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

基本信息

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
项目类别：
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

项目摘要

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 Our recent published and unpublished studies provide compelling insight into why ß-agonists are problematic while offering a solution to their clinical application.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）：β-2-肾上腺素受体激动剂（β2AR）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，但仍被使用。哮喘管理中存在问题，包括功能性快速耐受、哮喘控制恶化和死亡率问题。无法理解为什么存在此类问题以及无法显着改善 ß2AR。 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，这反映了药理学的重要性。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。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-激动剂引发促进哮喘表型的致病机制新数据表明，β2AR 在气道细胞中转导 2 种性质不同的信号传导途径：β-arrestin2 介导的促炎信号传导，以及 Gs 蛋白介导的抗炎和支气管保护信号传导。通过建立这些 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中进行识别，解决哮喘“ß2AR 悖论” ß2AR 配体或调节剂具有偏向信号传导特性，能够通过抑制蛋白拮抗致病性 ß2AR 信号传导，同时促进有益的 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枢。假设气道上皮中通过 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，并且偏向 ß2AR 配体或调节剂拮抗 ß-arrestin2 信号传导同时启用 Gs 蛋白信号传导在哮喘治疗中更有效。目标 1 将采用基因策略实现细胞特异性 ß2AR 基因消融或表达，以确定气道上皮细胞和平滑肌细胞中 ß2AR 激动的需求和充分性。在介导过敏性肺部炎症、粘蛋白产生和 AHR 方面，目标 2 将采用类似的遗传方法来确定 AHR 的作用。 ß2AR 介导的 PKA 和抑制蛋白依赖性信号传导在体内调节哮喘表型，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 和抑制蛋白依赖性调节。这些研究将利用药理学和遗传学方法，并确定已批准的和新的 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。通过确定与过敏性肺部炎症有关的基本致病信号机制，并表征用于治疗哮喘的最佳 ß2AR 配体，将显着推进哮喘生物学和哮喘药理学领域。