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 Our recent published and unpublished studies provide compelling insight into why ¿-agonists are problematic while offering a solution to their clinical application.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（应用程序提供）：β-2-肾上腺素受体的激动剂（2AR），通常称为 - 激动剂，已成为哮喘治疗的基石已有近半个世纪。然而，尽管有效用，但用于哮喘管理中的激动剂仍存在问题，包括功能性速度，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的原因以及未能显着改善的原因是2AR药理学反映了20多年的NIH计划公告宣布需要更安全，更有效的哮喘治疗替代方案。我们最近发表和未发表的研究提供了令人信服的见解，即为什么``激动人''在提供临床应用方案时会出现问题。我们的数据强烈表明 »2AR激动剂在过敏性肺部感染和相关气道高反应性（AHR）的发展中起允许的作用，并且内源性（肾上腺素）以及外源性�-激动剂激发了促进哮喘表型的致病机制。新数据表明，«2ARS在气道电池中的定性信号传导途径有2个定性的信号通路：由�-arrestin2介导的促炎性信号传导，以及由GS蛋白介导的抗炎和支气管保护信号传导。我们提出的研究通过建立这些细胞特异性作用来解决这些哮喘“ 2AR悖论”，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出具有偏见信号传导能力的最佳能力来促进传播的信号启动的传播源，从而促进了传达的传播，并促进了传播的能力。我们将采用许多系统，包括细胞，组织和体内模型，以测试中心假设，即``2AR信号传导通过气道上皮中的2AR信号传导对于过敏蛋白诱导的哮喘表型至关重要，并且有偏见�2AR和调节剂或调节剂可拮抗»aargagonic a anderestin2信号效果，同时又具有信号的效果。 AIM 1将采用遗传策略实现细胞特异性»2AR基因消融或表达来确定在介导过敏性肺部注射，粘蛋白产生和AHR的气道上皮和平滑肌细胞中2AR激动剂的需求和充分性。 AIM 2将采用类似的遗传学方法来确定2AR介导的PKA-和抑制蛋白依赖性信号在控制体内哮喘表型中以及分子生物学方法中表征PKA-和抑制蛋白依赖性调节粘蛋白和炎症剂的粘膜和炎症剂的方法。 AIM 3将利用药物和遗传方法，并确定批准和新的2AR配体的偏置信号传导特性，以最终确定PKA的作用，并在调节哮喘表型中的作用。总的来说，这些研究将通过确定参与过敏性肺部感染涉及的基本致病信号传导机制，并表征用于管理哮喘患者的最佳2AR配体，从而显着推动哮喘生物学和哮喘药理学领域。