CELL CELL INTERACTION AND HYPOXIC BRAIN INJURY

细胞相互作用和缺氧性脑损伤

• 批准号: 2332993
• 负责人: Dennis W Choi
• 金额: $ 103.67万
• 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 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2332993
• 关键词: cell cell interaction; cerebral ischemia /hypoxia; glutamate receptor; cell cell interaction; cerebral ischemia /hypoxia; glutamate receptor

Grant funds are requested to support a new research program project aimed at the long-term goal of understanding how cell-cell interactions influence the pathogenesis of hypoxic-ischemic brain injury. Glutamatergic neurotransmission in particular has been implicated in the pathogenesis of hypoxic-ischemia neuronal death. While attention in the area has centered historically around N-methyl-D-aspartate (NMDA) receptor-mediated contributions to hypoxic brain damage, recent evidence has indicated that alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionate/kainate (AMPA/KA) receptors may also be important mediators of injury in the hypoxic-ischemic brain. Elucidation of several mechanisms underlying this AMPA/KA receptor mediation is the specific goal of the present application. The proposed experiments enlist the efforts of 8 faculty investigators, collaborating on 4 highly interlinked experimental Projects and 5 supporting Cores. Project 1 will investigate the contribution of AMPA/KA receptors to hypoxic neuronal injury in cortical cell cultures, with special attention to the minority subset of AMPA/KA receptors which gate Ca2+-permeable channels. Project II will harness a recent discovery that certain benzothiadiazides can modify AMPA/KA receptor desensitization, using these drugs as probes to study the role of AMPA/KA receptor desensitization in limiting hypoxic neuronal injury. Project III will use fura-2 videomicroscopy to examine the hypothesis that AMPA/KA receptor overactivation contributes to hypoxic neuronal injury by disrupting neuronal intracellular Ca2+ homeostasis. Project IV will explore the relationship between hypoxic AMPA/KA receptor activation and free radical-mediated cell damage. These experimental sections are supported by an administrative core (A); an animal (in vivo ischemia) core (B); a histology core (C); a computing and image analysis core (D); and a statistics core (E). taken together, proposed experiments will combine molecular, cellular, and whole animal approaches to answer several specific 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.

要求赠款资金支持针对的新研究计划项目 以理解细胞电池相互作用的长期目标 影响缺氧 - 缺血性脑损伤的发病机理。 谷氨酸能神经传递特别是与 缺氧性缺氧神经元死亡的发病机理。 而关注 区域历史上以N-甲基-D-天冬氨酸（NMDA）为中心 受体介导的对低氧脑损伤的贡献，最近的证据 已经表明α-氨基-3-羟基-5-甲基-4-- 异恶唑磷酸/海藻酸盐（AMPA/KA）受体也可能很重要 缺氧 - 缺血大脑中损伤的介体。 阐明 此AMPA/KA受体介导的几种机制是 本应用程序的具体目标。 拟议的实验提出了8位教职员工的努力， 合作4个高度链接的实验项目和5个 支撑芯。 项目1将调查AMPA/KA的贡献 皮质细胞培养物中缺氧神经元损伤的受体， 特别关注AMPA/KA受体的少数子集 CA2+ - 可渗透通道。 第二个项目将利用最近发现的发现 某些苯甲酰二氮化物可以改变AMPA/KA受体脱敏， 使用这些药物作为探针研究AMPA/KA受体的作用 在限制缺氧神经元损伤中脱敏。 第三项目将 使用Fura-2视频显微镜检查AMPA/KA的假设 受体过度活化会导致缺氧神经元损伤 破坏神经元内CA2+稳态。 IV项目将 探索低氧AMPA/KA受体激活与 自由基介导的细胞损伤。 这些实验部分是 由行政核心（a）支持；动物（体内缺血） 核心（b）;组织学核心（C）；计算和图像分析核心（D）； 和统计核心（E）。 两者一起，提出的实验将 结合分子，细胞和整个动物的方法 与理解低氧的发病机理有关的几种特异性 缺血性脑损伤。 从这些研究中收集的信息可能有助于 有效的中风临床疗法的未来开发 心脏停搏。