SODIUM CHANNEL REGULATION AND DISEASE

钠通道调节与疾病

基本信息

批准号：
7389651
负责人：
Andrew P Escayg
金额：
$ 26.84万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7389651
关键词：
Action Potentials Adult Adverse effects Affect Age Antiepileptic Agents Ataxia Attention Biological Process Chickens Childhood Code Data Development Disease Elements Epilepsy Exons Febrile Convulsions Fever Functional RNA Functional disorder Generalized Epilepsy Genes Genome Goals Health Human Introns Knockout Mice Lead Length Mental Retardation Messenger RNA Mus Mutation Myoclonic Epilepsies Neurons Patients Pharmaceutical Preparations Phenotype Play Predisposition Promoter Regions Property Proteins RNA Splicing Regulation Regulatory Element Role Seizures Sequence Analysis Series Social Development Sodium Channel Symptoms Testing Transgenic Organisms Translating Untranslated Regions Variant clinically relevant embryonic stem cell homologous recombination human disease in vitro Assay infancy insight loss of function neuronal excitability promoter voltage

项目摘要

DESCRIPTION (provided by applicant): Epilepsy is a common disorder of aberrant neuronal excitability that has long-term consequences for health and intellectual and social development. Many antiepileptic medications have undesirable side effects and only target the symptoms of epilepsy leading to ineffective seizure control. Our long-term goal is to facilitate the development of more effective epilepsy treatments through a better understanding of the factors that affect neuronal excitability. Mutations in the voltage-gated sodium channel gene SCN1A, a critical regulator of neuronal excitability, have been identified in two forms of dominant idiopathic generalized epilepsy: Generalized Epilepsy with Febrile Seizures Plus (GEFSP2) and Severe Myoclonic Epilepsy of Infancy (SMEI). GEFSP2 is characterized by febrile (fever induced) seizures that persist beyond the age of six and the development of adult epilepsy. SMEI is a severe, debilitating childhood epilepsy characterized by febrile and afebrile seizures, mental retardation and ataxia. Many loss-of-function SCN1A mutations have been identified in SMEI patients, suggesting an important relationship between SCN1A expression levels and neuronal excitability. We hypothesize that sequence variation in critical SCN1A regulatory elements can also lead to altered expression and represent an important, but as yet unexplored, component of severe childhood epilepsies. We will test this hypothesis by functional analysis of SCN1A promoter variants identified in patients and in unaffected controls. By multi-species sequence analysis, we have identified 9 evolutionarily conserved non-coding sequences (> 143 bp in length) in the SCN1A gene. We hypothesize that these represent additional regulatory elements. The biological functions of these regions will be examined using a combination of in vitro assays and by targeted deletion in the mouse. To further investigate the relationship between SCN1A expression and seizure susceptibility, we will develop a series of mouse lines with 10-80% of endogenous Scnla expression levels. These expression levels will be generated by crossing well-characterized Scnla BAG transgenic lines to available heterozygous Scnla knock-out mice. This study will provide new, clinically relevant insights into the regulation of SCN1A and the mechanisms that determine neuronal excitability.

描述（由申请人提供）：癫痫是一种神经元兴奋性异常的常见疾病，对健康、智力和社会发展产生长期影响。许多抗癫痫药物具有不良副作用，并且仅针对癫痫症状，导致癫痫发作控制无效。我们的长期目标是通过更好地了解影响神经元兴奋性的因素来促进更有效的癫痫治疗方法的开发。电压门控钠通道基因 SCN1A 是神经元兴奋性的关键调节因子，已在两种形式的显性特发性全身性癫痫中发现突变：伴有热性惊厥的全身性癫痫 (GEFSP2) 和婴儿严重肌阵挛性癫痫 (SMEI)。 GEFSP2 的特点是持续六岁以上的热性（发烧引起的）癫痫发作以及成人癫痫的发展。 SMEI 是一种严重的、使人衰弱的儿童癫痫，其特征是热性和非热性惊厥、智力低下和共济失调。在 SMEI 患者中发现了许多功能丧失的 SCN1A 突变，表明 SCN1A 表达水平与神经元兴奋性之间存在重要关系。我们假设关键 SCN1A 调控元件的序列变异也可能导致表达改变，并代表严重儿童癫痫的一个重要但尚未探索的组成部分。我们将通过对患者和未受影响的对照中发现的 SCN1A 启动子变体进行功能分析来检验这一假设。通过多物种序列分析，我们在SCN1A基因中鉴定出9个进化保守的非编码序列（长度>143 bp）。我们假设这些代表了额外的监管要素。这些区域的生物学功能将通过体外测定和小鼠靶向删除相结合的方式进行检查。为了进一步研究SCN1A表达与癫痫易感性之间的关系，我们将开发一系列具有10-80%内源性Scnla表达水平的小鼠品系。这些表达水平将通过将充分表征的 Scnla BAG 转基因系与可用的杂合 Scnla 敲除小鼠杂交来产生。这项研究将为 SCN1A 的调节和决定神经元兴奋性的机制提供新的、临床相关的见解。