Molecular determinants of epileptic brain injury

癫痫性脑损伤的分子决定因素

• 批准号: 6988568
• 负责人: ROGER Pancoast SIMON
• 金额: $ 35.84万
• 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/6988568
• 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(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导致癫痫发作管理不善的患者的认知能力下降，或者导致癫痫脑内更严重的癫痫发作。短暂的癫痫发作激活了海马区内的一条协调的分子通路，该通路涉及Bcl2基因家族的促凋亡和抗凋亡成员及其卫星调节蛋白、蛋白激酶B和14-3-3蛋白的二聚化相互作用。药物干预证实，在癫痫发作后，这一途径导致了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，Bim和Bim的表达和相互作用，是癫痫发作是否导致神经元死亡的根本关键。癫痫发作诱导的叉头转录因子的激活驱动了Bim的过度表达，从而抑制了细胞死亡的内源性分子刹车Bclw。反过来，尽管保护性基因的反应性上调，但缺乏Bcl-w基因的小鼠在癫痫发作后表现出较低的损伤阈值。我们的中心假设是：BIM和Bc l-w调控着大多数短暂癫痫发作后的神经元死亡。本项目的具体目标是：1.研究细胞死亡调节因子Bc l-w和Bim在短暂性癫痫发作后和长期癫痫中的表达和相互作用。2.探讨调控Bcl一w基因表达对癫痫发作损伤和癫痫发生的影响。3.通过检测Bim和Bim基因缺陷小鼠癫痫发作诱导的神经元损伤，论证Bim和Bim基因在体内的功能意义。4.确定Bim和Bc l-w基因缺失对癫痫表型发生的影响。这些研究将确定分子通路中的有效调控部位，神经元在短暂的、电图学定义的癫痫发作后死亡，从而为治疗高危癫痫患者提供新的、重点突出的神经保护靶点，而不是抗惊厥药物。