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：
7656544
负责人：
Rishi Arora
金额：
$ 43.28万
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/7656544
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）是心脏最常见的节奏障碍，是严重发病率的主要原因，例如充血性心力衰竭和脑血管栓塞（“卒中”）。重要的是，这种心律不齐的发生率随着年龄的增长而增加，结果AF迅速成为老龄化人群中最新的“流行病”。因此，AF的诊断和管理已成为心血管医学的重要且充满挑战的方面。但是，有效治疗AF的进展非常缓慢，这在很大程度上是由于对这种心律不齐的潜在机制的了解不足。在这方面，最近的研究表明肺静脉和后心（PLA）在这种心律不齐的起源中起着重要作用。因此，在PLA中已经执行了几种开创性的消融程序，尽管取得了不同的成功。在心脏中，G蛋白偶联受体（GPCR）及其同源信号伴侣，异三聚体G蛋白调节最机械和电的功能。自主神经系统调节关键心脏参数，例如兴奋性，心率，收缩力，传导速度和难治性。与G1偶联的2-肾上腺素能受体的激活导致导致的传导速度和心脏中其他几种兴奋反应的增加。与G1I偶联的毒蕈碱M2受体的激活导致心房的耐火性缩短。结合使用，已经证明了自主神经系统的这两个肢体为AF创建底物。因此，肾上腺素能力和毒蕈碱受体或其伴侣G1I和G1可能是旨在调节心脏心脏病影响的治疗策略的可行替代靶标。由于被认为有利于AF的非常强大且独特的自主性概况，PLA可能是这些策略特别有吸引力的目标。为了修改AF的底物，我们建议使用针对GPCR/G蛋白界面的新型肽来选择性地抑制PLA中的副交感神经或交感神经途径。使用可以在短期和长期表达这些G蛋白抑制性肽的微型烯（质粒），拟议的研究将在急性和慢性AF模型中进行。在急性实验（AIM 1）中，将进行将小蛋白的局部注射到PLA中，以抑制正常狗的模糊或肾上腺素介导的AF。在AIM 2中，我们建议在慢性AF犬模型中使用这些微型烯。长效启动子控制下的微型元将被局部注入PLA，以防止为AF的自主基底物的发展。拟议的研究是旨在识别新型治疗剂的重要大步，这些治疗剂最终可能应用于危险心律失常的治疗。公共卫生相关性：心房颤动（AF）是心脏最常见的节奏障碍，并且是严重发病的主要原因，例如充血性心力衰竭和中风。但是，目前的AF治疗选择不是很有效。我们通过使用新型肽（蛋白质）抑制触发这种心律不齐的神经功能来治疗AF的新方法。