Optimizing Beta-Adrenoceptor Signaling Bias in Asthma

优化哮喘中的 β 肾上腺素受体信号传导偏差

• 批准号: 9275916
• 负责人: RICHARD Agustin BOND
• 金额: $ 61.49万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-18 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275916
• 关键词: Ablation; Address; Adrenergic Receptor; Adverse effects; Agonist; Allergens; Allergic; Anti-Inflammatory Agents; Anti-inflammatory; Arrestins; Asthma; Awareness; Biology; Breathing; Bronchoconstriction; Bronchodilation; Cells; Chronic; Chronic Obstructive Airway Disease; Congestive Heart Failure; Cyclic AMP-Dependent Protein Kinases; Data; Deterioration; Development; Disease; Epinephrine; Epithelial; Epithelial Cells; Event; Explosion; Failure; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Genetic; Human; In Vitro; Inflammatory; Intervention; Life; Ligands; Lung Inflammation; Maintenance; Mediating; Molecular; Molecular Biology; Mucins; Mus; NIH Program Announcements; Pathogenicity; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Preventive therapy; Production; Property; Proteins; Public Health; Publishing; Regulation; Role; Science; Severities; Signal Pathway; Signal Transduction; Signaling Protein; Smooth Muscle Myocytes; System; Tachyphylaxis; Testing; Therapeutic; Tissues; Treatment Efficacy; airway epithelium; airway hyperresponsiveness; asthmatic; beta-2 Adrenergic Receptors; clinical application; disorder control; drug development; drug discovery; genetic approach; improved; in vivo; in vivo Model; insight; mortality; permissiveness; prevent; public health relevance; receptor; theories

DESCRIPTION (provided by applicant): Agonists of the beta-2-adrenoceptor (ß2AR), commonly referred to as ß-agonists, have been a cornerstone of asthma treatment for nearly half a century. Despite their utility, however, ß-agonists used in asthma management have problems, including functional tachyphylaxis, deterioration of asthma control, and mortality concerns. The inability to understand why such problems exist and the failure to significantly improve ß2AR pharmacology is reflected by over 2 decades of NIH Program announcements declaring the need for safer, more efficacious alternatives to asthma treatment. Our recent published and unpublished studies provide compelling insight into why ß-agonists are problematic while offering a solution to their clinical application. Our data strongly suggest that ß2AR agonism plays a permissive role in the development of allergic lung inflammation and associated airway hyperresponsiveness (AHR), and that endogenous (epinephrine) as well as exogenous ß-agonists invoke pathogenic mechanisms promoting the asthma phenotype. New data suggest that ß2ARs transduce 2 qualitatively distinct signaling pathways in airway cells: pro-inflammatory signaling mediated by ß-arrestin2, and anti-inflammatory and bronchoprotective signaling mediated by Gs proteins. We propose studies to solve the asthma "ß2AR paradox" by establishing the cell-specific role of these ß2AR signaling pathways in regulating the asthma phenotype, and identifying from among current and newly generated ß2AR ligands or modulators those with biased signaling properties that are optimal in their ability to antagonize pathogenic ß2AR signaling via arrestins, yet promote beneficial G protein signaling. We will employ many systems, including cell, tissue, and in vivo models, to test the central hypothesis that ß2AR signaling via ß-arrestin2 in airway epithelia is critical to the allergen-induced asthma phenotype, and biased ß2AR ligands or modulators that antagonize ß-arrestin2 signaling while enabling Gs protein signaling are more efficacious in the treatment of asthma. Aim 1 will employ genetic strategies enabling cell-specific ß2AR gene ablation or expression to establish the requirement and sufficiency of ß2AR agonism in airway epithelial and smooth muscle cells in mediating allergic lung inflammation, mucin production, and AHR. Aim 2 will employ similar genetic approaches to establish the roles of ß2AR-mediated PKA- and arrestin-dependent signaling in regulating the asthma phenotype in vivo, as well as molecular biology approaches to characterize PKA- and arrestin-dependent regulation of mucin production and inflammatory agents in both human and murine airway epithelial cells. Aim 3 will utilize pharmacological and genetic approaches, and determine the biased signaling properties of approved and new ß2AR ligands to conclusively establish the roles for PKA and arrestin signaling in regulating the asthma phenotype. Collectively, these studies will significantly advance the fields of asthma biology and asthma pharmacology by identifying a fundamental pathogenic signaling mechanism involved in allergic lung inflammation, and by characterizing the optimal ß2AR ligands used to manage asthmatics.

描述（由申请人提供）：β2-肾上腺素受体（ß2AR）激动剂，通常称为β-激动剂，近半个世纪以来一直是哮喘治疗的基石。然而，尽管β-激动剂具有实用性，但用于哮喘治疗的β-激动剂也存在一些问题，包括功能性快速耐受、哮喘控制恶化和死亡率问题。 20 多年来 NIH 计划宣布需要更安全、更有效的哮喘治疗替代方案，这反映出无法理解为何存在此类问题以及未能显着改善 ß2AR 药理学。我们最近发表和未发表的研究提供了令人信服的见解，解释了β-激动剂为何存在问题，同时为其临床应用提供了解决方案。我们的数据强烈表明，β2AR 激动剂在过敏性肺部炎症和相关气道高反应性 (AHR) 的发展中发挥着许可作用，并且内源性（肾上腺素）和外源性 β-激动剂会引发促进哮喘表型的致病机制。新数据表明，ß2AR 在气道细胞中转导 2 条性质不同的信号通路：由 ß-arrestin2 介导的促炎信号传导，以及由 Gs 蛋白介导的抗炎和支气管保护信号传导。我们提出研究解决哮喘“ß2AR悖论”，方法是建立这些ß2AR信号通路在调节哮喘表型中的细胞特异性作用，并从当前和新产生的ß2AR配体或调节剂中识别出那些具有偏向信号特性的信号特性，这些特性在通过视紫红质抑制蛋白拮抗致病性ß2AR信号传导的能力方面处于最佳状态，同时又促进有益的G蛋白信号传导。我们将采用许多系统，包括细胞、组织和体内模型，来测试中心假设，即气道上皮中通过 ß-arrestin2 进行的 ß2AR 信号传导对于过敏原诱导的哮喘表型至关重要，并且拮抗 ß-arrestin2 信号传导同时启用 Gs 蛋白信号传导的偏向 ß2AR 配体或调节剂在哮喘治疗中更有效。目标 1 将采用遗传策略，实现细胞特异性 ß2AR 基因消融或表达，以确定气道上皮和平滑肌细胞中 ß2AR 激动作用的必要性和充分性，以介导过敏性肺部炎症、粘蛋白产生和 AHR。目标 2 将采用类似的遗传学方法来确定 ß2AR 介导的 PKA 和视紫红质抑制蛋白依赖性信号传导在调节体内哮喘表型中的作用，以及分子生物学方法来表征人和小鼠气道上皮细胞中粘蛋白产生和炎症因子的 PKA 和视紫红质抑制蛋白依赖性调节。目标 3 将利用药理学和遗传学方法，并确定已批准的新 ß2AR 配体的偏向信号传导特性，以最终确定 PKA 和抑制蛋白信号传导在调节哮喘表型中的作用。总的来说，这些研究将通过确定与过敏性肺部炎症有关的基本致病信号机制，并描述用于治疗哮喘的最佳 ß2AR 配体，显着推进哮喘生物学和哮喘药理学领域的发展。