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

• 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
• 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

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”）。最近，与正常的窦性律患者相比，已发现AF与死亡率显着增加有关。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GS偶联的2-肾上腺素能受体的激活导致传导速度增加和心脏中其他几种兴奋性反应。与GI偶联的毒蕈碱M2受体的激活导致心房的耐火性明显缩短。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，肾上腺素能和毒蕈碱受体或其伴侣GI和GS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。在许多系统中显示了模拟各种G1蛋白的C末端的肽，可以通过用作竞争性抑制剂并阻止受体将受体夫妇与适当的G蛋白搭配到适当的G蛋白的能力来选择性地抑制受体信号传导。试图修改AF的底物。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途径。我们将单独使用肽（即细胞穿透性肽）或可以表达肽的微酸（质粒）。我们将在A）孤立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作用，以及B）完整的犬，并在PLA中注射局部注射，以抑制模糊或肾上腺增强介导的AF。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。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中风。但是，目前的AF治疗选择不是很有效。我们建议使用一种新方法来治疗AF，通过抑制神经的功能，而神经的功能对这种心律不齐的起源至关重要。通过使用新的抑制蛋白，我们将在左心房中有选择地阻止这些神经。