INTRACELLULAR CALCIUM RELEASE IN ISCHEMIC NEURONAL DEATH

描述：来自心脏的脑缺血后神经细胞死亡 猝死或中风是发病率的主要来源。多条证据 提示钙调节的中断可能在这种情况下起作用 受伤。拟议的研究将检验这一新的假设，即 神经细胞损伤的部分原因是钙过量释放。 细胞内内质网(ER)储存，导致两者耗尽 和细胞内钙的增加。目标1将研究 内质网钙释放在神经元培养细胞毒性模型中的作用 靶向内质网储存的药物，评估细胞死亡、钙释放和 丹曲林对兰尼定受体的保护作用 (RyR)介导的内质网钙释放组分。AIM 2将延长这一期限 对同一体外制剂中缺氧/血糖损伤的探讨。这个 涉及一氧化氮的特定第二信使通路的可能激活 将评估氧化物、cGMP和cADP-核糖。目标3将决定是否 胞浆钙升高或内质网池耗尽对此有更大的贡献 对细胞死亡很重要，并将评估参与 线粒体。目标4将把研究扩展到活体模型并检查 丹曲林单独及与钙通道联合应用的作用 拦截者。这些研究将提供有关新的机制的信息 缺血性神经元死亡与可能的药物治疗 临床相关性。

DESCRIPTION: Neuron cell death following cerebral ischemia from cardiac arrest or stroke is a major source of morbidity. Many lines of evidence suggest that disruption of calcium regulation may play a role in such injury. The proposed studies will test the novel hypothesis that ischemic neuronal damage is caused in part by excessive release of calcium from intracellular endoplasmic reticulum (ER) stores, leading to both a depletion of these stores and increased cytosolic calcium. Aim 1 will examine the role of ER calcium release in neuron culture models of cytotoxicity by agents that target ER stores, evaluating cell death, calcium release and the protective effects of dantrolene, which inhibits the ryanodine receptor (RYR)-mediated component of ER calcium release. Aim 2 will extend this approach to anoxic/aglycemic insults in the same in vitro preparations. The possible activation of a specific second messenger pathway involving nitric oxide, cGMP and cADP-ribose will be evaluated. Aim 3 will determine whether increased cytosolic calcium or depletion of ER pools contribute more importantly to cell death, and will evaluate the involvement of mitochondria. Aim 4 will extend the studies to an in vivo model and examine the effect of dantrolene, alone and in combination with a calcium channel blocker. These studies will provide information on novel mechanisms of ischemic neuronal death and on potential drug treatments that will be of clinical relevance.