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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10405287
• 关键词: Apnea; Arrhythmia; Autonomic Dysfunction; Cardiac; Cells; Cerebrovascular Circulation; Epilepsy; Epileptogenesis; Event; Exhibits; Fill-It; Functional disorder; Future; General Population; Genes; Genetic Diseases; Grant; Homeostasis; Incidence; Lead; Mitochondria; Modeling; Mutation; Neurons; Other Genetics; Patients; Pattern; Phenotype; Pulmonary Edema; Risk; Role; Seizures; Sodium Channel; Sudden Death; Testing; Time; childhood epilepsy; dravet syndrome; experimental study; insight; interest; ionic balance; loss of function mutation; mutant; new therapeutic target; non-genetic; novel; novel therapeutics; parent project; prevent; sudden unexpected death in epilepsy; therapeutic target; Apnea; Arrhythmia; Autonomic Dysfunction; Cardiac; Cells; Cerebrovascular Circulation; Epilepsy; Epileptogenesis; Event; Exhibits; Fill-It; Functional disorder; Future; General Population; Genes; Genetic Diseases; Grant; Homeostasis; Incidence; Lead; Mitochondria; Modeling; Mutation; Neurons; Other Genetics; Patients; Pattern; Phenotype; Pulmonary Edema; Risk; Role; Seizures; Sodium Channel; Sudden Death; Testing; Time; childhood epilepsy; dravet syndrome; experimental study; insight; interest; ionic balance; loss of function mutation; mutant; new therapeutic target; non-genetic; novel; novel therapeutics; parent project; prevent; sudden unexpected death in epilepsy; therapeutic target

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）是一种灾难性的小儿癫痫，主要由功能丧失引起 钠通道基因中的突变。突变体的重叠神经元和心脏表达模式 提出了钠通道的基础，以基于许多遗传疾病的病理生理学 表现出癫痫和心脏表型。癫痫患者突然死亡的风险为二十 是普通人群的四倍。尽管近年来进步了 癫痫（SUDEP）突然意外死亡的机制仍然难以捉摸。建议的 SUDEP的机制牵涉到癫痫发作诱导的呼吸暂停，肺水肿，失调的失调 脑循环，自主功能障碍或心律不齐。除了成为 细胞，线粒体负责细胞中的长期离子平衡并损害 线粒体功能可能在心律不齐和癫痫事件之前。我们的中心假设是 这损害了线粒体能量学和离子稳态使DS患者易于心脏 心律不齐，癫痫发作和类似SUDEP的事件。家长项目试图发现新颖的机制 由于dravet中的线粒体能量受损而改变了心脏兴奋性 综合征（DS）模型，一种癫痫的形式，具有较高的SUDEP发生率。这种补充将重点放在 DS中癫痫发生的线粒体机制。该项目的意义在于它充满了重大 在理解DS中SUDEP的机理和提议的实验结果方面的空白具有 导致DS中新的治疗治疗的潜力。虽然这笔赠款专注于DS的角色 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。拟议的研究将为 该领域并可能导致发现DS的几个潜在治疗靶标。线粒体 代表了调查的理想目标，因为对线粒体机制的兴趣越来越大 心律失常发生和新药物可能很快可以在癫痫模型中进行测试。