Excitability mechanisms of neurocardiac regulation

神经心脏调节的兴奋机制

• 批准号: 8609178
• 负责人: Albert E Glasscock
• 金额: $ 23.7万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8609178
• 关键词: Action Potentials; Address; Affect; Age; Arrhythmia; Atrioventricular Block; Atropine; Axon; Baroreflex; Bradycardia; Brain; Brain Stem; Carbachol; Cardiac; Cardiology; Cessation of life; Comorbidity; Congenital Heart Defects; Defect; Diagnosis; Disease; Educational process of instructing; Electrocardiogram; Electroencephalography; Electrophysiology (science); Engineering; Epilepsy; Exhibits; FOS Protein; FOS gene; Functional disorder; Gene Expression; Gene Mutation; General Population; Genetic; Goals; Heart; Heart Atrium; Human; Image; Immediate-Early Genes; Immunohistochemistry; Institution; Ion Channel; Journals; K-Series Research Career Programs; KCNA1 channel; Knockout Mice; Lead; Leadership; Link; Maps; Measures; Mediating; Medicine; Mentors; Methoxamine; Missense Mutation; Modeling; Molecular; Monitor; Mus; Muscarinic Acetylcholine Receptor; Mutant Strains Mice; Mutation; Nervous system structure; Neurology; Neurons; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Phase; Potassium Channel; Prevalence; Recruitment Activity; Regulation; Research; Research Personnel; Research Training; Resources; Risk; Seizures; Signal Transduction; Slice; Students; Techniques; Testing; Time; Tissues; Training; Vagotomy; Vagus nerve structure; Ventricular Arrhythmia; Work; base; career; career development; college; extracellular; inhibitor/antagonist; interest; knowledge base; meetings; mouse model; neurotransmission; novel; premature; programs; relating to nervous system; response; responsible research conduct; skills

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.

拟议的研究检查了有助于神经心动的分子机制 癫痫和突然无法解释的癫痫病（SUDEP）的小鼠模型的功能障碍。有人 癫痫的可能是一般人群突然死亡的24倍 原因；因此，这些死亡被归类为SUDEP。该提案调查了 在两种不同的癫痫小鼠中，副交感神经传递潜在致命性心律失常 与SUDEP相关的大脑驱动心脏功能障碍的模型：1）KCNA1钾通道敲除鼠标 模型，尽管心脏表达最少，但表现出心脏缺陷； 2）KCNQ1钾通道 错义突变小鼠模型，该模型表现出与大脑共表达相关的心脏缺陷和 心。在AIM 1中，迷走神经切开术与同时的视频脑电图一起使用 - 心电图（EEG-ECG）评估副交感神经传递对心脏的影响 KCNA1-NULL小鼠的功能障碍和过早死亡。在AIM 2中，KCNA1-NULL小鼠是给药的药物 有选择地激活迷走神经，以确定副交感神经传递的刺激是否 通过EEG-ECG测量，会增加KCNA1-NULL小鼠的心脏功能障碍。在AIM 3中，迷走神经和 心脏内电生理学用于确定缺乏KV1.1通道是否会影响迷走神经兴奋性或 诱导心律不齐的脆弱性。在AIM 4中，免疫组织化学用于立即图像 早期基因表达生成由KCNA1-NULL小鼠癫痫激活的自主脑中心的图。在 AIM 5，AIMS 1-4中针对KCNA1-NULL小鼠所描述的相同的测试将用于确定是否心脏 脑心脏心脏通道功能障碍的KCNQ1小鼠模型中的缺陷具有潜在的神经 贡献并显示与KCNA1模型的机械相似性。 AIMS 1-4将在K99期间完成 阶段和目标5在R00阶段。 该职业发展奖的候选人正在从事职业 神经心理学，解决与大脑心脏相互作用有关的研究问题。特别有趣的是 兴奋性疾病，尤其是癫痫的遗传基础，以及基因突变如何引起兴奋性 同时出现多个组织中的缺陷，例如大脑和心脏，为患病率提供了新颖的解释 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大脑心脏知识基础； 3）通过指导学生，领先的研讨会和期刊俱乐部来提高他的领导力/教学能力。 候选人还将接受负责任的研究培训。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 它提供的实验资源及其神经病学和心脏病学专家的数量。