Excitability mechanisms of neurocardiac regulation

这项拟议的研究考察了神经心脏的分子机制。 癫痫小鼠模型的功能障碍和癫痫原因不明猝死(SUDEP)。具有以下特征的人 癫痫患者因不明原因的疾病突然死亡的可能性是普通人的24倍。 原因；因此，这些死亡被归类为SUDEP。该提案调查了以下方面的贡献 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相关的脑驱动心功能障碍模型：1)KcNA1钾通道基因敲除小鼠 模型，尽管心脏表达最少，但仍表现出心脏缺陷；2)KCNQ1钾通道 错义突变小鼠模型，表现出心脏缺陷与脑和 心。在目标1中，迷走神经切断术与同步视频脑电图术一起使用- 心电图评价副交感神经传递对心脏功能的影响 KcNA1基因缺失小鼠的功能障碍和过早死亡。在AIM 2中，KcNA1基因缺失的小鼠被给予 选择性激活迷走神经以确定刺激副交感神经传递 增加KcNA1基因缺失小鼠的心功能障碍，通过脑电-心电图测量。在目标3中，迷走神经和 心内电生理用于确定Kv1.1通道的缺乏是否影响迷走神经的兴奋性或 易诱发心律失常。在目标4中，使用免疫组织化学方法对即时图像进行成像 早期基因表达以生成KcNA1基因缺失小鼠癫痫发作激活的自主脑中心图。在……里面 AIM 5，将使用AIMS 1-4中描述的针对KcNA1基因缺失小鼠的同一组测试来确定心脏 KCNQ1小鼠脑心钾通道功能障碍模型的缺陷有神经基础 贡献，并显示出与Kcna1模型的机械相似性。目标1-4将在K99期间完成 阶段和目标5在R00阶段。 这一职业发展奖的候选人正在寻求作为一名独立调查员的职业生涯 神经心脏病学，解决与大脑-心脏相互作用相关的研究问题。特别值得关注的是 兴奋性障碍的遗传基础，特别是癫痫，以及基因突变如何引起兴奋性 多个组织同时存在缺陷，如大脑和心脏，为患病率提供了一个新的解释 疾病的合并症。对于K99阶段的职业发展活动，应聘者将：1)扩展 他的实验技能；2)通过参加科学会议，增加他的脑心知识基础； 3)通过指导学生、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进行研究的培训。候选人的机构， 贝勒医学院，非常适合拟议的研究和培训目标，因为它的广度 它提供的实验资源以及可接触到的神经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.