CELL CELL INTERACTION AND HYPOXIC BRAIN INJURY

要求拨款以支持一项新的研究项目，该项目旨在 长期目标是了解细胞与细胞之间的相互作用 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涉及到 缺氧缺血型神经元死亡的发病机制。当人们关注的时候 该地区历史上一直以N-甲基-D-天冬氨酸(NMDA)为中心 受体介导在缺氧性脑损伤中的作用，最新证据 已表明α-氨基-3-羟基-5-甲基-4- 异恶唑丙酸/海人藻酸(AMPA/KA)受体可能也很重要 缺氧缺血性脑损伤的介质。澄清： 这种AMPA/KA受体调节的几种机制是 本申请的具体目标。 这项拟议的实验征集了8名教职员工的努力， 在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 皮层细胞培养中缺氧性神经元损伤的受体 特别关注AMPA/KA受体的少数亚群 钙离子通透性通道。项目II将利用最近的一项发现 某些苯并硫二氮类化合物可以改变AMPA/KA受体的脱敏作用， 以这些药物为探针研究AMPA/KA受体的作用 脱敏在限制缺氧性神经元损伤中的作用。项目III将 用Fura-2视频显微镜检验AMPA/KA的假说 受体过度激活通过以下途径促进缺氧性神经元损伤 扰乱神经细胞内钙稳态。项目IV将 探讨缺氧性AMPA/KA受体激活与血管紧张素转换酶的关系 自由基介导的细胞损伤。这些实验部分是 由管理核心(A)支持；动物(体内缺血) 核心(B)；组织学核心(C)；计算机和图像分析核心(D)； 和一个统计核心(E)。综上所述，拟议的实验将 结合分子、细胞和整体动物方法来回答 与了解低氧发病机制相关的几个具体问题 缺血性脑损伤。从这些研究中收集的信息可能有助于 卒中和中风有效临床治疗方法的未来发展 心脏骤停。

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.