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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.

项目概要 Dravet 综合征 (DS) 是一种灾难性小儿癫痫，主要由功能丧失引起钠通道基因突变。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疾病的病理生理学的基础表现出癫痫和心脏病两种表型。癫痫患者猝死的风险是二十是一般人口的四倍。尽管近年来人们对尽管癫痫猝死（SUDEP）的机制尚不清楚，但它仍然难以捉摸。建议的 SUDEP 的机制涉及癫痫发作引起的呼吸暂停、肺水肿、脑循环、植物神经功能紊乱或心律失常。除了是实力雄厚的在细胞中，线粒体负责细胞内的长期离子平衡并受到损害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稳态受损使 DS 患者易患心脏病心律失常、癫痫发作和 SUDEP 样事件。父项目旨在发现新的机制 Dravet 中线粒体能量学受损导致心脏兴奋性改变综合征 (DS) 模型，一种 SUDEP 发病率较高的癫痫形式。本补充将重点关注 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重大空白无法理解 DS 中 SUDEP 的机制，并且所提出的实验结果开发 DS 新治疗方法的潜力。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遗传和非遗传癫痫症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：该领域并可能导致发现 DS 的几个潜在治疗靶点。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心律失常发生和新药物可能很快就能在癫痫模型中进行测试。