Disruption of Autonomic Pathways in the Left Atrium by Inhibition of G-proteins

描述（由申请人提供）：房颤（AF）是最常见的心脏节律紊乱，是导致严重疾病（如充血性心力衰竭和脑血管栓塞（“卒中”））的主要原因。重要的是，这种心律失常的发生率随着年龄的增长而增加，结果是AF正在迅速成为老龄化人群中的最新“流行病”。因此，房颤的诊断和管理已成为心血管医学的一个重要和具有挑战性的方面。然而，有效治疗房颤的进展缓慢，很大程度上是由于对这种心律失常的潜在机制了解不足。在这方面，最近的研究表明，肺静脉和左心房后壁（PLA）在这种心律失常的发生中起着重要作用。因此，在PLA中进行了一些开创性的消融手术，尽管成功率参差不齐。在心脏中，G蛋白偶联受体（GPCR）及其同源信号伴侣，异源三聚体G蛋白，调节大多数机械和电功能。自主神经系统调节关键的心脏参数，如兴奋性、心率、收缩力、传导速度和不应性。2-肾上腺素能受体的激活，这是耦合到G1，导致心脏中的传导速度和其他几个兴奋性反应的增加。与G1 i偶联的毒蕈碱M2受体的激活导致心房不应期显著缩短。结合，这两个分支的自主神经系统已被证明创建基板AF。因此，肾上腺素能受体和毒蕈碱受体或其合作伙伴G1 i和G1 s可能是可行的替代目标的治疗策略，旨在调节心脏中的致炎性影响。解放军可能是一个特别有吸引力的目标，这些策略，考虑到一个非常强大的和独特的自主配置文件，被认为是有利于AF。在尝试修改基板AF，我们建议使用新的肽直接在GPCR/G蛋白界面选择性地抑制副交感神经或交感神经通路的解放军。使用可以在短期和长期基础上表达这些G蛋白抑制肽的小基因（质粒），将在急性和慢性AF模型中进行拟定研究。在急性实验（目的1）中，将在PLA中局部注射小基因，以抑制正常犬的迷走神经或肾上腺素介导的AF。在目的2中，我们建议使用这些小基因在犬模型的慢性AF;小基因的控制下的长效启动子将被局部注射到解放军，以防止发展的自主底物AF。拟议的研究是一个重要的一步，确定新的疗法，最终可能被应用于治疗危及生命的心律失常。公共卫生相关性：心房颤动（AF）是最常见的心脏节律紊乱，是导致严重疾病如充血性心力衰竭和中风的主要原因。然而，目前可用的AF治疗方案不是很有效。我们提出了一种治疗房颤的新方法，通过使用一种新的肽（蛋白质）来抑制触发这种心律失常的神经的功能。

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the commonest rhythm disturbance of the heart, and is a major cause of serious morbidity such as congestive heart failure and cerebrovascular embolism (`stroke'). Importantly, the incidence of this arrhythmia increases with age, with the result that AF is fast becoming the latest `epidemic' in an aging population. The diagnosis and management of AF have therefore become an important and challenging aspect of cardiovascular medicine. However, progress in effectively treating AF has been slow, in large part due to a poor understanding of the underlying mechanisms of this arrhythmia. In this regard, recent studies indicate an important role for the pulmonary veins and the posterior left atrium (PLA) in the genesis of this arrhythmia. Several pioneering ablative procedures have therefore been performed in the PLA, albeit with mixed success. In the heart, G protein coupled receptors (GPCRs) and their cognate signaling partners, the heterotrimeric G-proteins, regulate most mechanical and electrical functions. The autonomic nervous system regulates critical cardiac parameters such as excitability, heart rate, force of contraction, conduction velocity and refractoriness. Activation of 2-adrenergic receptors, which are coupled to G1s, leads to an increase in conduction velocity and several other excitatory responses in the heart. Activation of muscarinic M2 receptors, which are coupled to G1i, leads to a marked shortening of refractoriness in the atria. In combination, these two limbs of the autonomic nervous system have been demonstrated to create substrate for AF. Thus, the adrenergic and muscarinic receptors or their partners G1i and G1s may be viable alternative targets for therapeutic strategies designed to modulate arrhythmogenic influences in the heart. The PLA may be an especially attractive target for these strategies, on account of a very robust and unique autonomic profile that is thought to be conducive to AF. In an attempt to modify substrate for AF, we propose to use novel peptides directed at the GPCR/G protein interface to selectively inhibit parasympathetic or sympathetic pathways in the PLA. Using minigenes (plasmids) that can express these G-protein inhibitory peptides on both a short and long term basis, the proposed studies will be performed in both an acute as well as a chronic model of AF. In the acute experiments (Aim 1), localized injection of minigene into the PLA will be performed in order to inhibit vagally or adrenergically-mediated AF in normal dogs. In Aim 2, we propose to use these minigenes in a canine model of chronic AF; minigenes under the control of a long-acting promoter will be injected locally into the PLA, to prevent the development of autonomic substrate for AF. The proposed studies are an important stride towards identifying novel therapeutics that may eventually be applied to the treatment of life threatening arrhythmias. PUBLIC HEALTH RELEVANCE: Atrial fibrillation (AF) is the commonest rhythm disturbance of the heart, and is a major cause of serious morbidity such as congestive heart failure and stroke. However, currently available treatment options for AF are not very effective. We propose a new method to treat AF, by using a novel peptide (protein) to inhibit the function of the nerves that trigger this arrhythmia.