SUDEP Research Alliance: Cardiac Gene and Circuit Mechanisms; Application 7 of 7

 描述（由申请方提供）：SRA的主要使命是了解基本生物学机制、遗传和生理风险因素、预测性诊断生物标志物以及预防突发意外死亡（人类癫痫过早死亡的最常见原因）的潜在方法。该项目将测试主要假设，即在脑，心脏和脑干中枢自主神经元中共表达的单基因突变通过促进心肺心律失常增加SUDEP风险。我们将在小鼠模型中识别和验证新的发作性心动过缓和SUDEP基因候选物，以扩大SUDEP风险基因组，并使用修饰基因抑制前脑和脑干自主神经回路中的这种风险，以从遗传学上剖析关键的SUDEP通路。我们将研究这些基因在大脑和心脏中的分子兴奋性机制，以及癫痫发作和缺氧在病理性网络去极化中的作用。我们还将探讨这些模型中的翻译药理学和遗传拯救策略。这些发现将有助于临床外显子组中SUDEP的未来遗传风险分析，并指出新的基因导向方法，以减少高风险患者的SUDEP。

 DESCRIPTION (provided by applicant): The primary mission of the SRA is to understand the basic biological mechanisms, genetic and physiological risk factors, predictive diagnostic biomarkers, and potential methods of preventing sudden unexpected death, the most common cause of premature mortality in human epilepsy. This project will test the principal hypothesis that mutation of single genes co-expressed in brain, heart, and brainstem central autonomic neurons increase SUDEP risk by promoting cardiorespiratory arrhythmias. We will identify and validate novel ictal bradycardia and SUDEP gene candidates in mouse models to expand the SUDEP risk genome, and use modifier genes that suppress this risk in forebrain and brainstem autonomic circuits to genetically dissect critical SUDEP pathways. We will examine molecular excitability mechanisms perturbed by these genes in brain and heart, and the role of seizures and hypoxia in pathological network depolarization. We will also explore translational pharmacologic and genetic rescue strategies in these models. These findings will contribute to future genetic risk profiling for SUDEP in clinical exomes and point to new gene-directed approaches to reduce SUDEP in patients at high risk.