Genetics /Mechanistic Determinants of Rv induced Asthma

Rv 诱发哮喘的遗传学/机制决定因素

• 批准号: 7151329
• 负责人: James E. Gern
• 金额: $ 21.23万
• 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: 2006-07-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7151329
• 关键词: asthma; common cold; cooperative study; functional /structural genomics; genetic polymorphism; genetic susceptibility; host organism interaction; human subject; immune response; immunogenetics; lung; microarray technology; pathologic process; patient oriented research; proteomics; respiratory epithelium; respiratory function; respiratory infections; respiratory virus; rhinovirus; sign /symptom; virus replication

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 initate 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. Lav 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.

病毒感染，尤其是鼻病毒感染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比例。当前的 哮喘治疗虽然有效控制过敏性哮喘，但并不总是能够防止 由于呼吸道感染而导致喘息的加剧。基于这种未满足的临床需求，我们建议 多面和高度互动研究的计划，以建立RV引起的机制 哮喘的恶化。病毒感染的严重程度及其对下气道的影响取决于 关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 由此产生的气道功能障碍严重取决于a）RV复制之间的相互作用 上皮细胞和早期先天抗病毒反应，b）宿主调节的变化 和对感染的抗病毒反应。我们以前的工作主要集中在能力上 RV感染下气道，上调炎症，从而引起较低的气道阻塞和 症状。这些回应的差异性可能可以确定某些人为什么 病毒感染哮喘的严重加剧，而其他人则只是临床“感冒”。我们现在 提出五个互动和创新的项目，涉及机械研究 细胞和人体和小鼠中的体内模型。体外项目包括实验 定义病毒诱导的巨噬细胞启动机制（伯蒂斯的项目），募集和激活 中性粒细胞进入气道（Huttenlocher的项目），并破坏上皮细胞核孔以转移细胞 对病毒蛋白质合成和复制的代谢（Palmenberg的项目）。这些体外研究是 补充了两个体内模型：一项遗传学研究，以鉴定与临床和生物学的关联 实验引起的RV感染的结果（Gern的项目）和Picornavirus的鼠模型 （Mengovirus）感染以评估病毒诱导的细胞炎症机制。这些项目 确定确定疾病严重程度和呼吸系统严重性的关键宿主/病毒相互作用的方法 功能障碍是协同的，互动的，并利用了一套独特的资源和数十年 在威斯康星大学发现的该领域的出版经验。总的来说，这些将研究 在我们当前对病毒诱导的气道功能障碍和 促进开发新的，更有效的治疗策略。 LAV摘要：鼻病毒感染是一种常见的冷病毒，是哮喘的主要原因 儿童加剧，并继续成为患有哮喘的成年人的问题。这个项目的目标是 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。