Excitability mechanisms of neurocardiac regulation

神经心脏调节的兴奋机制

基本信息

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
项目类别：
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

项目摘要

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.

拟议的研究探讨了导致神经心脏病的分子机制癫痫小鼠模型的功能障碍和癫痫原因不明的猝死（SUDEP）。人与癫痫患者因不明原因的病理原因突然死亡的可能性比普通人群高 24 倍原因；因此，这些死亡被归类为 SUDEP。该提案调查了以下贡献副交感神经传递导致两种不同癫痫小鼠潜在致命性心律失常与 SUDEP 相关的脑驱动心功能障碍模型：1) Kcna1 钾通道敲除小鼠模型，尽管心脏表达极少，但仍表现出心脏缺陷； 2) Kcnq1 钾通道错义突变小鼠模型，表现出与大脑和大脑中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）评估副交感神经传递对心脏的影响 Kcna1 缺失小鼠的功能障碍和过早死亡。在目标 2 中，对 Kcna1 缺失小鼠施用以下药物：选择性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，Kcna1 缺失小鼠的心脏功能障碍增加。在目标 3 中，迷走神经和心内电生理学用于确定 Kv1.1 通道的缺乏是否会影响迷走神经兴奋性或容易诱发诱发性心律失常。在目标 4 中，免疫组织化学用于立即成像早期基因表达可生成 Kcna1 缺失小鼠癫痫发作激活的自主大脑中心图谱。在目标 5，与目标 1-4 中描述的 Kcna1 缺失小鼠相同的一系列测试将用于确定心脏是否 Kcnq1 小鼠脑心钾通道功能障碍模型的缺陷具有潜在的神经贡献并显示出与 Kcna1 模型的机制相似性。目标 1-4 将在 K99 期间完成 R00 阶段期间的阶段和目标 5。该职业发展奖的候选人正在从事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障碍（尤其是癫痫）的遗传基础，以及基因突变如何导致兴奋性大脑和心脏等多个组织同时出现缺陷，为这种患病率提供了新的解释的疾病合并症。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的研究行为的培训。候选人的机构，贝勒医学院因其广泛的研究和培训目标而非常适合拟议的研究和培训目标它提供的实验资源以及神经病学和心脏病学专家的数量。