VIRAL ENZYMES & NEURONAL MUSCARINIC RECEPTORS IN LUNG

病毒酶

• 批准号: 3473101
• 负责人: ALLISON Deborah FRYER
• 金额: $ 10.71万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3473101
• 关键词: acetylcholine; diagnostic respiratory lavage; exo alpha sialidase; guinea pigs; influenza; inhibitor /antagonist; lung; muscarinic receptor; parainfluenza virus type 2; parasympathetic nervous system; receptor binding; respiratory hypersensitivity; smooth muscle; tissue /cell culture; vagus nerve; virus diseases; virus protein

Viral infections such as influenza are characterized by an increased bronchoconstriction to a variety of stimuli in vivo. Although this hyperreactivity is usually temporary, viral infections in childhood are associated with development of asthma. The hyperreactivity to any specific agonist could result from direct effects on smooth muscle or effects on cells that control smooth muscle contraction. A major indirect route of hyperreactivity Is via the vagus nerve. The vagus nerve releases acetylcholine that binds to muscarinic receptors on the smooth muscle resulting in bronchoconstriction. In preliminary data I have shown that the amount of acetylcholine released by the nerve terminals is regulated by muscarinic receptors which are located on the nerve terminals, and that these neuronal receptors are a different subtype than the muscarinic receptors on the smooth muscle. The neuronal muscarinic receptors are inhibitory in that when stimulated, they limit the amount of acetylcholine released from the nerves. Damage to these neuronal receptors would remove both the tonic inhibition and the negative feedback that occurs with all stimuli which increase vagal activity. It is my hypothesis that the pathologic absence of this normal negative feedback will result in airways hyperreactivity. Viral infections such as influenza and parainfluenza, temporarily increases the bronchoconstriction produced by a variety of stimuli. The mechanism of viral-induced airway hyperreactivity is poorly understood. However, there is evidence to suggest that part of the defect lies in the vagus nerves. Viruses contain enzymes on their surface which can damage cells and receptors on cells. One of these enzymes, neuraminidase, can damage receptors like the muscarinic receptor which inhibits acetylcholine release from the vagus nerves in the lung. Neuraminidase may be produced in large quantities during viral infection as new viruses grow in the airways. I have shown that during viral infection neuronal inhibitory muscarinic receptors are not functioning. The experiments in this proposal are designed to test whether damage to these receptors on the vagus nerves play an important role in the reactivity of the lungs, whether this effect is due specifically to inhibition of neuronal muscarinic receptors by neuraminidase, and what role neuraminidase plays in other models of airways disease, especially antigen challenge. This grant proposes studying muscarinic receptor function in vivo and in vitro as well as studying the receptors at a genetic level. It is expected that results from this study will provide important new insights into the mechanism of airway hyperreactivity induced by viral infection and may yield results which further our understanding of other models of airway disease.

病毒感染（例如流感）的特征是增加 支气管收缩到体内各种刺激。 虽然这个 高反应性通常是暂时的，儿童期病毒感染是 与哮喘的发展有关。 对任何的过度反应性 特定的激动剂可能是由于对平滑肌的直接影响而产生的 对控制平滑肌收缩的细胞的影响。 专业 间接过度反应性的途径是通过迷走神经。 迷走神 神经释放与毒蕈碱受体结合的乙酰胆碱 平滑肌导致支气管收缩。 在初步数据中 已经表明神经释放的乙酰胆碱量 末端受到毒蕈碱受体的调节，该受体位于 神经末端，这些神经元受体是不同的 亚型比平滑肌上的毒蕈碱受体。 神经元 毒蕈碱受体是抑制性的，因为在刺激时，它们会限制 从神经释放的乙酰胆碱量。 对这些损害 神经元受体会消除补品抑制和 所有刺激都会增加迷走神经的负反馈 活动。 我的假设是缺乏这种正常的病理学 负反馈将导致气道高反应性。 病毒感染，例如流感和副磷素氟萨， 暂时增加了各种各样的支气管收缩 刺激。 病毒引起的气道高反应性的机制很差 理解。 但是，有证据表明 缺陷在于迷走神经。 病毒在其上含有酶 表面会损害细胞上的细胞和受体。 其中之一 酶，神经氨酸酶会损害毒蕈碱受体等受体 抑制乙酰胆碱从肺部迷走神经中释放。 神经氨酸酶可能在病毒感染期间大量产生 随着新病毒在气道中的生长。 我已经表明，在病毒感染期间神经元抑制 毒蕈碱受体不起作用。 其中的实验 建议旨在测试这些受体是否损坏 迷走神经在肺的反应性中起重要作用， 这种效果是否特别是由于神经元的抑制 神经氨酸酶的毒蕈碱受体，以及神经氨酸酶发挥什么作用 在其他气道疾病模型中，尤其是抗原挑战。 这 Grant提议研究体内和体外的毒蕈碱受体功能 以及在遗传水平上研究受体。 预计 这项研究的结果将为您提供重要的新见解 病毒感染引起的气道高反应性机制，可能 产生结果，进一步了解其他模型的气道 疾病。