CARDIAC IMPULSE INITIATION AND REPOLARIZATION

这个项目的一般假设是交感神经支配 对离子通道的变化有重要作用 发育和特异性受体效应子的进化 途径。我们还假设，在不完全的情况下， 交感神经支配异常的特定离子通道和信号 转导通路为致命的心律失常奠定了基础。这 这一假说来自我们早期对β-和α-肾上腺素能的研究， 信号和发育变化的电生理在正常的 犬、大鼠和兔心脏。我们现在关注两个犬类模型， 神经支配紊乱：（a）交感神经的手术中断 （B）在出生后的前24小时内， 前间隔左心室部分神经支配失败， 细菌牧羊犬。重要，右侧胸骨切开术和胸部 交感神经切除术的特点是心脏骤停猝死， 生命数周;而神经支配的家庭失败会导致 室性心动过速和4-5个月时猝死。我们执行 完整的动物，分离的组织和单个肌细胞实验，以研究 电生理学（侧重于复极和脉冲启动）， 离子电流（最初集中在I/ks和I/kr），信号转导 （重点是β受体，G蛋白和腺苷酸环化酶）和 分子生理学（最初关注犬ERG的mRNA， KvLQT 1和minK），着眼于从以下ECG垂直工作： 完整的动物通过分子机制， 军事事件。此外，与所有其他项目合作， 方案，我们将实现之间的关系的理解 神经-肌细胞相互作用，信号过程的演变和进化 电生理学控制机制。建议的意义 它不仅利用多种方法试图 理解所提出的模型中的节律和心律失常的控制， 但这些模型本身包含了临床上重要的特征， 它们与暂停依赖性心动过速有关， 延迟后去极化，和儿茶酚胺或运动依赖性 通常会折磨健康年轻人的心动过速

The general hypothesis for this Project is that sympathetic innervation contributes importantly to the changes in ion channels that occur developmentally and to the evolution of specific receptor-effector pathways. We hypothesize as well that in the setting of incomplete sympathetic innervation abnormalities of specific ion channels and signal transduction pathways set the stage for lethal arrhythmias. This hypothesis derives from our earlier work on both beta-and alpha-adrenergic signaling and developmental changes in electrophysiology in the normal canine, rat and rabbit heart. We now focus on two canine models of disordered innervation: (a) surgical interruption of the sympathetic nerves to the heart in the first 24 hours of life, and (b) familial failure of innervation to a portion of the anteroseptal left ventricle in Germ Shepherd Dogs. Important, surgical right stellectomy and thoracic sympathectomy is characterized by asystolic sudden death in the first weeks of life; whereas the familial failure of innervation results in ventricular tachycardia and sudden death at 4-5 months of life. We perform intact animal, isolated tissue and single myocyte experiments to study the electrophysiology (focussing on repolarization and impulse initiation), ionic currents (focussing initially on I/ks and I/kr), signal transduction (focussing on beta-receptors, G proteins and adenylate cyclase) and molecular physiology (focusing initially on mRNA for canine ERG and on KvLQT1 and minK), with a view towards working vertically from the ECG of the intact animal through the molecular mechanisms responsible for arrhythmic events. Moreover, in cooperation with all other Projects on the Program, we shall achieve an understanding of the relationship between nerve-myocyte interaction, evolution of signaling processes and evolution of electrophysiologic control mechanisms. The significance of the proposed research is that it not only utilizes multiple approaches in an attempt to understand the control of rhythm and arrhythmias in the proposed models, but the models, themselves, incorporate features important clinically, in that they are relevant to pause-dependent tachycardias, those triggered by delayed after depolarizations, and to catecholamine-or exercise-dependent tachycardias that tend to afflict otherwise healthy young individuals.