CELL-CELL INTERACTION AND HYPOXIC BRAIN INJURY

细胞间相互作用和缺氧性脑损伤

• 批准号: 6661257
• 负责人: Mark Paul Goldberg
• 金额: $ 142.46万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6661257
• 关键词: apoptosis; cerebral ischemia /hypoxia

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.

这是一份修订后的申请，旨在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发病机制的生产性项目的继续。目前的批准期主要集中在α -氨基-3-羟基-5-甲基-4-异恶唑己丙酸(AMPA) / kainate受体介导的损伤，而本申请是在当前期间（1995年2月2日至00年1月31日，P01 NS32636）出现的几个新主题的基础上进行的。拟议的实验得到了10名教员的努力，在3个相互关联的实验项目和4个支持核心上合作。项目1将利用体外和体内损伤模型，验证毒性水平的Zn2+进入可能导致短暂性全身缺血和轻度短暂性局灶缺血后神经元死亡的假设。项目II和III通过Ca2+或Zn2+进入损伤的主要第二信使来检查后期事件。项目II将检查下游的细胞内过程，特别是检查缺氧诱导的星形胶质细胞线粒体自由基产生的变化，并验证星形胶质细胞自由基产生的增加有助于神经元死亡的新假设。最后，项目III将超越损伤范围，研究损伤后树突结构和功能突触的恢复，特别是测试由于轻度缺氧损伤而丢失的突触可以重建和恢复功能的假设。这些实验部分由管理，计算和统计核心(A)支持；a动物核心（体内缺血）(B)；a显微镜和成像核心(C)；和一个立体核心(D)。除了共享细胞-细胞相互作用的中心研究主题外，三个拟议的项目将合作进行涉及Zn2+或星形胶质细胞介导的特定信号传导过程的实验。综上所述，拟议的实验将结合分子、细胞和全动物方法来回答与理解缺氧缺血性脑损伤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。