：在美国每18例缺血性中风死亡中就有1例是中风导致的，缺血性中风是迄今为止最常见的中风病因（87%）。缺血性中风幸存者的死亡率和发病率是由于局部脑区血流量严重减少（脑缺血）引起的脑损伤以及血流返回缺血组织时伴随的促炎症反应（再灌注损伤）。缺血性卒中和再灌注引起的脑损伤与免疫细胞和促炎反应相关，有明确的证据表明，小胶质细胞，驻留的脑免疫细胞，是卒中的主要早期反应者。在损伤和疾病的反应中，小胶质细胞的形态从静止（小细胞体，长活动过程）到不同激活阶段（细胞体扩大和收缩/增厚过程）的变化来反映

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. PUBLIC HEALTH RELEVANCE: The outcomes of the proposed research project will serve the growing number of people who suffer a stroke each year by increasing our understanding of how brain cells contribute to brain injury after stroke. Findings from this application are intende to provide knowledge that will lead towards the development of new stroke therapies that will limit brain injury, extend healthy life, and reduce disability from ischemic stroke. An additional outcome of the proposed research plan will be to prepare, through focused training and mentoring, a research scientist and future nurse educator who, over the course of her career, will make significant contributions toward 1) understanding causes of brain injury after stroke, 2) the care of people who experience this kind of injury and 3) the education of future nurses who will care for stroke patients.