Adipokines in Pulmonary Viral Infection

 描述（由申请方提供）：A型流感病毒（IAV）是一种主要的人类病原体，能够在全球范围内迅速传播，并产生严重的、有时是致命的肺部感染，其特征为严重肺炎和明显的肺泡损伤。过去几十年积累的证据强烈表明，IAV感染引起的疾病不仅反映了病毒在呼吸道中复制的程度，而且还反映了宿主先天性和适应性免疫应答的强度或幅度。我们的实验室一直有一个长期的兴趣（超过30年的时间），在理解的作用，先天性和适应性免疫反应IAV清除感染的肺部和相关的肺部炎症和损伤的发展。这种探索性R21应用的基础是一组最近的偶然发现，其暗示IAV感染的肺中的瘦素/瘦素受体信号传导是肺部炎症和损伤程度以及因此IAV感染的严重性的重要调节剂。该应用被设计为在实验（鼠）模型中和通过SNP分析在人类中推断获得关键的额外数据，SNP分析对于瘦素/瘦素受体信号传导的未来更详细的分析是必要的 IAV感染。为此，我们提出了以下具体目标：1.确定瘦素和瘦素受体信号传导对IAV感染的严重程度和结果的贡献，并鉴定瘦素在感染肺中作用的细胞靶点; 2.鉴定瘦素受体信号传导途径，其介导IAV感染后促进增强的宿主应答的疾病。成功完成拟议的分析提供了新的治疗策略，以改善IAV感染的严重程度的可能性。

 DESCRIPTION (provided by applicant): Type A influenza virus (IAV) is a major human pathogen with the capacity to rapidly spread worldwide and to produce severe and sometimes fatal lung infections characterized by severe pneumonia and marked alveolar damage. Evidence accumulating over the past several decades strongly suggest that disease produced by IAV infection not only reflects the extent of virus replication in the respiratory tract but als the strength or magnitude of the host innate and adaptive immune response. Our laboratory has had a long-standing interest (over 30 years duration) in understanding the role of the innate and adaptive immune response in IAV clearance from the infected lungs and in the development of associated pulmonary inflammation and injury. The foundation of this exploratory R21 application is a set of recent fortuitous findings implicating leptin/leptin receptor signaling in he IAV infected lungs as an important regulator of the extent of pulmonary inflammation and injury and therefore the severity of IAV infection. This application is designed to obtain critical additional data both in an experimental (murine) model and by inference in the human via SNP analysis which is necessary for a future more detailed analysis of leptin/leptin receptor signaling in IAV infection. To this end we propose the following Specific Aims: 1.To establish the contribution of Leptin and Leptin Receptor signaling to the severity and outcome of IAV infection and to identify the cellular target(s) of Leptin action in the infected lungs;2.To identify the Lepin Receptor signaling pathway(s) mediating the disease promoting enhanced host response following IAV infection. The successful completion of the proposed analysis offers the possibility of novel therapeutic strategies to ameliorate the severity of IAV infection.