NEURONAL AND DEVELOPMENTAL REGULATION OF PACEMAKER CHANNELS

项目1的一般假设集中在心脏复极和速率的重塑上，如下所示：（1）心室心肌的出生后电生理建模导致复极的跨壁梯度及其分散的演变，当过度时可能是致心律失常的;（2）在心脏特定区域表达的工程起搏器通道将发展出规则的心脏反应性节律。检验这些假设将满足项目1的两个主要目标：（1）了解发育中心脏心室复极的演变，其临床意义及其与交感神经支配和血管紧张素II的联系，以及（2）了解体内表达的特定起搏器结构是否可以决定心律。在对完整动物的研究中，分离的组织和单个心肌细胞， 在犬和大鼠模型中，我们的5个目的是检验以下假设：1：复极和频率适应的跨壁离散度的演变重要地取决于I-to、I-Kr和I-Ks的演变; 2：I-to、I-Kr和I-Ks在年轻心脏的外膜、内膜和中层心肌中的分布倾向于I-Kr阻断药物的预防作用; 3：在犬心室中，约40-60天年龄的KChIP 2的跨壁梯度的发育演变决定了I-to的跨壁梯度; 4A：内源性血管紧张素II调节 4 B：出生后I-Ks的变化受交感神经支配的调节，因此去神经支配将减缓I-Ks的变化和跨壁梯度的表达; 4C：项目1的一般假设集中在心脏复极和速率的重塑上，如下：（1）出生后I-to的变化受交感神经支配和心脏血管紧张素II通路的调节;第五章：起搏器通道的特定α和β亚基结构可以在心脏原位起起搏器的作用。这一研究将有助于我们了解复极和复极率的生后演变及其调节机制。考虑到特定病毒的潜在致命性， 在儿童和成人中诱发心律失常的病理生理事件，以及需要更好地了解病因、预防和治疗。此外，如果起搏器电流的工程可以为心脏提供可再现的、一致的脉冲启动，这将为窦房结功能障碍和心脏传导阻滞的治疗提出重要的新治疗方向。

The general hypotheses of Project 1 center on remodeling of cardiac repolarization and rate as follows: (1) postnatal electrophysiologic modeling of ventricular myocardium results in evolution of transmural gradients for repolarization and its dispersion which, when excessive may be arrhythmogenic; (2) engineered pacemaker channels expressed in specific regions of the heart will develop regular, autonomic-responsive rhythms. Testing these hypotheses will satisfy the two major goals of Project 1: (1) to understand the evolution of ventricular repolarization in developing hearts, its clinical implications and its linkage to sympathetic innervation and angiotensin II, and (2) to learn whether specific pacemaker constructs expressed in vivo can determine cardiac rhythm. In studies of intact animals, isolated tissues and single myocytes in canine and rat models, our 5 aims are to test the following hypotheses: 1: Evolution of transmural dispersion of repolarization and of rate adaptation depends importantly on evolution of I-to, I-Kr and I-Ks; 2: The distribution of I-to, I-Kr and I-Ks in epi-, endo- and midmyocardium in young hearts predisposes to proarrhythmic actions of I-Kr blocking drugs; 3: In canine ventricle developmental evolution of a transmural gradient for KChlP2 around days 40-60 of age determines the transmural gradient for I-to; 4A: Endogenous angiotensin II modulates developmental evolution of repolarization; 4B: The postnatal changes in I-Ks are modulated by sympathetic innervation, such that denervation will slow the evolution of I-Ks and expression of the transmural gradient; 4C: The general hypotheses of Project 1 center on remodeling of cardiac repolarization and rate as follows: (1) postnatal changes in I-to are modulated by sympathetic innervation and the cardiac angiotensin II pathway; 5: Specific alpha and beta subunit constructs of the pacemaker channel can function as pacemakers in the heart in situ. This research will help us understand the mechanisms underlying postnatal evolution of repolarization and rate, and their modulation. The implications are far-reaching in light of the potential lethality of specific pathophysiologic events inducing arrhythmias in children and adults and the need for better understanding of etiology, prevention and treatment. Moreover, if the engineering of pacemaker current can provide reproducible, consistent impulse initiation for the heart this will suggest important new therapeutic directions for treatment of sinus node dysfunction and of heart block.