NEURONAL AND DEVELOPMENTAL REGULATION OF PACEMAKER CHANNELS

起搏器通道的神经元和发育调节

• 批准号: 7455920
• 负责人: Michael R. Rosen
• 金额: $ 223.85万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7455920
• 关键词: Accounting; Adolescence; Adrenergic Receptor; Adult; Age; Angiotensin II; Animals; Arrhythmia; Birth; Canis familiaris; Cardiac; Cells; Characteristics; Child; Clinical; Coculture Techniques; Collaborations; Complement; Cultured Cells; Denervation; Dependence; Development; Disease; Doctor of Medicine; Effectiveness; Engineering; Etiology; Event; Evolution; Functional disorder; Funding; GTP-Binding Proteins; Generations; Goals; Heart; Heart Block; Heart Rate; In Situ; Individual; Ion Channel; Kinetics; Learning; Light; Mediating; Microarray Analysis; Modeling; Molecular; Mus; Muscle Cells; Mutation; Myocardium; Neonatal; Nerve; Neurons; Norepinephrine; Pacemakers; Pathway interactions; Pharmaceutical Preparations; Play; Preparation; Prevention; Process; Protein Isoforms; Rate; Rattus; Regulation; Research; Role; Signal Transduction; Sinoatrial Node; Sinus; Speed; System; Testing; Tissues; Ventricular; Wild Type Mouse; age related; base; day; density; heart innervation; heart rhythm; in vivo; interest; nerve supply; neuropeptide Y; novel therapeutics; postnatal; programs; relating to nervous system; success; translational study; voltage

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.

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）出生后心室心肌电生理模型导致复极跨壁梯度及其分散的演变，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、自主反应的节律。测试这些假设将满足项目 1 的两个主要目标：(1) 了解发育中心脏中心室复极的演变、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、分离组织和单个肌细胞的研究中 在犬和大鼠模型中，我们的 5 个目标是测试以下假设： 1：复极跨壁色散和速率适应的演化在很大程度上取决于 I-to、I-Kr 和 I-Ks 的演化；图 2：年轻心脏中 I-to、I-Kr 和 I-Ks 在心外膜、心内膜和中层心肌中的分布易导致 I-Kr 阻断药物的致心律失常作用；图3：在40-60天左右的犬心室中，KChlP2的透壁梯度的发育进化决定了I-to的透壁梯度； 4A：内源性血管紧张素 II 调节 再极化的发展演变； 4B：I-K 的出生后变化受到交感神经支配的调节，这样去神经支配将减慢 I-K 的进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的变化受到交感神经支配和心脏血管紧张素II通路的调节；图 5：起搏器通道的特定 α 和 β 亚基结构可以在心脏原位起搏器的作用。这项研究将帮助我们了解出生后复极和速率演变及其调节的机制。鉴于特定病毒的潜在杀伤力，其影响是深远的。 诱发儿童和成人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设计能够为心脏提供可重复的、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供重要的新治疗方向。