CELL-CELL INTERACTION AND HYPOXIC BRAIN INJURY

这是一份修订后的意见书，请求对FIMD的支持，以支持一项旨在长期了解细胞-细胞相互作用如何影响缺氧缺血性脑损伤病因的生产性计划项目的继续。目前的赠款期间侧重于α-氨基丙酸(α-amino-3-hydroxy-5-methyl-4-isoxazolcpropionate)/海人藻酸受体介导的损伤，而本提议是对当前期间出现的几个较新主题的后续行动(2/02/95-1/31/00，P01 NS32636)。拟议的实验得到了10名教员研究人员的努力，他们在3个相互关联的实验项目和4个支持核心上进行了合作。项目1将利用体外和体内损伤模型，验证锌进入的毒性水平可能导致短暂性全脑缺血和轻度短暂性局灶性脑缺血后神经元死亡的假设。项目II和III越过了损伤的主要第二信使，即钙离子或锌离子的进入，以检查后来的事件。项目二将研究下游的细胞内过程，特别是研究低氧诱导的星形胶质细胞线粒体自由基产生的变化，并测试一个新的假设，即星形胶质细胞自由基产生的增加有助于神经元死亡。最后，项目III将着眼于损伤地平线之外，检查损伤后树突状结构和功能性突触的恢复，特别是测试因轻度缺氧侮辱而丢失的突触可以重建和恢复功能的假设。这些实验部分由行政、计算和统计核心(A)、动物核心(活体缺血)(B)、显微镜和成像核心(C)和体视学核心(D)支持。除了共享细胞间相互作用的中心研究主题外，这三个拟议的项目还将在涉及由锌离子或星形胶质细胞介导的特定信号过程的实验上进行合作。综上所述，拟议的实验将结合分子、细胞和整个动物的方法来回答与理解缺氧缺血性脑损伤的发病机制相关的几个具体问题。从这些研究中收集的信息可能有助于未来开发有效的中风和心脏骤停临床治疗方法。

This is a revised submission to request support for fimds to support continuation of a productive Program Project aimed in the long-term at understanding how cell-cell interactions influence the pathogencsis of hypoxic-ischemic brain injury. The current grant period focused on alpha- amino-3-hydroxy-5-methyl-4-isoxazolcpropionate (AMPA) / kainate receptor-mediated injury, whereas the present proposal follows up on several newer themes that emerged during the current period (2/02/95 - 1/31/00, P01 NS32636). The proposed experiments enlist the efforts of 10 faculty investigators, collaborating on 3 interlinked experimental Projects and 4 supporting Cores. Project 1 will test the hypothesis that toxic levels of Zn2+ entry may contribute to neuronal death after transient global ischemia and mild transient focal ischemia, utilizing both in vitro and in vivo injury models. Project II and III move past the main second messenger of injury, entry of Ca2+ or Zn2+, to examine later events. Project II will examine downstream intracellular processes, specifically examining hypoxia- induced changes in astrocyte mitochondrial free radical production, and testing a novel hypothesis that this increase in astrocyte free radial production contributes to neuronal death. Finally, Project III will look beyond the injury horizon and examine the recovery of dendritic structures and fimctional synapses post injury, specifically testing the hypothesis that synapses lost due to mild hypoxic insults can reform and regain firnction. These experimental sections are supported by an Administrative, Computing, and Statistics Core (A); an Animal Core (in vivo ischemia) (B); a Microscopy and Imaging Core (C); and a Stereology Core (D). Besides sharing a central investigative theme of cell-cell interactions, the three proposed Projects will collaborate on experiments involving specific signaling processes mediated by Zn2+ or astrocytes. Taken together, proposed experiments will combine molecular, cellular, and whole animal approaches to answer several specific questions relevant to understanding the pathogenesis of hypoxic-ischemic brain damage. Information gathered from these studies may aid the future development of effective clinical therapies for stroke and cardiac arrest.