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: 10057795
• 负责人: Chad Frasier
• 金额: $ 39.41万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057795
• 关键词: Affect; Animals; Apnea; Arrhythmia; Asses; Autonomic Dysfunction; Brain; Buffers; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular system; Cells; Cerebrovascular Circulation; Electrophysiology (science); Epilepsy; Event; Exhibits; Fill-It; Fluorescent Dyes; Functional disorder; Future; General Population; Genes; Genetic Diseases; Grant; Heart; Homeostasis; Human; Impairment; Incidence; Individual; Lead; Link; Measures; Membrane Potentials; Methods; Mitochondria; Modeling; Mus; Mutation; Neurons; Organ; Organelles; Other Genetics; Oxidative Stress; Oxygen; Pathway interactions; Patients; Pattern; Permeability; Phenotype; Physiological; Play; Prevention; Production; Pulmonary Edema; Reactive Oxygen Species; Regulation; Respiration; Risk; Role; Seizures; Sodium; Sodium Channel; Sodium-Calcium Exchanger; Stress; Sudden Death; Symptoms; Testing; Time; Work; Workload; childhood epilepsy; density; dravet syndrome; experimental study; heart cell; heart preservation; indium arsenide; inhibitor/antagonist; innovation; insight; interest; ionic balance; loss of function mutation; mitochondrial membrane; mouse model; mutant; neurotransmitter release; new therapeutic target; non-genetic; novel; novel therapeutic intervention; novel therapeutics; premature; prevent; sudden unexpected death in epilepsy; therapeutic target; uptake; voltage

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. This 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. My central hypothesis is that compromised mitochondrial energetics and ionic homeostasis predisposes DS patients to cardiac arrhythmias, seizures, and SUDEP-like events. I plan to test this hypothesis through the following two specific aims: 1) we will determine if mitochondria play a role in ionic homeostasis in mouse models of DS. This aim will test the hypothesis that DS mice have an impaired ability to buffer changes in cytosolic Na+ and Ca2+ during times of stress. Using multiple models, we will determine the role that the mitochondria plays in long-term cellular ionic balance. 2) We will determine if mitochondrial energetics and the ability to match ATP supply with demand is compromised in DS mice. This aim will test the hypothesis that mitochondrial energetic of DS mice have increased reactive oxygen species (ROS) production and a decreased ability match ATP supply with demand. Experiments will investigate the ability of mitochondria in our DS mouse models to generate ATP at the whole organ, isolated cell, and organelle level. 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, due to the high incidence of SUDEP, 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 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。这一项目旨在 发现线粒体受损导致心脏兴奋性改变的新机制 德拉韦特综合征(DS)模型中的能量学，这是一种癫痫形式，SUDEP的发生率很高。我的 中心假说是线粒体能量学和离子动态平衡受损易于 患者会出现心律失常、癫痫发作和SUDEP样事件。我计划检验这一假设 通过以下两个具体目标：1)我们将确定线粒体是否在离子 DS小鼠模型的动态平衡。这一目标将检验以下假设：DS小鼠有受损的 在应激期间缓冲胞浆Na+和Ca~(2+)变化的能力。使用多种型号，我们将 确定线粒体在长期细胞离子平衡中所起的作用。2)我们将确定 如果DS小鼠的线粒体能量学和匹配ATP供需的能力受到损害。 这一目标将检验DS小鼠线粒体能量增加了活性氧的假设 物种(ROS)的产生和能力的下降使ATP供需相匹配。实验将会 在我们的DS小鼠模型中，研究线粒体在整个器官产生ATP的能力， 分离的细胞和细胞器水平。这个项目的意义在于它填补了 对DS中SUDEP机制的理解和拟议实验的结果 有可能导致DS的新治疗方法。虽然这笔赠款的重点是DS的作用 突变，由于SUDEP的高发，我们希望这些结果可能适用于 其他遗传性和非遗传性癫痫将是未来项目的重点。建议进行的研究 将为该领域提供有价值的见解，并可能导致发现几种潜在的治疗方法 DS的目标。线粒体是一个理想的研究对象，因为人们对 心律失常发生的线粒体机制和新药可能很快就会在 癫痫模型。