The role of cardiac mitochondrial energetics in cardiac arrhythmias and SUDEP

项目摘要 德拉韦综合征(DS)是一种主要由功能丧失引起的灾难性的儿童癫痫 钠通道基因突变。突变体的重叠神经元和心脏表达模式 钠通道被认为是许多遗传性疾病的病理生理学基础 表现出癫痫和心脏的表型。癫痫患者猝死的风险是20 是普通人口的四倍。尽管近几年来在理解 关于癫痫猝死的机制(SUDEP)，它仍然难以捉摸。建议 SUDEP的机制与癫痫引起的呼吸暂停、肺水肿、肺功能紊乱有关。 脑循环、自主神经功能障碍或心律失常。除了成为全球最大的 细胞，线粒体负责细胞内长期的离子平衡， 线粒体功能可能先于心律失常和癫痫事件。我们的中心假设是 线粒体能量学和离子动态平衡受损使DS患者易患心脏病 心律失常、癫痫发作和类SUDEP事件。母项目试图发现新的机制 通过这种方式，心脏的兴奋性被改变，由于线粒体能量学受损在德拉韦特 综合征(DS)模型，癫痫的一种形式，SUDEP的发生率很高。本副刊将重点介绍 DS患者癫痫发生的线粒体机制。这个项目的意义在于它填补了一个主要的 在理解DS的SUDEP机制和拟议的实验结果方面存在空白 为DS带来新的治疗方法的潜力。虽然这笔赠款的重点是DS的作用 突变，我们希望这些结果可以适用于其他基因和非基因 癫痫将是未来项目的重点。拟议的研究将为以下方面提供宝贵的见解 并可能导致发现几个潜在的DS治疗靶点。线粒体 是一个理想的研究对象，因为人们对线粒体的机制越来越感兴趣 心律失常的发生和新药可能很快就会在癫痫模型中进行测试。

Project Summary Dravet Syndrome (DS) is a catastrophic pediatric epilepsy that largely arises from loss-of-function mutations in sodium channel genes. Overlapping neuronal and cardiac expression patterns of mutant sodium channels are proposed to underlie the pathophysiology of a number of genetic diseases that exhibit both epileptic and cardiac phenotypes. The risk of sudden death in epilepsy patients is twenty four times greater than the general population. Despite advances in recent years to understand the mechanisms of Sudden Unexpected Death in Epilepsy (SUDEP), it has remained elusive. Proposed mechanisms of SUDEP have implicated seizure-induced apnea, pulmonary edema, dysregulation of cerebral circulation, autonomic dysfunction, or cardiac arrhythmias. Besides being the powerhouse of the cell, the mitochondria is responsible for long term ionic balance in the cell and compromised mitochondrial function may precede cardiac arrhythmias and epileptic events. Our central hypothesis is that compromised mitochondrial energetics and ionic homeostasis predisposes DS patients to cardiac arrhythmias, seizures, and SUDEP-like events. The parent project seeks to uncover novel mechanisms by which cardiac excitability is altered due to compromised mitochondrial energetics in Dravet Syndrome (DS) models, a form of epilepsy with a high incidence of SUDEP. This supplement will focus on mitochondria mechanisms of epileptogenesis in DS. The significance of this project is that it fills a major void in understanding the mechanism of SUDEP in DS and results from the proposed experiments have the potential to lead to new therapeutic treatments in DS. While this grant focuses on the role of DS mutations, it is our hope that these results may be applicable to other genetic and non-genetic epilepsies that will be the focus of future projects. The proposed studies will provide valuable insight to the field and may lead to the discovery of several potential therapeutic targets for DS. The mitochondria represent an ideal target to investigate, as there is growing interest in the mitochondrial mechanisms of arrhythmogenesis and novel drugs may soon be available to test in epilepsy models.