Disruption of Autonomic Pathways in Left Atrium by Inhibition of G Proteins

抑制 G 蛋白扰乱左心房自主神经通路

基本信息

批准号：
7844919
负责人：
Alan H Kadish
金额：
$ 15.14万
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：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7844919
关键词：
Accounting Acetylcholine Achievement Acute Adenylate Cyclase Adrenergic Agents Adrenergic Receptor Age Arrhythmia Atrial Fibrillation Autonomic Pathways Autonomic nervous system Binding Sites Biological Assay Bypass C-terminal Calcium Signaling Canis familiaris Cardiac Cardiac Myocytes Cardiovascular system Catecholamines Cells Characteristics Cholinergic Receptors Congestive Heart Failure Coupled Coupling Diagnosis Dose Electrophysiology (science)Embolism Epidemic Event G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors G-substrate GTP-Binding Proteins Genes Goals Heart Heart Atrium Heart Rate Heterotrimeric GTP-Binding Proteins Hour In Vitro Incidence Injection of therapeutic agent Ion Channel Left atrial structure Life Ligand Binding Limb structure MLLT2 gene Maintenance Measures Mechanics Mediating Medicine Membrane Methods Microscopy Morbidity - disease rate Muscarinic Acetylcholine Receptor Muscarinic M2 Receptor Muscarinics Muscle Cells Nerve Nerve Block Parasympathectomy Pathway interactions Patients Peptides Plasmids Play Procedures Protein Isoforms Proteins Pulmonary veins Receptor Signaling Refractory Role Signal Pathway Signal Transduction Sinus Stroke Sympathectomy System Testing Tissues adrenergic aging population cerebrovascular design drug development fluorescence imaging improved in vivo inhibitor/antagonist mortality novel therapeutics patch clamp peptide G 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'). More recently, AF has been found to be associated with significantly increased mortality, compared to patients in normal sinus rhythm. 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 Gs, leads to an increase in conduction velocity and several other excitatory responses in the heart. Activation of muscarinic M2 receptors, which are coupled to Gi, 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 Gi and Gs 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. Peptides which mimic the C-terminus of the various G1 proteins have been shown in a number of systems to selectively inhibit receptor signaling by serving as competitive inhibitors and blocking the ability of the receptor to couple to the appropriate G protein. In an attempt to modify substrate for AF. We propose to use peptides directed at the GPCR/G protein interface to selectively inhibit parasympathetic or sympathetic pathways in the PLA. We will use either the peptide alone (i.e. cell-penetrating peptides) or a minigene (plasmid) that can express the peptide. We will perform these studies in a) isolated canine cardiomyocytes, to study the effects of the peptide(s) on ion-channels that mediate autonomic effects, and in b) intact dogs, with localized injection into the PLA in order to inhibit vagally or adrenergically-mediated AF. The proposed studies are an important stride towards identifying novel therapeutics that may eventually be applied to the treatment of life threatening arrhythmias. 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 to use a new method to treat AF, by inhibiting the function of the nerves that are critical to the genesis of this arrhythmia. By using a new inhibitory protein, we will selectively block these nerves in the left atrium.

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。最近发现，与正常窦性心律的患者相比，房颤与死亡率显着增加相关。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 G 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 Gi 偶联的毒蕈碱 M2 受体的激活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Gi和Gs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。模拟各种 G1 蛋白 C 末端的肽已在许多系统中显示出通过充当竞争性抑制剂并阻断受体与适当 G 蛋白偶联的能力来选择性抑制受体信号传导。尝试修改 AF 的基材。我们建议使用针对 GPCR/G 蛋白界面的肽来选择性抑制 PLA 中的副交感神经或交感神经通路。我们将单独使用肽（即细胞穿透肽）或可以表达肽的小基因（质粒）。我们将在 a) 分离的犬心肌细胞中进行这些研究，以研究肽对介导自主神经效应的离子通道的影响，以及 b) 完整的狗中，局部注射到 PLA 中以抑制迷走神经或肾上腺素介导的房颤。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。心房颤动（AF）是最常见的心律紊乱，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。我们建议使用一种新方法来治疗房颤，通过抑制对这种心律失常的发生至关重要的神经功能。通过使用新的抑制蛋白，我们将选择性地阻断左心房的这些神经。