Complex genetic interactions in mouse model of sudden death in epilepsy (SUDEP)

癫痫猝死小鼠模型 (SUDEP) 中复杂的遗传相互作用

基本信息

批准号：
8841421
负责人：
Albert E Glasscock
金额：
$ 18.13万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8841421
关键词：
Action Potentials Alleles Area Biological Markers Bradycardia Brain Brain region Cardiac Cessation of life Complex Congenital Heart Defects Data Disease susceptibility Electrocardiogram Electroencephalography Employee Strikes Epilepsy Exhibits FOS gene Functional disorder Future General Population Generalized seizures Genes Genetic Genetic Predisposition to Disease Genetic Risk Genotype Goals Health Heart Heterozygote Human Immediate-Early Genes Immunohistochemistry Incidence Ion Channel Knock-out Knockout Mice Link Modeling Molecular Mus Mutant Strains Mice Mutation Myocardial dysfunction Neuronal Dysfunction Neurons Patients Phenotype Predisposition Prevention therapy Research Risk SCN2A protein Seizures Site Sodium Channel Sudden Death Susceptibility Gene Testing Time Translating Voltage-Gated Potassium Channel Work base endophenotype genetic variant improved loss of function mortality mouse model mutant neuronal excitability novel postnatal premature prevent research study respiratory response therapeutic target voltage

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this work is to examine digenic interactions between mutations in the Kcna1 and Scn2a ion channel genes in the context of sudden unexpected death in epilepsy (SUDEP). People with epilepsy are 24 times more likely than the general population to die suddenly for unknown pathological reasons; these deaths are classified as SUDEP and represent the leading cause of epilepsy-related mortality. Several genes have been linked anecdotally to SUDEP, but its genetic etiology is largely unknown and likely complex involving the co-inheritance of multiple susceptibility gene variants. This proposal investigates the ability of subclinical Scn2a-null heterozygosity to act as a protective genetic modifier of epilepsy and premature death in the Kcna1 knockout mouse model of SUDEP. Scn2a, a human epilepsy gene, encodes Nav1.2 voltage-gated sodium channel Alpha-subunits but the knockout mutation utilized here has not been found to cause epilepsy. Kcna1, also a human epilepsy gene, encodes Kv1.1 voltage-gated potassium channel Alpha-subunits that normally act to dampen neuronal excitability. Kcna1 knockout mice accurately model human SUDEP by exhibiting severe epilepsy, brain-driven cardiac dysfunction, and premature death. Given the expression overlap and mutually opposing excitability effects of the two genes, the proposed research tests the hypothesis that subclinical Scn2a-null heterozygosity reduces SUDEP incidence in Kcna1-null mice by suppressing neurocardiac dysfunction and neuronal hyperexcitability associated with the absence of Kv1.1 channels. Preliminary data shows that Scn2a-null heterozygosity prevents SUDEP in Kcna1 knockouts increasing their survival threefold. In Aim 1, video electroencephalography-electrocardiography (EEG-ECG) is used to determine whether Scn2a-null heterozygosity reduces epileptiform discharges and/or cardiac abnormalities in Kcna1-null mice. Aim 2 seeks to identify neuronal networks exhibiting functional interaction between Scn2a and Kcna1 by analyzing changes in expression of molecular biomarkers associated with abnormal neuronal activation, such as c-Fos. This research utilizes a novel digenic mouse model as an important first step towards understanding the complex genetic interactions underlying SUDEP with the ultimate goal of improving genotype-based risk prediction, prevention, and therapy in epilepsy. The ability of Scn2a-null heterozygosity to suppress the Kcna1 SUDEP phenotype would demonstrate a proof-of-principle that even subclinical gene variants without obvious phenotypes must be considered when evaluating the genetic risk profiles of epilepsy patients since those alleles can also be critical modifiers of disease susceptibility. Furthermore, the examination of molecular biomarker endophenotypes in this digenic model has the potential to identify previously unrecognized brain networks that are important for SUDEP pathophysiology and candidate therapeutic targets for future studies.

描述（由申请人提供）：这项工作的总体目标是检查癫痫猝死（SUDEP）背景下 Kcna1 和 Scn2a 离子通道基因突变之间的双基因相互作用。癫痫患者因不明病理原因突然死亡的可能性是普通人群的 24 倍；这些死亡被归类为 SUDEP，是癫痫相关死亡的主要原因。据传闻，有几个基因与 SUDEP 有关，但其遗传病因很大程度上未知，并且可能很复杂，涉及多个易感基因变体的共同遗传。这个提议研究人员在 Kcna1 敲除小鼠 SUDEP 模型中研究了亚临床 Scn2a 缺失杂合性作为癫痫和过早死亡的保护性遗传修饰剂的能力。 Scn2a 是一种人类癫痫基因，编码 Nav1.2 电压门控钠通道 Alpha 亚基，但尚未发现此处使用的敲除突变会导致癫痫。 Kcna1 也是人类癫痫基因，编码 Kv1.1 电压门控钾通道 Alpha 亚基，通常起到抑制神经元兴奋性的作用。 Kcna1 基因敲除小鼠通过表现出严重的癫痫、脑驱动的心功能障碍和过早死亡来准确地模拟人类 SUDEP。考虑到这两个基因的表达重叠和相互对立的兴奋性效应，拟议的研究测试了以下假设：亚临床 Scn2a-null 杂合性通过抑制与 Kv1.1 通道缺失相关的神经心脏功能障碍和神经元过度兴奋性来降低 Kcna1-null 小鼠中 SUDEP 的发生率。初步数据显示，Scn2a 缺失杂合性可阻止 Kcna1 敲除中的 SUDEP，使存活率提高三倍。在目标 1 中，使用视频脑电图-心电图 (EEG-ECG) 来确定 Scn2a-null 杂合性是否会减少 Kcna1-null 小鼠的癫痫样放电和/或心脏异常。目标 2 旨在通过分析与异常神经元激活相关的分子生物标志物（例如 c-Fos）的表达变化，来识别 Scn2a 和 Kcna1 之间表现出功能相互作用的神经元网络。这项研究利用新型双基因小鼠模型作为了解 SUDEP 背后复杂的遗传相互作用的重要第一步，最终目标是改善基于基因型的癫痫风险预测、预防和治疗。 Scn2a 缺失杂合性抑制 Kcna1 SUDEP 表型的能力将证明，在评估癫痫患者的遗传风险概况时，即使是没有明显表型的亚临床基因变异也必须考虑在内，因为这些等位基因也可能是癫痫患者的关键修饰因子。疾病易感性。此外，在该双基因模型中检查分子生物标志物内表型有可能识别以前未被识别的大脑网络，这些网络对于 SUDEP 病理生理学和未来研究的候选治疗靶点非常重要。