POTASSIUM CHANNELS AND EPILEPTOGENESIS

钾通道与癫痫发生

• 批准号: 2891439
• 负责人: Jong Min Rho
• 金额: $ 10.56万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-23 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2891439
• 关键词: aging; brain disorder chemotherapy; developmental genetics; developmental neurobiology; electroencephalography; epilepsy; genetically modified animals; hippocampus; kainate; laboratory mouse; neural plasticity; neurogenetics; neurotoxicology; nonhuman therapy evaluation; phenobarbital; potassium channel; protein structure function; voltage /patch clamp

This application is for a Mentored Clinical Scientist Development Award (K08). The candidate obtained clinical training in Child Neurology at UCLA, and then completed a two-year fellowship in neuropharmacology at the National Institutes of Health (Epilepsy Research Branch, NINDS) prior to taking his current faculty appointment in 1994 at the University of Washington. The long- term career goal of the candidate is to study the relationship between ion channels and epileptogenesis, to identify potentially novel treatments for developmental epilepsies that have a rational molecular basis, and to explore the relationship between genetic susceptibility and environmental influence in the pathogenesis of the developmental epilepsies. The university medical center and Children's Hospital possess complementary strengths in the basic neurosciences and clinical pediatric epileptology, respectively. Laboratory space, equipment, and specialized consultants are available to the candidate on a collaborative basis provided by several academic departments. This environment is ideally suited for supporting and fostering the candidate's long-term professional goals. We have chosen as our experimental model the mKv1.1 potassiumchannel single gene mouse mutant which exhibits spontaneous seizures early in development. First, we hypothesize that loss of a specific potassium channel subunit in the CA 3 region of the hippocampus results in a functional alteration in physiological properties of pyramidal neurons such that they became hyperexcitable and prone to excessive synchronization of discharge. Second, we postulate that pharmacological treatment can alter the natural course of the epilepsy and may protect the animal from neuronal injury as a consequence of repeated seizures. Finally, we will explore whether partial expression of the mKv1.1 gene in plus/minus mice, resulting in an enhanced susceptibility to seizures, can be modified by secondary exposure to kainic acid (a potent convulsant and neurotoxin) early in development. Initial efforts will involve electrophysiological recordings from CA3 pyramidal neurons in hippocampal slices taken from null mutants at different ages; intrinsic and synaptic properties of these cells, as well as whole-cell potassium currents, will be measured with extracellular, intracellular and patch-clamp recording techniques. Video-EEG monitoring (with depth electrodes) will be employed to document epileptiform or seizure activity in the hippocampus, and histochemical analysis of neuronal damage and/or plasticity will be made with routine and special (e.g., Timm) stains. The results of these studies may lead to an improved understanding of the role ion channels play in epileptogenesis, may shed light on the controversial issue of whether chronic seizures can cause brain damage, and will provide a framework for further studies examining genetic and environmental interactions in the developing brain.

该应用是针对受过指导的临床科学家发展的 奖项（K08）。候选人获得了儿童的临床培训 加州大学洛杉矶分校的神经病学，然后完成了为期两年的奖学金 美国国立卫生研究院的神经药理（癫痫病 研究部门，Ninds） 1994年在华盛顿大学任命。 长期 候选人的职业生涯目标是研究关系 离子通道和癫痫发生之间，以识别潜在的 具有理性的发育癫痫的新颖治疗方法 分子基础，并探索遗传之间的关系 易感性和环境影响在发病机理中 发展性癫痫。 大学医学中心和 儿童医院在基本中具有互补的优势 神经科学和临床小儿癫痫学。 实验室空间，设备和专业顾问是 由候选人提供的协作基础 几个学术部门。 这种环境非常适合 支持和培养候选人的长期专业人员 目标。 我们选择了我们的实验模型MKV1.1 钾通道单基因小鼠突变体 发展初期自发癫痫发作。 首先，我们假设 Ca 3中特定钾通道亚基的损失 海马区域导致功能改变 锥体神经元的生理特性使它们 过度兴奋，容易过度同步 释放。 其次，我们假设药理治疗 可以改变癫痫的自然过程，并可以保护 由于重复而导致神经元损伤的动物 癫痫发作。 最后，我们将探索是否部分表达 Plus/减小鼠中的MKV1.1基因，导致增强 可以通过次要暴露来修改癫痫发作的敏感性 早期到海藻酸（一种有效的抽搐和神经毒素） 发展。 最初的努力将涉及电生理学 来自海马切片中CA3锥体神经元的记录 取自不同年龄的零突变体；内在和突触 这些细胞的特性以及全细胞钾电流， 将用细胞外，细胞内和斑块钳测量 记录技术。视频EEG监视（深度 电极）将用于记录癫痫样或癫痫发作 海马的活性，以及​​组织化学分析 神经元损害和/或可塑性将通过常规和/或 特殊（例如，蒂姆）污渍。 这些研究的结果可能会导致 对离子频道在 癫痫发生，可能会阐明有争议的问题 慢性癫痫发作是否会导致大脑损伤，并将提供 进一步研究遗传和 发育中的大脑中的环境相互作用。