Excitability mechanisms of neurocardiac regulation

描述(由申请人提供)：这项拟议的研究在癫痫和原因不明猝死的小鼠模型(SUDEP)中检查了导致神经心脏功能障碍的分子机制。癫痫患者因不明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。这项建议研究了副交感神经传递在两种与SUDEP相关的脑驱动心功能障碍的不同癫痫小鼠模型中对潜在致命性心律失常的贡献：1)KcNA1钾通道基因敲除小鼠模型，尽管心脏有少量表达，但仍显示出心脏缺陷；2)KCNQ1钾通道错义突变小鼠模型，显示出与脑和心脏共表达相关的心脏缺陷。在目标1中，迷走神经切断术与同步视频脑电-心电图术(EEG-ECG)相结合，以评估副交感神经传递对KcNA1基因缺失小鼠心功能障碍和过早死亡的影响。在目标2中，给KcNA1基因缺失的小鼠注射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会增加KcNA1基因缺失小鼠的心功能障碍，如脑电-心电图所测量的那样。在目标3中，迷走神经和心内电生理学被用来确定Kv1.1通道的缺乏是否影响迷走神经的兴奋性或对诱导性心律失常的易感性。在目标4中，免疫组织化学被用来成像即时早期基因表达，以生成KcNA1基因缺失小鼠癫痫发作激活的自主神经中枢的地图。在目标5中，将使用AIMS 1-4中描述的针对KcNA1基因缺失小鼠的相同组测试，以确定脑心钾通道功能障碍的KCNQ1小鼠模型中的心脏缺陷是否具有潜在的神经贡献，并显示出与KcNA1模型的机制相似。目标1-4将在K99阶段完成，目标5将在R00阶段完成。这一职业发展奖的候选人正在寻求作为一名神经心脏病学独立研究员的职业，解决与大脑-心脏相互作用相关的研究问题。尤其令人感兴趣的是兴奋性障碍，特别是癫痫的遗传基础，以及基因突变如何同时导致大脑和心脏等多个组织的兴奋性缺陷，为疾病共存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)扩大他的实验技能；2)通过参加科学会议增加他的大脑-心脏知识基础；以及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，因为它提供了广泛的实验资源，以及可以接触到的神经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，在癫痫中是原因不明猝死的缩写。尽管SUDEP的确切原因仍然神秘且知之甚少，但这一提议探索了一种假设，即癫痫发作引发大脑和心脏之间的致病神经信号，导致SUDEP患者发生致命性心律失常。

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.