Excitability mechanisms of neurocardiac regulation

这项拟议中的研究检查了导致神经心脏疾病的分子机制。 癫痫小鼠模型的功能障碍和癫痫中的不明原因的猝死（SUDEP）。人 癫痫患者因不明原因的病理性猝死的可能性是普通人群的24倍。 这些死亡被归类为SUDEP。本提案探讨了 两种不同癫痫小鼠对潜在致死性心律失常的副交感神经传递 与SUDEP相关的脑驱动性心功能障碍模型：1）Kcna 1钾通道敲除小鼠 模型，其表现出心脏缺陷，尽管心脏表达最小;和2）Kcnq 1钾通道 错义突变小鼠模型，其表现出与脑中的共表达相关的心脏缺陷， 心在目标1中，迷走神经切断术与同步视频脑电图结合使用- 心电图（EEG-ECG），以评估副交感神经传递对心脏的影响 Kcna 1基因敲除小鼠的功能障碍和过早死亡。在目标2中，给予Kcna 1缺失小鼠药物， 选择性地激活迷走神经，以确定是否刺激副交感神经传递 通过EEG-ECG测量，增加Kcna 1基因敲除小鼠的心功能障碍。在目标3中，迷走神经和 心内电生理学用于确定Kv1.1通道的缺乏是否影响迷走神经兴奋性或 易诱发心律失常。在目标4中，免疫组织化学用于成像立即 早期基因表达，以生成由Kcna 1缺失小鼠癫痫发作激活的自主脑中心的地图。在 目的5，将使用目的1-4中描述的针对Kcna 1-敲除小鼠的相同测试组合来确定心脏 Kcnq 1小鼠脑心钾通道功能障碍模型中的缺陷具有潜在的神经毒性， 贡献，并显示与Kcna 1模型的机制相似性。目标1-4将在K99期间完成 在R 00阶段，目标5。 该职业发展奖的候选人正在追求作为独立调查员的职业生涯， 神经心脏病学，解决与脑-心相互作用相关的研究问题。特别感兴趣的是 兴奋性疾病的遗传基础，特别是癫痫，以及基因突变如何导致兴奋性 同时在多个组织中存在缺陷，如大脑和心脏，为患病率提供了新的解释。 疾病合并症。对于K99阶段的职业发展活动，候选人将：1）扩展 他的实验技能; 2）通过参加科学会议来增加他的脑-心知识基础; 及3）透过指导学生及领导研讨会及期刊社，提升其领导/教学技巧。 候选人还将接受负责任地开展研究的培训。候选人所在的机构， 贝勒医学院，是非常适合拟议的研究和培训目标，因为广度 它提供的实验资源以及神经病学和心脏病学专家的数量。

The proposed research examines the molecular mechanisms that contribute to neurocardiac dysfunction in mouse models of epilepsy and sudden unexplained death in epilepsy (SUDEP). People with epilepsy are 24 times more likely than the general population to die suddenly for unexplained pathological reasons; therefore, these deaths are classified as SUDEP. This proposal investigates the contribution of parasympathetic neurotransmission to potentially lethal heart arrhythmias in two different epilepsy mouse models of brain-driven cardiac dysfunction linked to SUDEP: 1) a Kcna1 potassium channel knockout mouse model, which exhibits cardiac defects despite minimal cardiac expression; and 2) a Kcnq1 potassium channel missense mutation mouse model, which exhibits cardiac defects associated with co-expression in brain and heart. In Aim 1, vagotomy is used in conjunction with simultaneous video electroencephalography- electrocardiography (EEG-ECG) to assess the effect of parasympathetic neurotransmission on cardiac dysfunction and premature death in Kcna1-null mice. In Aim 2, Kcna1-null mice are administered drugs that selectively activate the vagus nerve to determine whether stimulation of parasympathetic neurotransmission increases cardiac dysfunction in Kcna1-null mice as measured by EEG-ECG. In Aim 3, vagus nerve and intracardiac electrophysiology are used to determine if the lack of Kv1.1 channels affects vagal excitability or vulnerability to inducible cardiac arrhythmias. In Aim 4, immunohistochemistry is used to image immediate early gene expression to generate a map of autonomic brain centers activated by seizures in Kcna1-null mice. In Aim 5, the same battery of tests described in Aims 1-4 for Kcna1-null mice will be used to determine if cardiac defects in Kcnq1 mouse models of brain-heart potassium channel dysfunction have an underlying neural contribution and show mechanistic similarities with Kcna1 models. Aims 1-4 will be completed during the K99 phase and Aim 5 during the R00 phase. The candidate for this career development award is pursuing a career as an independent investigator in neurocardiology, addressing research questions related to the brain-heart interaction. Of particular interest is the genetic basis of excitability disorders, especially epilepsy, and how gene mutations can cause excitability defects in multiple tissues at once, such as the brain and heart, providing a novel explanation for the prevalence of disease comorbidities. For career development activities during the K99 phase, the candidate will: 1) expand his experimental skillset; 2) increase his brain-heart knowledge-base by participating in scientific meetings; and 3) enhance his leadership/teaching skills by mentoring students and leading seminars and journal clubs. The candidate will also receive training in the responsible conduct of research. The candidate's institution, Baylor College of Medicine, is well-suited for the proposed research and training goals because of the breadth of experimental resources it offers and the number of accessible experts in neurology and cardiology.