CELL CELL INTERACTION AND HYPOXIC BRAIN INJURY

细胞相互作用和缺氧性脑损伤

• 批准号: 6135996
• 负责人: Dennis W Choi
• 金额: $ 2.58万
• 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 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6135996
• 关键词: 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.

赠款资金被要求支持一个新的研究计划项目， 长期目标是了解细胞间的相互作用 影响缺氧缺血性脑损伤的发病机制。 谷氨酸能神经传递尤其与 缺氧缺血性神经元死亡的发病机制。 虽然注意力集中在 该领域历史上以N-甲基-D-天冬氨酸（NMDA）为中心 受体介导的缺氧性脑损伤，最近的证据 已经表明α-氨基-3-羟基-5-甲基-4- 异恶唑丙酸/红藻氨酸（AMPA/KA）受体也可能是重要的 缺氧缺血性脑损伤的介质。 阐明 AMPA/KA受体介导的几种机制是 本申请的具体目的。 拟议的实验招募了8名教师调查员的努力， 4个高度关联的实验项目和5个 支持核心。 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， 特别注意少数AMPA/KA受体亚群， Ca 2+渗透通道。 项目二将利用最近的一项发现， 某些苯并噻二叠氮可以改变AMPA/KA受体脱敏， 以这些药物为探针，研究AMPA/KA受体的作用 脱敏在限制缺氧神经元损伤中的作用。 项目三将 使用Fura-2视频显微镜检查AMPA/KA 受体的过度激活通过以下途径导致缺氧性神经元损伤： 破坏神经元细胞内Ca 2+稳态。 项目四将 探讨缺氧性AMPA/KA受体激活与缺氧性心肌缺血的关系。 自由基介导的细胞损伤。 这些实验部分是 由给药核心（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）。 综合考虑，拟议的实验将 联合收割机结合分子、细胞和整个动物的方法来回答 几个具体的相关了解缺氧的发病机制- 缺血性脑损伤 从这些研究中收集的信息可能有助于 中风有效临床治疗的未来发展， 心脏骤停