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

抑制 G 蛋白扰乱左心房的自主神经通路

基本信息

批准号：
7795813
负责人：
Rishi Arora
金额：
$ 43.18万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7795813
关键词：
Accounting Acetylcholine Achievement Acute Adenylate Cyclase Adrenergic Agents Adrenergic Receptor Age Agreement Animals Arrhythmia Atrial Fibrillation Autonomic Pathways Autonomic nervous system Binding Sites CMV promoter Calcium Canis familiaris Cardiac Cardiovascular system Catecholamines Cells Characteristics Cholinergic Receptors Chronic Complex Congestive Congestive Heart Failure Coupled Data Denervation Development Diagnosis Dose Embolism Epidemic Event Fibrosis Functional disorder G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Gene Expression Genes Goals Heart Heart Atrium Heart Rate Heart failure Heterotrimeric GTP-Binding Proteins Hour Human Incidence Inflammation Injection of therapeutic agent Isoproterenol Laboratories Left atrial structure Life Ligand Binding Limb structure Mechanics Mediating Medicine Membrane Methods Modeling Morbidity - disease rate Muscarinic Acetylcholine Receptor Muscarinic M2 Receptor Muscarinics Nerve Nervous system structure Oxidative Stress Pathway interactions Patients Peptides Plasmids Play Polyubiquitin Procedures Protein Isoforms Proteins Pulmonary veins Refractory Rest Role Signal Pathway Signal Transduction Signaling Molecule Sinus Stretching Stroke Sympathetic Nervous System Testing Tissues Toxic effect Transfection adrenergic aging population base cerebrovascular cytotoxicity design drug development improved mortality novel novel therapeutic intervention novel therapeutics prevent promoter public health relevance receptor research study response success therapeutic target

项目摘要

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.

描述（由申请人提供）：心房颤动（AF）是最常见的心律紊乱，并且是充血性心力衰竭和脑血管栓塞（“中风”）等严重发病的主要原因。重要的是，这种心律失常的发生率随着年龄的增长而增加，导致房颤迅速成为老龄化人口中的最新“流行病”。因此，房颤的诊断和治疗已成为心血管医学的一个重要且具有挑战性的方面。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甚少。在这方面，最近的研究表明肺静脉和左后心房（PLA）在这种心律失常的发生中发挥着重要作用。因此，中国人民解放军实施了几项开创性的消融手术，尽管成功程度参差不齐。在心脏中，G 蛋白偶联受体 (GPCR) 及其同源信号传导伙伴（异三聚体 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，例如兴奋性、心率、收缩力、传导速度和不应期。与 G1 偶联的 2-肾上腺素能受体的激活会导致心脏传导速度增加和其他几种兴奋反应。与 G1i 偶联的毒蕈碱 M2 受体的激活会导致心房不应期显着缩短。结合起来，自主神经系统的这两个分支已被证明可以为 AF 创造基础。因此，肾上腺素能受体和毒蕈碱受体或其伴侣 G1i 和 G1s 可能是旨在调节心脏致心律失常影响的治疗策略的可行替代靶点。对于这些策略来说，PLA 可能是一个特别有吸引力的目标，因为它具有非常强大和独特的自主特征，被认为有利于 AF。在尝试修改 AF 的底物时，我们建议使用针对 GPCR/G 蛋白界面的新型肽来选择性抑制 PLA 中的副交感神经或交感神经通路。使用可以短期和长期表达这些 G 蛋白抑制肽的小基因（质粒），拟议的研究将在 AF 的急性和慢性模型中进行。在急性实验（目标 1）中，将向 PLA 中局部注射小基因，以抑制正常狗中迷走神经或肾上腺素介导的 AF。在目标 2 中，我们建议在慢性 AF 犬模型中使用这些小基因；长效启动子控制下的小基因将被局部注射到 PLA 中，以防止 AF 自主底物的发展。拟议的研究是朝着确定最终可能应用于治疗危及生命的心律失常的新疗法迈出的重要一步。公共卫生相关性：心房颤动 (AF) 是最常见的心律紊乱，也是充血性心力衰竭和中风等严重发病的主要原因。然而，目前可用的 AF 治疗方案并不是很有效。我们提出了一种治疗房颤的新方法，即使用一种新型肽（蛋白质）来抑制引发这种心律失常的神经功能。