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

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.

项目总结

项目成果

Teriflunomide treatment exacerbates cardiac ischemia reperfusion injury in isolated rat hearts.

• DOI: 10.1007/s10557-022-07341-z
• 发表时间: 2023-10
• 期刊: Cardiovascular drugs and therapy
• 影响因子: 3.4