ASTROGLIAL REACTION TO ISCHEMIC BRAIN INJURY

星形胶质细胞对缺血性脑损伤的反应

• 批准号: 2037109
• 负责人: Richard P Kraig
• 金额: $ 22.02万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2037109
• 关键词: acid base balance; astrocytes; bicarbonates; biomarker; bromodeoxyuridine; cerebral ischemia /hypoxia; disease /disorder model; dyes; electrophysiology; enzyme linked immunosorbent assay; fluorescence microscopy; glial fibrillary acidic protein; hippocampus; hypercapnia; immunocytochemistry; induced hypothermia; laboratory rat; membrane potentials; microelectrodes; monoclonal antibody; neural degeneration; neurophysiology; potassium; pyramidal cells; spreading cortical depression; stainings; statistics /biometry; western blottings

Astrocytes are highly interactive and reactive brain cells that are essential for brain function. Accordingly, damage to brain will evolve directly from injury to astrocytes or these cells will modify their behavior in response to injury of adjacent cells. Examination of how astrocytes respond to injury from brain ischemia should lead to an improved understanding of the cellular pathogenesis of this malady. This philosophy guides the long term goal of this project: To understand how astrocytes respond to ischemic brain injury and how acid-base fluctuations participate in their response. Astrocytes either degenerate from severe ischemia (i.e. infarction) or they are transformed into reactive species by less lethal reduction in flow. Little physiologic information exists that characterizes these two cell changes or alludes to what causes the alterations. Since H+i and K+i modulate vital activities in eukaryotic cells, are interrelated in astrocytes, and are two principal ionic species regulated by these cells, the interrelation of changes in astrocytic H+i and K+i to ischemic injury will be examined in detail here. Ion-selective microelectrodes for pH, K+, as well as a newly developed triple barrel microelectrode array sensitive to pH & CO32, will be used to correlate the patterns of astrocytic acid- base and K+ change from ischemia that are associated with structural markers for these cells (i.e measurements of the cell body size, degree of DNA replication, intensity and distribution of GFAP staining as well as change in regional brain GFAP content). Degeneration of astrocytes will be studied in vivo using a rodent model of focal infarction since this type of ischemic brain injury is clinically most prevalent. Astrocytes become severely acidotic and lose their processes during infarction from global ischemia, perhaps because of a critical reduction in [HCO3-]i. How astrocytic pHi, [HCO3-]I and morphology change with focal infarction is unknown and will be determined. Astrocytic changes in H+i and K+i associated with reactive astrocytosis will be studied in vivo using global ischemia and correlated to the above structural markers of astrocytosis. Furthermore, the effect of hypothermia, which retards neuronal destruction from global ischemia, on ionic and structural variables associated with reactive astrocytosis will be examined since such destruction is thought to be necessary for astrocytic proliferation. Additionally, since astroglial pHi rises at the onset of reactive astrocytosis, the effect of hypercarbia, which acidifies these cells will be studied. Finally, the in vitro brain slice preparation will be used to determine plasma membrane-based mechanisms which interrelate changes in astrocytic pHi and K+i.

星形胶质细胞是高度互动和反应性脑细胞， 对于大脑功能至关重要。 因此，大脑的损害将进化 直接从损伤到星形胶质细胞，或这些细胞会改变其 响应相邻细胞损伤的行为。 检查如何 星形胶质细胞应对脑缺血受伤的反应应导致改善 了解这种疾病的细胞发病机理。 这个哲学 指导该项目的长期目标：了解星形胶质细胞如何 应对缺血性脑损伤以及酸碱波动如何参与 在他们的回应中。 星形胶质细胞从严重的缺血（即梗死）退化，或者它们 通过减少致命的流量减少，将其转化为反应性物种。 描述了这两个细胞的很少的生理信息 改变或暗示导致改变的因素。 由于h+i和k+i 调节真核细胞中的重要活性在 星形胶质细胞，是由这些细胞调节的两个主要离子物种， 星形胶质细胞H+I和K+I与缺血性损伤的变化的相互关系 将在此处详细检查。 pH，K+的离子选择性微电极 以及新开发的三桶微电极阵列敏感 到pH＆co32，将用于将星形胶质酸的模式相关联 与结构性相关的缺血的基础和K+变化 这些细胞的标记（即细胞体大小的测量，程度 GFAP染色的DNA复制，强度和分布以及 改变区域脑GFAP含量）。 星形胶质细胞的变性将是 使用焦点梗塞的啮齿动物模型在体内研究 缺血性脑损伤在临床上最普遍。 星形胶质细胞变成 严重的酸性酸性并在全球梗塞期间失去过程 缺血，也许是因为[hco3-] i的严重减少。 如何 星形胶质细胞PHI，[HCO3-] I和局灶性梗死的形态变化是 未知，将被确定。 H+I和K+I的星形细胞变化 将使用全局研究与反应性星形细胞增多症相关 缺血并与星形胶质细胞增多症的上述结构标记相关。 此外，体温过低的作用，会阻碍神经元破坏 来自全球性缺血，关于与离子和结构变量有关的 由于认为这种破坏是 对于星形胶质细胞增殖是必要的。 此外，由于星形胶质体 PHI在反应性星形胶质细胞增多症开始时升起，高碳酸盐的影响， 将研究这些细胞的酸化。 最后，体外大脑 切片制剂将用于确定基于质膜的 与星形胶质细胞PHI和K+I相互关联的机制。