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）：神经元在某些简短癫痫发作后死亡。这种神经元死亡可能导致癫痫发作不良的患者认知能力下降，或导致癫痫大脑中更严重的癫痫发作。简短癫痫发作在海马内激活了一个协调的分子途径，涉及Bcl-2基因家族的促凋亡和抗凋亡构件及其卫星调节剂，蛋白激酶B和14-3-3-3蛋白的相互作用。药理学干预措施证实了该途径在癫痫发作后驱动多达一半的细胞死亡。我们的初步数据表明，两个细胞死亡调节剂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的激活驱动BIM过表达，该过表达驱散了Bcl-W，这是细胞死亡时内源性分子制动的Bcl-W。反过来，尽管有反应性上调保护性基因，但缺乏BCl-W基因的小鼠在癫痫发作后显示出损伤的阈值。我们的中心假设是：短暂癫痫发作后，BIM和BCL-调节大多数神经元死亡。该项目的具体目的是：1。表征细胞死亡调节剂Bcl-W和BIM的表达和相互作用，并在短期癫痫发作中表征。 2。研究操纵Bcl-W表达对癫痫发作诱导的损伤和癫痫发生的影响。 3。通过检查每个基因缺乏小鼠的癫痫发作诱导的神经元损伤，证明了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的产生的结果。这些研究将在分子途径中确定有效的调节位点，该途径在神经元之后死亡。