Respiratory mechanisms of epilepsy with high risk of SUDEP

SUDEP高危癫痫的呼吸机制

• 批准号: 10019170
• 负责人: Albert E Glasscock
• 金额: $ 17.17万
• 依托单位: SOUTHERN METHODIST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019170
• 关键词: Respiratory; mechanisms; epilepsy; risk; SUDEP

Our long-term goal is to understand how channelopathies can cause epilepsy with cardiorespiratory comorbidities and susceptibility to sudden unexpected death in epilepsy (SUDEP), the leading cause of epilepsy-related mortality. Deaths are classified as SUDEP when people with epilepsy die suddenly for unknown pathological reasons. SUDEP is hypothesized to result from seizure-related cardiorespiratory dysfunction that culminates in death. However, the relative importance and interrelationship of cardiac and respiratory factors underlying SUDEP is unclear, posing a significant barrier to progress in the field. Mutations in ion channel genes with brain-heart expression patterns, such as the Kcna1 gene, have been proposed to be a molecular cause of seizure-related cardiac arrhythmias underlying SUDEP. Kcna1, a human epilepsy gene associated with increased SUDEP risk in patients, encodes voltage-gated Kv1.1 potassium channel α-subunits that are expressed in neurons and cardiomyocytes where they act to control action potential firing properties. The Kcna1 knockout (KO) mouse is an often utilized model of SUDEP since it recapitulates key aspects of the human condition, including tonic-clonic seizures, ictal bradycardia, and premature death. Whereas the epilepsy and cardiac phenotypes of Kcna1 KO mice have been studied extensively in relation to SUDEP, a possible contribution by respiratory dysfunction has not been explored. In preliminary experiments, we used plethysmography to identify several types of breathing abnormalities in Kcna1 KO mice. During spontaneous seizures, KO mice exhibited apneas, suggesting respiratory dysfunction may be the primary factor contributing to their sudden death. During interictal periods, they exhibited alterations in post-sigh apnea frequency and respiratory variability suggesting a role for Kv1.1 in maintaining normal respiratory physiology. The goal of this project is to test the hypothesis that Kv1.1 channels are required for normal respiratory physiology and that their absence leads to respiratory abnormalities that contribute to SUDEP risk. Aim 1 will test the hypothesis that respiratory dysfunction precedes bradycardia during seizures in Kcna1 KO mice. Aim 2 will test the hypothesis that sleep-wake status contributes to the occurrence of interictal and ictal apneas in Kcna1 KO mice. To acquire in vivo biosignals in aims 1 and 2, we have established a novel, state-of-the-art mouse epilepsy monitoring unit to record simultaneous brain-heart-muscle-respiratory activity. Aim 3 will use immunohistochemistry to test the hypothesis that Kv1.1 channels are expressed in brainstem respiratory networks and that their deficiency leads to seizure-related damage. This research will illuminate the crossroads between respiratory and cardiac mechanisms underlying SUDEP, while elucidating a novel role for Kv1.1 channels in regulating basal respiratory physiology. The results of this study will impact the development of future preventative measures for SUDEP by identifying new cardiorespiratory strategies for intervention.

我们的长期目标是了解通道病如何导致癫痫伴心肺功能障碍。 癫痫合并症和对癫痫猝死（SUDEP）的易感性， 癫痫相关死亡率。当癫痫患者因癫痫发作而突然死亡时，死亡被归类为SUDEP 未知的病理原因。假设SUDEP是由糖尿病相关的心肺功能 功能障碍，最终导致死亡。然而，心脏和心脏病的相对重要性和相互关系， SUDEP的呼吸因素尚不清楚，这对该领域的进展构成了重大障碍。 具有脑-心表达模式的离子通道基因突变，如Kcna 1基因， 被认为是SUDEP基础上的心律失常的分子原因。Kcna 1，a 与患者SUDEP风险增加相关的人类癫痫基因，编码电压门控Kv1.1 钾通道α亚基，在神经元和心肌细胞中表达，在那里它们控制 动作电位放电特性。Kcna 1敲除（KO）小鼠是SUDEP的常用模型，因为它 概括了人类状况的关键方面，包括强直阵挛性癫痫发作，发作性心动过缓， 过早死亡然而，Kcna 1基因敲除小鼠的癫痫和心脏表型已经被研究， 广泛地与SUDEP相关，尚未探讨呼吸功能障碍的可能贡献。在 初步实验中，我们使用体积描记法来识别几种类型的呼吸异常， Kcna 1 KO小鼠。在自发性癫痫发作期间，KO小鼠表现出呼吸暂停，表明呼吸功能障碍 可能是导致他们突然死亡的主要因素。在发作间期，他们表现出 叹息后呼吸暂停频率和呼吸变异性的改变表明Kv1.1在维持 正常的呼吸生理 本项目的目标是测试Kv1.1通道是正常呼吸所需的假设。 生理学和它们的缺乏导致呼吸异常，导致SUDEP风险。目标1将 在Kcna 1基因敲除小鼠中检验癫痫发作期间呼吸功能障碍先于心动过缓的假设。目的2 将检验睡眠-觉醒状态有助于发作间期和发作性呼吸暂停发生的假设， Kcna 1 KO小鼠。为了获得目标1和2中的体内生物信号，我们建立了一种新的、最先进的 小鼠癫痫监测单元记录同时的脑-心脏-肌肉-呼吸活动。目标3将使用 免疫组化检测Kv1.1通道在脑干呼吸道表达的假设 网络，其缺陷导致与网络相关的损害。这项研究将照亮十字路口 呼吸和心脏机制之间的SUDEP，同时阐明了一个新的作用Kv1.1 通道调节基础呼吸生理。这项研究的结果将影响发展， 通过确定新的心肺干预策略，为SUDEP制定未来的预防措施。