Enhanced excitation and epilepsy with chloride channel dysfunction

氯离子通道功能障碍导致兴奋增强和癫痫

基本信息

批准号：
8385715
负责人：
Mark Beenhakker
金额：
$ 24.9万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-15 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8385715
关键词：
9-anthroic acid Address Affinity Antiepileptic Agents Benzoic Acids Brain CLC Gene Cannulas Chloride Channels Collaborations Data Disease Drug Delivery Systems Dyes Electroencephalogram Enrollment Epilepsy Etiology Fast Green Fees Functional disorder Future Generalized Epilepsy Genes Glass Goals Imaging Techniques Implant Infusion Technique Infusion procedures International Label Learning Light Mentors Methods Migraine Monitor Mus Mutation Neurons Opsin Peptides Perfusion Pharmaceutical Preparations Pharmacology Phase Population Predisposition Reporting Research Resources Scientist Scorpions Seizures Source Specificity Staining method Stains Structure Synapses Techniques Testing Thalamic Nuclei Thalamic structure Toxin Training United States Universities Update Virginia cost design fenamic acid in vivo innovation nervous system disorder neural circuit optogenetics presynaptic professor research study skills volunteer

项目摘要

Epilepsy is the second most common neurological disorder in the United States - the first being migraine headaches - and is estimated to cost the US $2 billion annually. The idiopathic generalized epilepsies (IGEs) are the most common of the genetically acquired forms of the disease. While the etiology of the IGEs is poorly understood, evidence suggests that pathological circuits in the thalamus, a subcortical brain structure, are the cause. Several factors establish the excitability of neural circuits within the thalamus. One critical component is a population of neurons within the reticular thalamic (RT) nucleus. RT neurons are GABAergic and normally exert a powerful inhibitory effect on the thalamus. This inhibition minimizes the likelihood that the thalamus will generate epileptic activity. The CLC2 chloride channel is highly expressed in the thalamus and is important for establishing the excitability of RT neurons. Indeed, evidence suggests that mutations in the gene encoding CLC2 cause thalamic circuits to become hyperexcitable and may underlie some IGEs. My data indicates that CLC2 dysfunction strengthens the excitation of RT neurons, thereby potentially enabling them to overcome the anti-epileptic effects of RT neuron inhibition. My project aims to determine the mechanism(s) that causes over-excitation of RT neurons during CLC2 disruption. I have designed several experiments to this end. As some of these experiments utilize techniques with which I have limited expertise - EEG recording/interpretation, local brain perfusion, imaging techniques - I have assemble a team consultants that have agreed to train me. 1 have received such training during the K99 phase of my K99/R00. I now apply for the independent phase of my K99/R00. I will carry out this phase as an assistant professor in the pharmacology department at the University of Virginia. The university has provided me with sufficient space/resources to carry out the experiments I have outlined in my proposal. I begin August 24, 2011.

癫痫是美国第二大常见的神经系统疾病 - 第一个是偏头痛 - 估计花费 20 亿美元每年。特发性全身性癫痫 (IGE) 是最常见的该疾病的遗传形式。虽然 IGE 的病因是人们对此知之甚少，有证据表明丘脑中的病理回路（皮质下的大脑结构，都是原因。有几个因素决定了丘脑内神经回路的兴奋性。一个关键组件是网状丘脑 (RT) 核内的神经元群。 RT 神经元是 GABA 能，通常对丘脑产生强大的抑制作用。这抑制可最大限度地减少丘脑产生癫痫的可能性活动。 CLC2 氯离子通道在丘脑中高度表达，并且对于建立 RT 神经元的兴奋性很重要。确实有证据表明编码 CLC2 的基因突变导致丘脑回路变得过度兴奋，可能是某些 IGE 的根源。我的数据表明 CLC2 功能障碍会增强 RT 神经元的兴奋，从而可能使他们能够克服 RT 神经元抑制的抗癫痫作用。我的项目旨在确定导致 RT 过度激励的机制 CLC2 破坏期间的神经元。我为此设计了几个实验结尾。由于其中一些实验使用了我有限的技术专业知识 - 脑电图记录/解释、局部脑灌注、成像技术 - 我已经组建了一个顾问团队，他们同意对我进行培训。 1 在我的K99/R00的K99阶段接受过这样的培训。我现在申请对于我的 K99/R00 的独立阶段。我将把这个阶段作为弗吉尼亚大学药理学系助理教授。大学为我提供了足够的空间/资源来开展我在提案中概述了实验。我从 2011 年 8 月 24 日开始。