POTASSIUM CHANNELS AND EPILEPTOGENESIS

钾通道与癫痫发生

• 批准号: 2735506
• 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/2735506
• 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.

此应用程序适用于指导临床科学家发展 奖项(K08)。应聘者在儿童医院接受临床培训 在加州大学洛杉矶分校学习神经学，然后在 国立卫生研究院的神经药理学(癫痫 NINDS研究部)在接受目前的教职之前 1994年在华盛顿大学任职。长的- 应聘者的任期职业目标是研究关系 离子通道与癫痫发生之间的关系，以确定潜在的 对发育性癫痫有合理治疗的新疗法 分子基础，并探讨基因与遗传的关系 易感性和环境影响在致病机制中的作用 发育性癫痫。大学医学中心和 儿科医院与基层医院优势互补 神经科学和临床儿科癫痫学。 实验室空间、设备和专业顾问 在协作的基础上提供给候选人 几个学术部门。这个环境非常适合 用于支持和培养候选人的长期专业 目标。我们选择了mKv1.1作为我们的实验模型 钾通道单基因小鼠突变体 发育早期的自发性癫痫。首先，我们假设 CA_3中特定钾通道亚基的丢失 海马区导致脑组织功能改变 锥体神经元的生理特性使得它们 变得极度兴奋，并容易过度同步 出院。第二，我们假设药物治疗 可以改变癫痫的自然病程，并可以保护 反复出现神经元损伤的动物 癫痫发作。最后，我们将探讨部分表达是否 MKv1.1基因在正/负小鼠中的表达，导致增强 对癫痫的易感性，可以通过二次暴露而改变 对红藻氨酸(一种强效惊厥剂和神经毒素)的早期反应 发展。最初的努力将涉及电生理 海马脑片CA3区锥体神经元的记录 取自不同年龄的零突变体；固有的和突触的 这些细胞的特性，以及全细胞钾电流， 将通过细胞外、细胞内和膜片钳进行测量 录音技术。视频-脑电监测(带深度 电极)将被用于记录癫痫样或癫痫发作 在海马区的活性，以及组织化学分析 神经损伤和/或可塑性将通过常规和 特殊(例如，TIMM)污渍。这些研究的结果可能会导致 为了更好地理解离子通道在 癫痫的发生，可能会揭示有争议的问题 慢性癫痫发作是否会导致大脑损伤，并将提供 进一步研究的框架，检查遗传和 发育中大脑中的环境相互作用。