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在癫痫突然意外死亡的背景下，KCNA1和SCN2A离子通道基因之间的突变之间的二元相互作用（SUDEP）。出于未知的病理原因，癫痫患者突然死亡的可能性高24倍。这些死亡被归类为SUDEP，代表了与癫痫有关的死亡率的主要原因。几个基因已与SUDEP轶事，但其遗传病因在很大程度上是未知的，并且可能复杂，涉及多个敏感性基因变体的共同传播。这个建议研究亚临床SCN2A无效杂合性充当癫痫的保护性遗传修饰剂和SUDEP的KCNA1基因敲除小鼠模型中的早期死亡的能力。人类癫痫基因SCN2A编码NAV1.2电压门控钠通道α-固体，但此处使用的敲除突变尚未发现引起癫痫。 KCNA1也是人类癫痫基因，它编码KV1.1电压门控通道α-基因基因，通常作用于抑制神经元兴奋性。 KCNA1基因敲除小鼠通过表现出严重的癫痫，脑驱动心脏功能障碍和过早死亡来准确地对人类SUDEP进行建模。鉴于这两个基因的表达重叠和相互对立的兴奋性影响，该研究检验了以下假设：亚临床SCN2A-NULL杂合性降低了KCNA1-NULL小鼠的SUDEP发病率，通过抑制神经心动功能障碍和神经脱神经脱发性障碍性和神经性障碍性障碍性与KV1.1.1.1.1.1.1.1.1.1.1.1.1.1.1.1.1.初步数据表明，SCN2A无效的杂合性可防止KCNA1敲除中的SUDEP，从而增加了其生存率三倍。在AIM 1中，视频脑电图 - 心电图学（EEG-ECG）用于确定SCN2A无效的杂合性是否会减少KCNA1-NULL小鼠的癫痫样放电和/或心脏异常。 AIM 2试图通过分析与异常神经元激活相关的分子生物标志物表达的变化（例如C-FOS），旨在鉴定SCN2A和KCNA1之间表现出功能相互作用的神经元网络。这项研究利用一种新型的挖掘小鼠模型作为了解SUDEP基础的复杂遗传相互作用的重要第一步，其最终目的是改善基于基因型的风险预测，预防和癫痫的治疗。 SCN2A无效的杂合性抑制KCNA1 SUDEP表型的能力将证明一种原则证明，即当评估癫痫患者的遗传风险概况时，也必须考虑没有明显表型的亚临床基因变异，因为这些等位基因也可以成为疾病易感性的重要修饰。此外，在这种二元模型中对分子生物标志物内表型的检查具有鉴定先前未认识到的脑网络，这对于SUDEP病理生理学和候选治疗靶点至关重要，以便将来研究。