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）：神经元在某些短暂发作后死亡。这种神经元死亡可能导致癫痫发作管理不善患者的认知能力下降，或导致癫痫脑更严重的癫痫发作。短暂的癫痫发作激活了海马体内一个协调的分子通路，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，这一途径驱动癫痫发作后多达一半的细胞死亡。我们的初步数据显示，两种细胞死亡调节因子Bcl-w和Bim的表达和相互作用对癫痫发作是否导致神经元死亡至关重要。癫痫诱导的叉头转录因子激活驱动Bim过表达，从而抑制Bcl-w，这是一种内源性的细胞死亡分子制动器。反过来，缺乏Bcl-w基因的小鼠在癫痫发作后表现出较低的损伤阈值，尽管保护性基因反应性上调。我们的中心假设是：Bim和Bcl-w调节了短暂癫痫发作后的大部分神经元死亡。本项目的具体目标是：1。描述细胞死亡调节因子Bcl-w和Bim在短暂癫痫发作和长期癫痫发作后的表达和相互作用。2. 探讨调控Bcl-w表达对癫痫致损伤和癫痫发生的影响。3. 通过检测各基因缺失小鼠癫痫引起的神经元损伤，证明Bcl-w和Bim在体内的功能意义。4. 确定Bim和Bcl-w基因缺失对癫痫表型产生的影响。这些研究将在神经元死亡的分子途径中确定有效的调控位点。简短的，电图定义癫痫发作，从而提供新的，集中的神经保护靶点，超越抗惊厥药物治疗高危癫痫患者。