ITO IN DOGS WITH INHERITED VENTRICULAR ARRHYTHMIAS

患有遗传性室性心律失常的狗中的 ITO

• 批准号: 6733503
• 负责人: BRUCE G KORNREICH
• 金额: $ 9.62万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-15 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6733503
• 关键词: arrhythmia; beta adrenergic receptor; congenital heart disorder; dogs; enkephalins; gene expression; heart innervation; heart ventricle; muscle cells; nerve growth factors; norepinephrine; potassium channel; protein isoforms; second messengers; sympathetic nervous system; voltage /patch clamp; western blottings

Abnormalities of ventricular repolarization have been identified in a number of cardiac disease states and may predispose to malignant or fatal ventricular arrhythmias. The transient outward potassium current, I- to, is an important determinant of ventricular repolarization. The potassium channel isoform responsible for I-to varies between species. Kv1.4, Kv1.5, Kv4.2, and Kv4.3 have been identified as contributors to ventricular repolarization in various species, with Kv1.4, Kv4.2, and Kv4.3 representing the most likely contributors to I-to in canine cardiac myocytes. Decreased I-to density has been found in several pathologic states including myocardial hypertrophy, terminal heart failure, and acute Trypanosoma cruzi infection, and prolonged ventricular repolarization may increase the morbidity and mortality of these conditions. Moise and collaborators have previously reported a line of German Shepherd dogs with inherited ventricular arrhythmias and sudden death. Affected dogs have a decreased sympathetic innervation of the left ventricle and decreased left ventricular I-to density. Norepinephrine application rescues I-to in myocytes isolated from affected regions in these dogs, suggesting that the decreased I-to may result from a loss of the trophic influence of the sympathetic nervous system during development. Nerve growth factor and enkephalins have been shown to promote growth and survival of central and peripheral neurons. Using whole cell patch clamp recording ribonuclease protection assays, and Western blot techniques, we will address the following questions: (1) Is decreased NGF and ppENK expression responsible for the abnormal peripheral sympathetic innervation in the hearts of affected dogs? (2) Which potassium channels (Kv1.4, Kv1.5, Kv4.2, and Kv4.3) are responsible for I-to in affected dogs? Is the decreased expression of one or a combination of these channel isoforms responsible for deceased I-to in affected dogs? Is the increased expression of one or a combination of these isoforms responsible for NE mediated restoration of I-to in affected dogs?, and (3) Is the restoration of I-to by NE in the hearts of affected dogs mediated by alpha or beta adrenergic receptors and their associated second messenger cascades? The scientific training obtained while performing this research in a vital and supportive intellectual environment will provide valuable theoretical and technical experience for the applicant to expand upon his clinical and basic scientific experience to achieve his goal of a link between the basic scientific study of membrane bound ion channels/receptors and clinical cardiology.

在许多心脏病状态下已经鉴定出心室复极异常，并且可能易于恶性或致命的心室心律不齐。临时向外钾电流I-到，是心室复极的重要决定因素。钾通道同工型在物种之间导致I-t-t-t-t-t-t-to。 KV1.4，KV1.5，KV4.2和KV4.3已被鉴定为各种物种中心室复极化的贡献者，KV1.4，KV4.2和KV4.3代表了犬心脏心肌细胞中I-TO的最有可能的贡献者。在几种病理状态下发现了I-TO密度降低，包括心肌肥大，末端心力衰竭和急性锥虫症状感染，并且延长心室重极化可能会增加这些疾病的发病率和死亡率。 Moise和合作者此前曾报道过一系列德国牧羊犬，具有遗传性心律失常和猝死。受影响的狗的左心室交感神经支配下降，左心室I-TO密度降低。去甲肾上腺素的应用从这些狗中受影响区域分离的肌细胞中拯救了I-TO，这表明I-to降低可能是由于发育过程中交感神经系统的营养影响而导致的。已证明神经生长因子和Enkephalins可促进中枢神经元和周围神经元的生长和存活。使用全细胞贴片夹记录核糖核酸酶保护测定法和蛋白质印迹技术，我们将解决以下问题：（1）降低了NGF和PPENK表达，导致受影响狗心脏中异常的外周外交感神经神经神经神经神经？ （2）哪些钾通道（KV1.4，KV1.5，KV4.2和KV4.3）负责受影响的狗I-TO？这些通道同工型的一个或组合的表达是否降低，导致患者在受影响的狗中已故的I-to？这些同工型的一个或组合的表达增加，导致受影响的狗中NE介导的I-TO恢复吗？（3）是否在由alpha或beta肾上腺素能受体介导的受影响的狗的心脏中恢复I-to-to-to，及其相关的第二使者cascades？在重要且支持性的知识环境中进行这项研究时获得的科学培训将为申请人提供宝贵的理论和技术经验，以扩展其临床和基本科学经验，以实现其在膜结合离子渠道/受体/受体和临床心脏病学基础科学研究之间建立联系的目标。