Molecular determinants of epileptic bran injury

癫痫麸皮损伤的分子决定因素

• 批准号: 7068632
• 负责人: ROGER Pancoast SIMON
• 金额: $ 35万
• 依托单位: LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7068632
• 关键词: BCL2 gene /protein; brain electrical activity; clinical research; electroencephalography; epilepsy; gene deletion mutation; gene expression; gene interaction; genetically modified animals; human subject; laboratory mouse; neural degeneration; neuroprotectants; patient oriented research; phenotype; protein structure; transcription factor

DESCRIPTION (provided by applicant): Neurons die following certain brief seizures. Such neuronal death may contribute to cognitive decline in patients with poorly managed seizures, or contribute to more severe seizures in epileptic brain. Brief seizures activate a coordinated molecular pathway within the hippocampus that involves dimerization interactions of pro- and antiapoptotic members of the Bcl-2 gene family and their satellite regulators, protein kinase B and 14-3-3 proteins. Pharmacological interventions confirm this pathway drives as much as half of cell death after seizures. Our preliminary data reveals that expression and interaction of two cell death regulators, Bcl-w and Bim, are fundamentally critical to whether seizures cause neuronal death. Seizure-induced activation of forkhead transcription factors drive Bim overexpression, which quenches Bcl-w, an endogenous molecular brake on cell death. In turn, mice deficient in the Bcl-w gene exhibit a lowered threshold for injury following seizures, despite reactive upregulation of protective genes. Our central hypothesis is: Bim and Bcl-w regulate the majority of neuronal death after brief seizures. The specific aims of this project are: 1. Characterize the expression and interactions of cell death regulators Bcl-w and Bim following brief seizures and in long-term epilepsy. 2. Investigate the effects of manipulating Bcl-w expression on seizure-induced damage and epileptogenesis. 3. Demonstrate the in vivo functional significance of Bcl-w and Bim by examining seizure-induced neuronal damage in mice deficient in each gene. 4. Determine the consequence of Bim and Bcl-w gene deletions on the generation of an epileptic phenotype. These studies will identify potent regulatory sites in the molecular pathways by which neurons die following .brief, electrographically defined seizures, thereby offering novel, focused neuroprotective targets beyond anticonvulsants for treating at-risk epilepsy patients.

描述（由申请人提供）：神经元在某些短暂的癫痫发作后死亡。这种神经元死亡可能会导致癫痫发作管理不善的患者认知能力下降，或者导致癫痫脑中更严重的癫痫发作。短暂的癫痫发作会激活海马体内的协调分子通路，该通路涉及 Bcl-2 基因家族的促凋亡和抗凋亡成员及其卫星调节因子、蛋白激酶 B 和 14-3-3 蛋白的二聚化相互作用。药理学干预证实该途径导致癫痫发作后多达一半的细胞死亡。我们的初步数据表明，两种细胞死亡调节因子 Bcl-w 和 Bim 的表达和相互作用对于癫痫发作是否导致神经元死亡至关重要。癫痫发作诱导的叉头转录因子激活会驱动 Bim 过度表达，从而淬灭 Bcl-w（细胞死亡的内源性分子制动器）。反过来，尽管保护性基因发生反应性上调，但 Bcl-w 基因缺陷的小鼠在癫痫发作后表现出较低的损伤阈值。我们的中心假设是：Bim 和 Bcl-w 调节短暂癫痫发作后的大部分神经元死亡。该项目的具体目标是： 1. 表征短暂癫痫发作和长期癫痫中细胞死亡调节因子 Bcl-w 和 Bim 的表达和相互作用。 2. 研究操纵 Bcl-w 表达对癫痫引起的损伤和癫痫发生的影响。 3. 通过检查每种基因缺陷的小鼠癫痫发作引起的神经元损伤，证明 Bcl-w 和 Bim 的体内功能意义。 4. 确定 Bim 和 Bcl-w 基因缺失对癫痫表型产生的影响。这些研究将确定分子途径中神经元在短暂的、电图定义的癫痫发作后死亡的有效调节位点，从而为治疗高危癫痫患者提供抗惊厥药物之外的新颖、集中的神经保护靶点。