Astrocyte-Microglia communication and function in response to ischemic stroke

星形胶质细胞-小胶质细胞对缺血性中风的通讯和功能

• 批准号: 8316966
• 负责人: Helena Willington Morrison
• 金额: $ 4.92万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316966
• 关键词: Acute Brain Injuries; Address; Age; Anti-Inflammatory Agents; Anti-inflammatory; Area; Astrocytes; Blood flow; Brain; Brain Injuries; Caring; Cause of Death; Cells; Cellular Morphology; Cerebral Ischemia; Cerebrum; Cessation of life; Coagulation Process; Communication; Contralateral; Development; Disease; Education; Environment; Etiology; Future; Goals; Image Analysis; Imaging Techniques; Immune; Immune response; Incidence; Individual; Infarction; Inflammatory; Inflammatory Response; Injury; Investigation; Ischemic Stroke; Knowledge; Lead; Life; Link; Measures; Mediating; Mediator of activation protein; Mentors; Methods; Microglia; Minocycline; Morbidity - disease rate; Morphology; Neuroglia; Nurses; Nursing Faculty; Outcome; Pathologic; Patients; Physiological; Physiological Processes; Population; Process; Reperfusion Injury; Reperfusion Therapy; Research; Research Project Grants; Rest; Role; Scientist; Slice; Speed; Staging; Stroke; Testing; Tissues; Training; Work; base; brain cell; brain tissue; career; disability; experience; improved; mortality; mouse model; neuronal cell body; neurotrophic factor; novel; response; response to injury; stroke therapy

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.

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 例是中风造成的，迄今为止，缺血性中风是最常见的中风病因 (87%)。对于缺血性中风幸存者来说，死亡率和发病率是由于流向局部大脑区域的血流严重减少（脑缺血）以及血流返回缺血组织时发生的促炎反应（再灌注损伤）引起的脑损伤造成的。缺血性中风和再灌注引起的脑损伤与免疫细胞和促炎症反应相关，有明确的证据表明小胶质细胞（常驻脑免疫细胞）是中风的主要早期反应者。为了响应损伤和疾病，小胶质细胞形态从静止（具有长活跃过程的小细胞体）变化到激活的各个阶段（扩大细胞体和收缩/增厚过程）以反映 他们的生理和病理环境。在功能上，小胶质细胞对损伤有两种不同的反应，产生（1）促炎因子和（2）促生存/神经营养因子。本项目提出的我们的目标是将小胶质细胞形态与小胶质细胞功能联系起来 确定星形胶质细胞-小胶质细胞相互作用是否导致缺血性中风和再灌注后小胶质细胞形态变化。我们的中心假设是，活化的小胶质细胞形态和促炎功能的测量将在空间和时间上与脑损伤增加的区域呈正相关，并且星形胶质细胞-小胶质细胞的相互作用有助于缺血性中风和再灌注后小胶质细胞活化的增加。我们将在缺血性中风和再灌注的小鼠模型中使用固定脑组织的免疫组织化学和新颖的图像分析方法，以及在活体脑切片中使用高速共聚焦成像技术来解决两个主要问题。在目标 1 中，我们将鉴定激活的小胶质细胞形态和功能与缺血性中风和再灌注后脑损伤的空间和时间关系。在目标 2 中，我们将确定星形胶质细胞与小胶质细胞的通讯如何改变缺血性中风和再灌注后小胶质细胞的形态。这项研究将增加我们对缺血性中风和再灌注后小胶质细胞行为和功能的理解，并阐明改变小胶质细胞激活的小胶质细胞-星形胶质细胞相互作用 缺血性中风后。对局部免疫反应和神经胶质细胞间相互作用对缺血性中风和再灌注后脑损伤的贡献的了解将指导未来新型中风疗法的开发。 公共健康相关性：拟议研究项目的成果将通过增加我们对脑细胞如何导致中风后脑损伤的理解，为每年越来越多的中风患者提供服务。该申请的研究结果旨在提供知识，促进新中风疗法的开发，从而限制脑损伤、延长健康寿命并减少缺血性中风造成的残疾。拟议研究计划的另一个成果将是通过集中培训和指导，培养一名研究科学家和未来的护士教育工作者，他们在其职业生涯中将为以下方面做出重大贡献：1）了解中风后脑损伤的原因， 2） 对遭受此类伤害的人的护理以及 3) 对未来护理中风患者的护士的教育。