Biased Muscarinic Acetylcholine Receptor Signaling in Obstructive Lung Disease Pathology and Therapy

阻塞性肺疾病病理学和治疗中的偏毒蕈碱乙酰胆碱受体信号传导

• 批准号: 10090480
• 负责人: Tonio Pera
• 金额: $ 39万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090480
• 关键词: Acetylcholine; Adrenal Cortex Hormones; Agonist; Arrestins; Asthma; Biological Assay; Biological Models; Biology; Cell Surface Receptors; Cell physiology; Cells; Chemotaxis; Chronic Obstructive Airway Disease; Clinical Management; Complement; Contracts; Coupled; Data; Development; Disease; Disease Management; Drug Design; Drug Prescriptions; Engineering; Event; Exhibits; Fibrosis; Functional disorder; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Genetic; Growth; Hand; Heart failure; Inflammation; Lead; Ligands; Link; Lung; Lung diseases; Maps; Mediating; Molecular; Molecular Conformation; Mus; Muscarinic Acetylcholine Receptor; Muscarinic Acetylcholine Receptor M3; Muscarinic M3 Receptor; Muscarinics; Muscle Contraction; Muscle function; Obstructive Lung Diseases; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Permeability; Pharmaceutical Preparations; Pharmacology; Play; Production; Property; Proteins; Publishing; Pulmonary Emphysema; Pulmonary Inflammation; Receptor Signaling; Regulation; Role; Safety; Science; Signal Pathway; Signal Transduction; Signaling Protein; Structure; System; Testing; Therapeutic; Tissues; Work; airway hyperresponsiveness; antagonist G; base; beta-adrenergic receptor; beta-arrestin; carvedilol; chemokine; clinical application; cysteinyl leukotriene receptor; cytokine; desensitization; design; drug development; drug discovery; experience; experimental study; genetic regulatory protein; high throughput screening; in vivo Model; mucus hypersecretion; novel; novel strategies; novel therapeutics; receptor; receptor function; respiratory smooth muscle; scaffold; screening; small molecule; small molecule libraries; targeted treatment

Project Summary Clinical management of obstructive lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) relies heavily of drugs that are either agonist or antagonists of G protein-coupled receptors (GPCRs). This is because GPCRs control important airway cell functions (contraction, growth, cytokine/chemokine production, chemotaxis, and permeability) that become dysregulated in disease. Unfortunately, these drugs have limitations with respect to both efficacy and safety, and many patients experience suboptimal control. We propose to identify new, more effective ligands that target the M3 muscarinic acetylcholine receptor (M3 mAChR) as a potential COPD therapy, by embracing the emerging concept of biased agonism pharmacology. Biased agonism pharmacology is based on the discovery that GPCRs can assume multiple conformations that transduce qualitatively different signals, and ligands can “tune” GPCRs to bias signaling to one pathway or another. We propose to discern qualitative signaling properties of the M3 mAChR and determine how canonical (G protein-dependent) versus non-canonical (arrestin-dependent) signaling regulates airway smooth muscle (ASM) functions that are often dysregulated in COPD. We have discovered both small molecule orthosteric ligands as well as a peptide that can bias M3 mAChR signaling toward the arrestin signaling pathway. Preliminary data also strongly suggest arrestin-dependent signaling mediates therapeutically beneficial ASM functions. Lead agents in hand as well as those that emerge in focused screens will be tested in cell- and tissue-based studies of ASM signaling and function, and ultimately in an in vivo model of COPD to discern the utility of these drugs as COPD therapeutics. Three Aims are proposed. Aim 1 will employ genetic and molecular strategies, including use of mice with arrestin subtype genes ablated, to establish the regulatory effects of arrestins on M3 mAChR-mediated functions (contraction, growth, and synthetic functions) in airway smooth muscle. Aim 2 will employ semi-high throughput screening systems, ASM signaling and functional assays, and novel engineered M3 receptors to fully characterize those biased agents in hand and to discover additional biased ligands and peptides. Aim 3 will test our lead biased M3 ligands in an in vivo model of COPD to verify the ability of a biased pharmacology approach to manage the disease. The impact of the proposed studies lies in their ability to significantly advance the science underlying, and ultimate clinical application of, biased agonism pharmacology.

项目摘要 阻塞性肺疾病如哮喘和慢性阻塞性肺疾病的临床管理 慢性阻塞性肺疾病（COPD）严重依赖G蛋白偶联受体（GPCR）的激动剂或拮抗剂药物。 这是因为GPCR控制重要的气道细胞功能（收缩、生长、细胞因子/趋化因子） 生产，趋化性和渗透性），在疾病中变得失调。不幸的是，这些药物 在疗效和安全性方面都有局限性，许多患者的控制效果不佳。我们 建议识别针对M3毒蕈碱乙酰胆碱受体（M3）的新的、更有效的配体 mAChR）作为一种潜在的COPD治疗，通过拥抱新出现的偏向激动药理学概念。 偏性激动药理学基于GPCR可以呈现多种构象的发现， 不同性质的信号，配体可以“调节”GPCR，使信号偏向一种途径， 另我们建议辨别M3 mAChR的定性信号传导特性，并确定如何 经典（G蛋白依赖性）与非经典（抑制蛋白依赖性）信号调节气道平滑 肌肉（ASM）功能在COPD中经常失调。我们发现了两种小分子 正构配体以及可以使M3 mAChR信号传导偏向抑制蛋白信号传导的肽 通路初步数据也强烈表明，抑制蛋白依赖性信号传导介导的治疗 有益的ASM功能手头的主要代理以及那些出现在聚焦屏幕上的代理将接受测试 在ASM信号传导和功能的基于细胞和组织的研究中，并最终在COPD的体内模型中， 辨别这些药物作为COPD治疗剂的效用。提出了三个目标。目标1将采用遗传 和分子策略，包括使用抑制蛋白亚型基因消除的小鼠，以建立调节 抑制蛋白对气道中M3 mAChR介导的功能（收缩、生长和合成功能）的影响 平滑肌Aim 2将采用半高通量筛选系统，ASM信号传导和功能性筛选系统。 分析，和新的工程M3受体，以充分表征这些偏向剂在手，并发现 另外的偏向配体和肽。目的3将在COPD的体内模型中测试我们的铅偏向M3配体 以验证有偏见的药理学方法管理疾病的能力。建议的影响 研究在于它们能够显著推进基础科学，以及最终的临床应用， 偏性激动药理学