ALTERED CA2+ HOMEOSTASIS IN POST ISCHEMIC NEURON DEATH

描述：(申请人摘要) 大脑中特定和重要的神经元群体受到 短时血流中断后的延迟性死亡 中风、头部创伤或心脏骤停。当许多神经元被直接杀死时 由于受到缺血的侮辱，许多人口在一段时间内遭受磨损 几天，在此期间，它们保留了许多正常的信号功能 时间到了。其中一些易受延迟性死亡影响的人群，如CA1 海马区的锥体神经元是学习和记忆的重要部分 大脑的回路。这些神经元有可能被拯救 考虑到他们所经历的漫长的死亡计划。如果是这样，则 不断增加的恢复和支助的财政和社会成本 脑损伤的幸存者，在老龄化的人口中，人数不断增加， 可能会减少。许多证据汇聚在一起，表明了严重的 侮辱期间和之后不久细胞内钙离子水平的中断是 延迟性神经元死亡的直接触发因素，然而延长的链条 可能会被适当的干预措施打断的后续事件是 人们对此知之甚少。我们使用体内缺血模型进行的研究表明 神经元中钙信号活性的迟发性抑制 注定要死。这组数据清楚地表明， 目前持有的观点认为，细胞死亡主要来自体外培养 实验表明，损伤后增加神经元上的钙负荷会导致 延缓死亡。在此，建议，1)进一步研究抑郁症 缺血后CA1神经元中的钙信号，2)研究这是否 抑郁症是导致重要的细胞功能紊乱的原因 延迟性神经元死亡，以及3)确定某些程序和 已被证明有效防止神经元死亡的药物是通过 防止钙信号的抑制。如果成功，这项研究将 建议新的治疗模式，或为现有的治疗提供科学依据 中风或创伤的实验性治疗，可能被证明是有效的 在显著延迟后开始。

DESCRIPTION: (Applicant's Abstract) Specific and important populations of neurons in the brain are subject to delayed death following short periods of blood flow disruption as occurs in stroke, head trauma, or cardiac arrest. While many neurons are killed outright by the ischemic insult, many populations suffer attrition over a period of several days, retaining many of their normal signaling functions during that time. Some of these populations vulnerable to the delayed death, such as CA1 pyramidal neurons of the hippocampus, are vital parts of learning and memory circuitry of the brain. It is possible that these neurons could be rescued given an understanding of the drawn out death program they undergo. If so, the increasing financial and social costs of rehabilitation and support of survivors of brain injury, an ever-increasing number in an aging population, might be reduced. Many lines of evidence, converge to indicate that severe disruptions in intracellular Ca2+ levels during and shortly after an insult are the immediate trigger for delayed neuronal death, however the drawn out chain of subsequent events, that might be interrupted by suitable interventions, is poorly understood. Our research, using an in vivo model of ischemia has shown that there is a delayed depression of Ca2+ signaling activity in neurons destined to die. This body of data suggests clearly different mechanisms of cell death from currently held views, derived largely from in vitro, culture experiments, that increased Ca2+ burdens on the neurons after insult cause the delayed death. It is proposed here, 1) to investigate further the depression of Ca2+ signaling in post-ischemic CA1 neurons, 2) to investigate whether this depression is responsible for disrupting vital cellular functions that result in delayed death of neurons, and 3) to determine whether certain procedures and drugs that have proven effective in preventing neuronal death are acting by preventing the depression of Ca2+ signaling. If successful this research would suggest new modes of treatment, or give scientific basis for existing experimental treatments, of stroke or trauma that could prove to be effective when begun after significant delay.