ALTERED CA2+ HOMEOSTASIS IN POST-ISCHEMIC NEURON DEATH

缺血后神经元死亡中 CA2 稳态的改变

• 批准号: 6393828
• 负责人: John A Connor
• 金额: $ 29.4万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6393828
• 关键词: calcium channel; calcium flux; cell death; cerebral ischemia /hypoxia; cysteine endopeptidases; disease /disorder model; electrophysiology; gerbil /jird; glutamates; hippocampus; homeostasis; immunocytochemistry; neural degeneration; neurons; potassium channel; pyramidal cells; voltage gated channel

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.

描述：（申请人摘要） 大脑中特定且重要的神经元群体受到 短暂的血流中断后延迟死亡，如发生在 中风、头部外伤或心脏骤停。虽然许多神经元被彻底杀死 由于缺血性损伤，许多人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。其中一些人群容易延迟死亡，例如 CA1 海马体的锥体神经元是学习和记忆的重要部分 大脑的电路。这些神经元有可能被拯救 了解他们所经历的漫长的死亡计划。如果是这样，则 增加康复和支持的财务和社会成本 脑损伤的幸存者在人口老龄化中不断增加， 可能会减少。许多证据集中表明，严重的 损伤期间和损伤后不久细胞内 Ca2+ 水平的破坏 延迟性神经元死亡的直接触发因素，然而拉长的链条 可能被适当的干预措施打断的后续事件是 不太了解。我们使用缺血体内模型的研究表明 神经元中 Ca2+ 信号活动延迟抑制 注定要死。这些数据表明了明显不同的机制 目前持有的观点认为细胞死亡主要源自体外、培养 实验表明，损伤后神经元的 Ca2+ 负担增加，导致 延迟死亡。这里建议，1）进一步调查抑郁症 缺血后 CA1 神经元中的 Ca2+ 信号传导，2) 研究这是否 抑郁症会破坏重要的细胞功能，从而导致 神经元延迟死亡，以及 3) 确定某些程序和 已被证明能有效预防神经元死亡的药物的作用是 防止 Ca2+ 信号传导的抑制。如果这项研究成功的话 提出新的治疗模式，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 在严重延迟后开始。