REGULATION OF M2 MUSCARINIC RECEPTORS IN AIRWAY DISEASE

M2 毒蕈碱受体在气道疾病中的调节

• 批准号: 2685369
• 负责人: CAROL A HIRSHMAN
• 金额: $ 2.92万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-30 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2685369
• 关键词: REGULATION; M2; MUSCARINIC; RECEPTORS; AIRWAY

Because increased airway smooth muscle (ASM) tone is an important contributor to airflow obstruction in asthma, our goal is to understand how signals transduced by beta2 adrenergic receptors (beta2AR) (which promote relaxation) and m2 muscarinic receptors (m2AChR) (which inhibit betaAR-mediated relaxation) are regulated in ASM. Recent studies have linked chronic use of betaAR agonists with increased asthma deaths, apparently via their effects on AH. Furthermore, decreased relaxation of ASM by betaAR agonists in vitro is associated with airway hyperresponsiveness (AH) and disease severity. Although the pathogenesis of AH and overt disease is thought to involve increased numbers of inflammatory cells in the lung, the relationship between inflammation, betaAR function, and AH is poorly understood. Preliminary Studies for this proposal indicate that inflammatory cytokines and betaAR agonists each up- regulate m2AChR and that stimulation of these receptors not only antagonizes the relaxant effects of betaAR agonists but also induces betaAR dysfunction by uncoupling the betaAR from adenylyl cyclase. Up- regulation of m2AChR is seen in the dog model of AH, but has never been investigated in human ASM. Hence, we hypothesize that interdependent regulation of m2AChR and betaAR cytokines, exogenous betaAR agonists, and endogenous cholinergic tone may contribute significantly to the deleterious effects of lung inflammation and betaAR agonist therapy. Using physiological, biochemical, and molecular techniques to study bovine, canine, and human ASM and the dog model of AH, we propose: a) to identify the biochemical mechanisms by which beta2AR activation increases expression of m2AChR and m2AChR activation uncouples beta2AR ; b) to identify the cellular pathways whereby TNFalpha alters beta2AR and m2AChR expression and function; c) to determine if the m2AChR pathway is up- regulated in ASM from humans with asthma; and d) to evaluate the importance of increased m2AChR expression in the exacerbation of AH by chronic in vivo treatment with BAR agonists. This study will provide important new information regarding beta2AR and m2AChR cross-regulation, will clarify the link between AH and inflammation, and will help to resolve the controversy about the use of betaAR agonists in chronic asthma therapy.

因为增加气道平滑肌 (ASM) 张力是重要的 导致哮喘气流阻塞的因素，我们的目标是了解 β2 肾上腺素能受体 (beta2AR) 是如何转导信号的（其中 促进放松）和 m2 毒蕈碱受体 (m2AChR)（抑制 betaAR 介导的松弛）在 ASM 中受到调节。最近的研究有 长期使用 betaAR 激动剂与哮喘死亡率增加有关， 显然是通过它们对 AH 的影响。 此外，松弛度降低 体外 betaAR 激动剂的 ASM 与气道相关 高反应性（AH）和疾病严重程度。虽然发病机制 AH 和明显疾病的发生被认为涉及数量增加 肺部炎症细胞，炎症之间的关系， betaAR 功能，而 AH 则知之甚少。对此的初步研究 提案表明炎症细胞因子和 betaAR 激动剂各自增强 调节 m2AChR 并且刺激这些受体不仅 拮抗 betaAR 激动剂的松弛作用，但也诱导 通过将 betaAR 与腺苷酸环化酶解偶联来导致 betaAR 功能障碍。向上- 在 AH 狗模型中发现了 m2AChR 的调节，但从未被研究过 在人类 ASM 中进行了研究。因此，我们假设相互依赖 m2AChR 和 betaAR 细胞因子、外源 betaAR 激动剂的调节，以及 内源性胆碱能张力可能对 肺部炎症和βAR激动剂治疗的有害影响。使用 研究牛的生理、生化和分子技术， 犬、人类 ASM 和狗 AH 模型，我们建议：a) 识别 beta2AR 激活增加的生化机制 m2AChR 的表达和 m2AChR 激活解偶联 beta2AR ； b) 到 确定 TNFα 改变 beta2AR 和 m2AChR 的细胞途径 表达与功能； c) 确定 m2AChR 通路是否上行 哮喘患者的 ASM 中受到调节； d) 评估 m2AChR 表达增加在 AH 恶化中的重要性 使用 BAR 激动剂进行慢性体内治疗。这项研究将提供 关于 beta2AR 和 m2AChR 交叉调节的重要新信息， 将阐明 AH 与炎症之间的联系，并有助于 解决关于使用βAR激动剂治疗慢性哮喘的争议 治疗。