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 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。这个项目试图 发现因线粒体受损而改变心脏兴奋性的新型机制 Dravet综合征（DS）模型中的能量学，一种癫痫的形式，具有较高的SUDEP发生率。我的 中心假设是线粒体能量学和离子稳态受损易感性 DS患者发生心律不齐，癫痫发作和SUDEP样事件。我计划检验这个假设 通过以下两个具体目标：1）我们将确定线粒体是否在离子中起作用 DS的鼠标模型中的体内平衡。这个目标将检验DS小鼠有障碍的假设 在压力时期，能够缓冲胞质Na+和Ca2+的变化。使用多种型号，我们将 确定线粒体在长期细胞离子平衡中发挥的作用。 2）我们将确定 如果线粒体能量和将ATP供应与需求匹配的能力在DS小鼠中受到损害。 该目的将检验以下假设：DS小鼠的线粒体能量增加了活性氧 物种（ROS）生产和能力降低与需求相匹配的ATP供应。实验会 研究线粒体在我们的DS小鼠模型中在整个器官中生成ATP的能力， 孤立的细胞和细胞器水平。该项目的意义在于它填补了一个主要空隙 了解DS中SUDEP的机制以及提出的实验的结果具有 可能导致DS中新的治疗治疗。虽然这笔赠款专注于DS的角色 由于SUDEP的发病率很高，我们希望这些结果可能适用于 其他遗传和非遗传性癫痫将成为未来项目的重点。提出的研究 将为该领域提供宝贵的见识，并可能导致发现几种潜在的治疗性 DS的目标。线粒体是调查的理想目标，因为对 心律失常发生和新药物的线粒体机制可能很快可以在 癫痫模型。