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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：
8770676
负责人：
RICHARD Agustin BOND
金额：
$ 71.08万
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/8770676
关键词：
Ablation Address Adrenergic Receptor Adverse effects Agonist Allergens Allergic Anti-Inflammatory Agents Anti-inflammatory Arrestins Asthma Awareness Biology Boxing Breathing Bronchoconstriction Bronchodilation Cells Chronic Chronic Obstructive Airway Disease Clara cell Code Color Congestive Heart Failure Cyclic AMP-Dependent Protein Kinases Data Deterioration Development Disease Epinephrine Epithelial Epithelial Cells Evaluation Event Excision Explosion Failure G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Genes Genetic Genetic Recombination Government Human In Vitro Inflammatory Intervention Knock-out Life Ligands Lung Inflammation Maintenance Mediating Molecular Biology Molecular Genetics Mucins Mus NIH Program Announcements Persons Pharmaceutical Preparations Pharmacology Phenotype Play Production Property Proteins Public Health Publishing Regulation Research Role Science Severities Signal Pathway Signal Transduction Signaling Protein Site Smooth Muscle Myocytes Solutions System Tachyphylaxis Tamoxifen Testing Text Therapeutic Tissues Treatment Efficacy Validation Walkers airway epithelium airway hyperresponsiveness beta-2 Adrenergic Receptors clinical application disorder control drug development drug discovery improved in vivo in vivo Model insight mortality prevent public health relevance receptor theories

项目摘要

DESCRIPTION (provided by applicant): Agonists of the beta-2-adrenoceptor (¿2AR), commonly referred to as ¿-agonists, have been a cornerstone of asthma treatment for nearly half a century. Despite their utility, however, ¿-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 ¿2AR 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 Our recent published and unpublished studies provide compelling insight into why ¿-agonists are problematic while offering a solution to their clinical application. Our data strongly suggest that ¿2AR 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 ¿-agonists invoke pathogenic mechanisms promoting the asthma phenotype. New data suggest that ¿2ARs transduce 2 qualitatively distinct signaling pathways in airway cells: pro-inflammatory signaling mediated by ¿-arrestin2, and anti-inflammatory and bronchoprotective signaling mediated by Gs proteins. We propose studies to solve the asthma "¿2AR paradox" by establishing the cell-specific role of these ¿2AR signaling pathways in regulating the asthma phenotype, and identifying from among current and newly generated ¿2AR ligands or modulators those with biased signaling properties that are optimal in their ability to antagonize pathogenic ¿2AR 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 ¿2AR signaling via ¿-arrestin2 in airway epithelia is critical to the allergen-induced asthma phenotype, and biased ¿2AR ligands or modulators that antagonize ¿-arrestin2 signaling while enabling Gs protein signaling are more efficacious in the treatment of asthma. Aim 1 will employ genetic strategies enabling cell-specific ¿2AR gene ablation or expression to establish the requirement and sufficiency of ¿2AR 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 ¿2AR-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 ¿2AR 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 ¿2AR ligands used to manage asthmatics.

描述(申请人提供)：β-2肾上腺素能受体激动剂，通常被称为激动剂，近半个世纪以来一直是哮喘治疗的基石。然而，尽管用于哮喘治疗的激动剂有效，但仍存在问题，包括功能性快速反应、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药物，这反映了无法理解为什么存在这样的问题，以及未能显著改善2AR的药理作用。我们最近发表和未发表的研究提供了令人信服的洞察为什么-激动剂是有问题的，同时为它们的临床应用提供了解决方案。我们的数据有力地表明 AR激动剂在过敏性肺部炎症和相关的气道高反应性(AHR)的发展中起允许的作用，内源性(肾上腺素)和外源性激动剂激活促进哮喘表型的致病机制。新的数据表明，2ARs在呼吸道细胞中有两种不同的信号转导途径：抑制素-2介导的促炎信号和Gs蛋白介导的抗炎和支气管保护信号。我们建议进行研究，通过建立这些2AR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2AR配体或调节剂中识别那些具有偏见的信号特性的配体或调节剂，这些配体或调节剂在通过拦阻蛋白拮抗致病的2AR信号，同时促进有益的G蛋白信号的能力方面是最佳的，从而解决哮喘的2AR悖论。我们将使用多种系统，包括细胞、组织和活体模型，来检验这一中心假设，即通过气道上皮细胞中的arrestin2介导的2AR信号对过敏原诱导的哮喘表型至关重要，而有偏倚的2AR配体或调节剂可以对抗-arrestin2信号，同时使Gs蛋白信号转导在哮喘治疗中更有效。目的1将采用基因策略，使细胞特异性的2AR基因消融或表达，以确定在介导过敏性肺部炎症、粘蛋白产生和AHR的过程中，呼吸道上皮和平滑肌细胞中2AR激动剂的需求和充分性。目的2将采用类似的遗传学方法，在体内建立2AR介导的PKA和arrestin依赖的信号在调节哮喘表型中的作用，以及分子生物学方法来表征PKA和arrestin依赖的人和小鼠呼吸道上皮细胞粘蛋白产生和炎症介质的调节。目的3将利用药理学和遗传学方法，并确定已批准的和新的2AR配体的有偏信号特性，以最终确定PKA和arrestin信号在调节哮喘表型中的作用。总而言之，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，并通过表征用于治疗哮喘患者的最佳受体配体，显著推动哮喘生物学和哮喘药理学领域的发展。