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：
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
项目类别：
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

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. 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。该项目旨在揭示因线粒体受损而改变心脏兴奋性的新机制 Dravet 综合征 (DS) 模型中的能量学，这是一种 SUDEP 发病率较高的癫痫形式。我的中心假设是线粒体能量学和离子稳态受损容易导致 DS 患者会出现心律失常、癫痫发作和 SUDEP 样事件。我打算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发挥作用 DS 小鼠模型中的稳态。该目标将检验 DS 小鼠的大脑功能受损的假设在应激期间缓冲细胞质 Na+ 和 Ca2+ 变化的能力。使用多个模型，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 小鼠的线粒体能量和 ATP 供应与需求相匹配的能力受到损害。该目标将检验 DS 小鼠线粒体能量增加活性氧的假设 ROS 的产生和 ATP 供应与需求匹配能力的下降。实验将研究 DS 小鼠模型中线粒体在整个器官中产生 ATP 的能力，分离的细胞和细胞器水平。该项目的重大意义在于填补了了解 DS 中 SUDEP 的机制以及所提出的实验结果有可能会导致 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 的高发生率，我们希望这些结果可以适用于其他遗传性和非遗传性癫痫将成为未来项目的重点。拟议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目标，因为人们对线粒体的兴趣越来越大心律失常发生的线粒体机制和新药物可能很快就能用于测试癫痫模型。