NEURONAL AND DEVELOPMENTAL REGULATION OF PACEMAKER CHANNELS

项目1的一般假设集中在心脏复极和复极速度的重塑上，如下：(1)出生后对心室肌进行电生理学建模导致跨壁复极梯度的演变及其离散，当过度时可能导致心律失常；(2)在心脏特定区域表达的工程起搏器通道将形成规则的自主神经反应节律。验证这些假说将满足项目1的两个主要目标：(1)了解心脏发育过程中心室复极的演变、临床意义及其与交感神经支配和血管紧张素II的联系；(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、分离组织和单个心肌细胞的研究中 在犬和大鼠模型中，我们的5个目标是验证以下假设：1：复极和速率适应跨壁离散的演变重要取决于I-to、I-Kr和I-Ks的演变；2：I-to、I-Kr和I-Ks在年轻心脏外膜、内膜和中层心肌的分布易受I-Kr阻滞剂的诱发心律失常作用；3：在犬的心室中，40-60天左右KChlP2的跨壁梯度的演变决定了I-to的跨壁梯度；4A：内源性血管紧张素II调节I-to的跨壁梯度 复极的发育演变；4B：I-K s的出生后变化受交感神经支配的调制，从而失神经将减缓I-K s的演变和跨壁梯度的表达；4C：项目1的一般假设集中在心脏复极和速度的重塑上，如下：(1)I-TO的出生后变化受交感神经支配和心脏血管紧张素II途径的调节；5：起搏器通道的特定α和β亚基结构可在心脏原位起起搏器的作用。这项研究将有助于我们理解复极和复极速率的后天进化及其调控机制。鉴于特定病毒的潜在致命性，其影响是深远的 引起儿童和成人心律失常的病理生理事件，以及更好地了解病因、预防和治疗的必要性。此外，如果起搏器电流的工程化能够为心脏提供可重复的、一致的脉冲启动，这将为治疗窦房结功能障碍和心脏传导阻滞提供重要的新的治疗方向。

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.