QUANTITATIVE GENETIC STUDY OF SEIZURES

癫痫发作的定量遗传学研究

• 批准号: 6195841
• 负责人: THOMAS N FERRARO
• 金额: $ 35.66万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6195841
• 关键词: Xenopus oocyte; electrostimulus; epilepsy; genetic mapping; genetic models; genetic polymorphism; genetic susceptibility; genetically modified animals; inbreeding; kainate; laboratory mouse; neurogenetics; nucleic acid sequence; pentylenetetrazole; potassium channel; quantitative trait loci

DESCRIPTION (adapted from applicant's abstract): This application is requesting 5 years of funding to identify genes that play a major role in a multifactorial mouse model of seizure susceptibility involving DBA/2 (D2) and C57BL/6 (B6) mice. Over the past 5 years, we used quantitative trait locus (QTL) mapping to characterize the polygenic nature of this model and document the presence of a major genetic effect, termed Szs1, originating from the distal portion of chromosome 1. Then, using congenic strains, we narrowed the region that harbors Szs1 to a defined segment of DNA (3-6 cM) with a strategy in place that will allow additional significant reductions in the size of this critical interval. Thus, the prime focus of this application is to identify the gene, which underlies Szs1. Specific Aims of the current proposal include: 1) continuation of congenic strain development for reduction of Szs1 critical interval to 1-2 cM and for study of Szs1 modifying loci; 2) molecular analysis and strain sequence comparison of a select group of candidate genes from the critical interval; 3) functional studies of the significance of a threonine/serine polymorphism in a potassium ion channel candidate gene KCNJ10 including in vitro (electrophysiology) and in vivo (transgenesis) experiments; 4) construction of a physical map of the Szs1 critical interval. The first 3 Aims will be pursued in parallel fashion with continued, systematic refinement of the Szs1 critical interval directing a search for the underlying seizure susceptibility gene. Functional KCNJ10 studies will be undertaken immediately and could redirect planned strategy if results provide evidence that this K+-channel gene represents Szs1. If analysis of known gene candidates does not result in identification of Szs1, a physical map will be constructed and used to discover novel genes, which can then be studied as Szs1 candidates. Overall, this set of Aims represents a logical extension of 5 years of previous work and it is believed that the proposed congenic strain-candidate gene-positional cloning strategy will lead to the identification of a fundamentally important seizure susceptibility gene in mice. Hopefully, these findings will lead as well to new and important information regarding the pathogenesis of human epilepsy.

描述（根据申请人的摘要改编）： 该应用程序要求提供5年的资金来识别发挥作用的基因 在涉及DBA/2的癫痫发作易感性的多因素小鼠模型中的作用 （D2）和C57BL/6（B6）小鼠。在过去的5年中，我们使用了定量性状 基因座（QTL）映射以表征该模型的多基因性质和 记录存在称为SZS1的主要遗传作用的存在，该作用源自 1染色体的远端部分。然后，使用先天性菌株，我们缩小了 将SZS1固定到DNA（3-6 cm）的段的区域 制定的策略将允许大小额外减少 这个关键间隔。因此，此应用程序的主要重点是 识别基因，该基因是SZS1的基础。 当前建议的具体目的包括：1） 将SZS1关键间隔减少至1-2 cm的应变发展，用于 SZS1修改基因座的研究； 2）分子分析和应变序列 从关键间隔比较一组候选基因； 3） 苏氨酸/丝氨酸多态性在A中的意义的功能研究 钾离子通道候选基因KCNJ10包括体外 （电生理学）和体内（转基因）实验； 4）建设 SZS1关键间隔的物理图。将追求前3个目标 以持续的，系统的精制SZS1关键 间隔指导搜索潜在的癫痫发作基因。 功能性KCNJ10研究将立即进行，并可以重定向 计划的策略如果结果提供证据表明该K+通道基因 代表SZS1。如果对已知基因候选者的分析不会导致 识别SZS1，将构建物理图并用于发现 新型基因，然后可以作为SZS1候选者进行研究。 总体而言，这组目标代表了前5年的逻辑扩展 工作，据信，提议的先天性应变候选 基因定位克隆策略将导致鉴定 小鼠中重要的癫痫发作基因。希望这些 调查结果也将导致有关有关的新的重要信息 人癫痫的发病机理。