CARDIAC IMPULSE INITIATION AND REPOLARIZATION

这个项目的一般假设是交感神经支配 对离子通道发生的改变起重要作用 发育与特定受体-效应器的进化 小路。我们还假设，在不完全的情况下 特定离子通道和信号的交感神经支配异常 转导通路为致命性心律失常奠定了基础。这 假说源于我们早期对β和α-肾上腺素能的研究 正常人电生理学的信号与发育变化 狗、老鼠和兔心。我们现在集中在两个犬类模型上 无序的神经支配：(A)交感神经的外科阻断 在生命的头24小时内神经到心脏，和(B)家族 左前间隔部分神经支配衰竭 细菌牧羊犬。重要的是，手术切除右侧星体和胸腔 交感神经切除术的特点是第一次出现心搏停止猝死。 而家族性神经功能衰竭会导致 出生4-5个月时出现室性心动过速和猝死。我们表演 完整动物、分离组织和单个心肌细胞实验研究 电生理学(专注于复极和脉冲激发)， 离子电流(最初集中在I/Ks和I/Kr)，信号转导 (专注于β受体、G蛋白和腺苷环化酶)和 分子生理学(最初侧重于犬视网膜电信号的mRNA等 KvLQT1和Mink)，以期从 完整的动物通过分子机制负责 心律失常事件。此外，通过与所有其他项目合作， 程序，我们将实现对 神经-肌细胞相互作用、信号过程的进化和进化 电生理控制机制。建议的重要意义 研究表明，它不仅利用多种方法试图 了解所提出的模型中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，在 它们与暂停依赖型心动过速有关，这些心动过速由 去极化后延迟，并对儿茶酚胺或运动依赖 心动过速倾向于折磨其他健康的年轻人。

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.