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The role of cardiac mitochondrial energetics in cardiac arrhythmias and SUDEP

心脏线粒体能量学在心律失常和 SUDEP 中的作用

基本信息

批准号：
10405287
负责人：
Chad Frasier
金额：
$ 5.9万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

项目摘要

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.

项目摘要 Dravet综合征（DS）是一种严重的儿童癫痫，主要由功能丧失引起钠离子通道基因突变。突变体的重叠神经和心脏表达模式钠通道被认为是许多遗传疾病的病理生理学基础，表现出癫痫和心脏病的表型。癫痫患者猝死的风险为20 比一般人多四倍。尽管近年来在了解癫痫猝死（Sudden Unexpected Death in Epilepsy，SUDEP）的发病机制至今仍不清楚。提出 SUDEP的机制涉及呼吸暂停、肺水肿、呼吸系统功能失调、脑循环、自主神经功能障碍或心律失常。除了作为一个发电站，线粒体负责细胞内的长期离子平衡，线粒体功能可能先于心律失常和癫痫事件。我们的核心假设是损害线粒体能量和离子稳态使DS患者易患心脏病，心律失常、癫痫发作和SUDEP样事件。母项目旨在揭示新的机制，由于Dravet的线粒体能量学受损，综合征（DS）模型，一种具有高SUDEP发生率的癫痫形式。本附录将重点介绍 DS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中SUDEP的机制方面存在空白，并且从所提出的实验中得到的结果可能导致DS的新治疗方法。虽然这项赠款的重点是DS的作用突变，我们希望这些结果可能适用于其他遗传和非遗传癫痫病将是未来项目的重点。拟议的研究将提供宝贵的见解，该领域的研究，并可能导致发现几个潜在的治疗目标的DS。线粒体代表了一个理想的研究目标，因为人们对线粒体机制越来越感兴趣，癫痫发生和新药可能很快就可以在癫痫模型中进行测试。