Excitability mechanisms of neurocardiac regulation

描述（由申请人提供）：拟议的研究检查了导致癫痫和癫痫猝死（SUDEP）小鼠模型中神经心脏功能障碍的分子机制。癫痫患者因无法解释的病理原因突然死亡的可能性是普通人群的24倍;因此，这些死亡被归类为SUDEP。该提议在与SUDEP相关的脑驱动的心功能障碍的两种不同癫痫小鼠模型中研究副交感神经传递对潜在致死性心律失常的贡献：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，其表现出与脑和心脏中的共表达相关的心脏缺陷。在目的1中，迷走神经切断术与同步视频脑电图-心电图（EEG-ECG）结合使用，以评估副交感神经传递对Kcna 1缺失小鼠的心功能障碍和过早死亡的影响。在目的2中，向Kcna 1缺失小鼠施用选择性激活迷走神经的药物，以确定刺激副交感神经传递是否增加Kcna 1缺失小鼠的心功能障碍，如通过EEG-ECG测量的。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。在目的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中，将使用目的1-4中描述的针对Kcna 1缺失小鼠的相同测试组合来确定脑-心钾通道功能障碍的Kcnq 1小鼠模型中的心脏缺陷是否具有潜在的神经贡献，并显示与Kcna 1模型的机制相似性。目标1-4将在K99阶段完成，目标5将在R 00阶段完成。 该职业发展奖的候选人正在追求作为神经心脏病学独立研究者的职业生涯，解决与脑心相互作用相关的研究问题。特别令人感兴趣的是兴奋性疾病，特别是癫痫的遗传基础，以及基因突变如何同时导致多个组织（如大脑和心脏）的兴奋性缺陷，为疾病合并症的流行提供了新的解释。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）通过参加科学会议增加他的脑-心知识库; 3）通过指导学生和领导研讨会和期刊俱乐部来提高他的领导/教学技能。候选人还将接受负责任地开展研究的培训。候选人所在的贝勒医学院非常适合拟议的研究和培训目标，因为它提供了广泛的实验资源，以及神经病学和心脏病学专家的数量。 公共卫生相关性：癫痫患者因不明病理原因突然死亡的比率是普通人群的24倍。这种死亡被归类为SUDEP，即癫痫中突然不明原因死亡的简称。虽然SUDEP的确切原因仍然神秘且知之甚少，但该提案探讨了癫痫发作引发大脑和心脏之间的致病性神经信号传导的假设，导致SUDEP受害者的致命心律失常。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: People with epilepsy die suddenly for unknown pathological reasons at a rate 24 times greater than the general population. Such deaths are classified as SUDEP, short for Sudden Unexplained Death in Epilepsy. Although the exact cause of SUDEP remains mysterious and poorly understood, this proposal explores the hypothesis that seizures initiate pathogenic neural signaling between the brain and heart leading to lethal cardiac arrhythmias in victims of SUDEP.