CELL-CELL INTERACTION AND HYPOXIC BRAIN INJURY

细胞间相互作用和缺氧性脑损伤

• 批准号: 6393656
• 负责人: Chung Y. Hsu
• 金额: $ 135.8万
• 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/6393656
• 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.

这是一份修订后的提交文件，旨在请求支持fimds，以支持继续开展一项富有成效的计划项目，该项目旨在长期了解细胞间相互作用如何影响缺氧缺血性脑损伤的发病机制。目前的资助期集中于α-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯（AMPA）/红藻氨酸受体介导的损伤，而目前的提议则是对当前期间出现的几个较新的主题（2/02/95 - 1/31/00，P01 NS 32636）进行跟进。拟议的实验招募了10名教师研究人员的努力，在3个相互关联的实验项目和4个支持核心上进行合作。项目1将利用体外和体内损伤模型，检验毒性水平的Zn 2+进入可能导致短暂性全脑缺血和轻度短暂性局灶性缺血后神经元死亡的假设。项目II和III移动过去的主要第二信使的伤害，进入的Ca 2+或Zn 2+，检查以后的事件。项目II将检查下游细胞内过程，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将超越损伤范围，研究损伤后树突结构和功能性突触的恢复，特别是测试由于轻度缺氧损伤而丢失的突触可以改革并重新获得突触的假设。这些实验部分由管理、计算和统计学核心（A）;动物核心（体内缺血）（B）;显微镜和成像核心（C）;以及体视学核心（D）支持。除了共享细胞间相互作用的中心研究主题外，三个拟议的项目将在涉及由Zn 2+或星形胶质细胞介导的特定信号传导过程的实验上进行合作。总之，拟议的实验将结合联合收割机分子，细胞和整体动物的方法来回答几个具体的问题，了解缺氧缺血性脑损伤的发病机制。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。