Mechanisms of Rhinovirus-Induced Exacerbations of Asthma

鼻病毒引起的哮喘恶化的机制

• 批准号: 7919648
• 负责人: James E. Gern
• 金额: $ 60.32万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919648
• 关键词: Mechanisms; Rhinovirus; Induced; Exacerbations; Asthma

DESCRIPTION (provided by applicant): Infections with viruses, and rhinoviruses in particular, are major causes of asthma exacerbations, and account for a large percentage of the morbidity and economic costs associated with asthma. Current asthma treatment, although effective in the control of allergic asthma, is not always capable of preventing exacerbations of wheezing due to respiratory infections. Based on this unmet clinical need, we propose a program of multifaceted and highly interactive studies to establish the mechanisms by which RV cause exacerbations of asthma. The severity of viral infections and their effects on the lower airway are dependent on factors related to the virus and the host. Our overall hypothesis is that the severity of RV infections and resulting airway dysfunction is critically dependent on a) the interplay between RV replication in the epithelial cell and early innate antiviral responses, and b) variations in the host regulation of proinflammatory and antiviral responses to infection. Our previous work has focused primarily on the ability of RV to infect the lower airway, upregulate inflammation and thereby initiate lower airway obstruction and symptoms. The differential nature of these responses may well determine why certain individuals have significant exacerbations of asthma with virus infections, while others simply have clinical "colds." We now propose five interactive and innovative projects that involve mechanistic studies in isolated populations of cells, and in vivo models in both the human and the mouse. The in vitro projects include experiments to define virus-induced mechanisms of macrophage priming (Project by Bertics), recruitment and activation of neutrophils into the airway (Project by Huttenlocher), and the destruction of epithelial cell nuclear pores to divert cellular metabolism towards viral protein synthesis and replication (Project by Palmenberg). These in vitro studies are complemented by two in vivo models: a genetics study to identify associations with clinical and biologic outcomes of experimentally-induced RV infection (Project by Gern), and a murine model of picornavirus (mengovirus) infection to evaluate mechanisms of virus-induced cellular inflammation. These projects' approach to identify critical host/virus interactions that determine the severity of illness and respiratory dysfunction are synergistic, interactive, and take advantage of a unique set of resources and decades of published experience in this area found at the University of Wisconsin. Collectively, these will studies address clinically relevant gaps in our current understanding of virus-induced airway dysfunction and facilitate the development of new and more efficacious therapeutic strategies. Lay Summary: Infections with rhinovirus, a common cold virus, are the major cause of asthma exacerbations in children, and continue to be a problem for adults with asthma. The goal of this project is to determine why this is so, and identify new approaches to either prevent or treat rhinovirus-induced asthma.

描述（由申请人提供）： 病毒的感染，尤其是鼻病毒是哮喘加重的主要原因，并且占与哮喘相关的发病率和经济成本的很大一部分。目前的哮喘治疗虽然有效控制过敏性哮喘，但并不总是能够防止由于呼吸道感染引起的喘息加剧。基于这种未满足的临床需求，我们提出了一个多方面且高度互动研究的程序，以建立RV引起哮喘加重的机制。病毒感染的严重程度及其对下气道的影响取决于与病毒和宿主有关的因素。我们的总体假设是，RV感染的严重程度和导致的气道功能障碍严重取决于a）上皮细胞中RV复制与早期先天抗病毒反应之间的相互作用，以及b）宿主调节促症和抗病毒反应对感染的宿主调节的变化。我们以前的工作主要集中在RV感染下气道，上调炎症的能力上，从而引发了下气道阻塞和症状。这些反应的差异性可能可以确定某些人对病毒感染的哮喘患者的严重恶化，而其他人则只是临床“感冒”。现在，我们提出了五个互动和创新的项目，这些项目涉及细胞孤立人群的机理研究，以及人和小鼠的体内模型。体外项目包括定义病毒诱导的巨噬细胞启动机制的实验（Bertics的项目），中性粒细胞募集和激活进入气道（Huttenlocher的项目），以及将细胞核孔破坏，以将细胞代谢的核孔分散到病毒蛋白质的蛋白质蛋白质合成和重复（PARMEN）（PARMEN）（项目）。这些体外研究得到了两个体内模型的补充：一项遗传学研究，旨在鉴定与实验诱导的RV感染（GERN Project）的临床和生物学结局的关联，以及Picornavirus（Mengovirus）感染的鼠模型，以评估病毒诱导的细胞炎症机制。这些项目的方法是确定确定疾病和呼吸功能障碍严重程度的关键宿主/病毒相互作用是协同的，互动的，并利用了在威斯康星大学发现的一套独特的资源和数十年的出版经验。总的来说，这些将研究在我们当前对病毒引起的气道功能障碍的理解中解决临床相关的差距，并促进新的，更有效的治疗策略的发展。摘要摘要：鼻病毒感染是一种常见的冷病毒，是儿童哮喘患病的主要原因，对于患有哮喘的成年人而言仍然是一个问题。该项目的目的是确定为什么这样做，并确定预防或治疗鼻病毒引起的哮喘的新方法。