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 短暂的血流中断后的延迟性死亡， 中风头部外伤或心脏骤停虽然许多神经元被直接杀死 由于缺血性损伤，许多人群在一段时间内遭受损耗， 几天，在此期间保留了许多正常的信号功能， 时间这些人群中的一些容易受到延迟死亡的影响，如CA1 海马体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 因为他们了解了他们所经历的漫长的死亡计划。如果是则 康复和支助的财政和社会费用不断增加 脑损伤的幸存者，在老龄化人口中不断增加， 可能会减少。许多证据表明， 损伤期间和损伤后不久细胞内Ca2+水平的破坏是 延迟性神经元死亡的直接触发因素， 随后的事件，可能会被适当的干预中断， 不太了解。我们的研究，使用体内缺血模型， 在神经元中， 注定要死这些数据表明， 细胞死亡从目前持有的观点，主要来自体外培养， 实验中，损伤后神经元上的Ca2+负荷增加， 延迟死亡建议：1）进一步研究抑郁症 缺血后CA1神经元中的Ca 2+信号，2）为了研究这是否 抑郁症会破坏重要的细胞功能， 在神经元的延迟死亡，和3），以确定是否某些程序和 已被证明有效预防神经元死亡的药物通过以下方式起作用： 防止Ca2+信号转导的抑制。如果这项研究成功， 提出新的治疗模式，或为现有的治疗提供科学依据。 实验性治疗，中风或创伤，可以证明是有效的 在重大延误后开始。

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.