Adipokines in Pulmonary Viral Infection

 描述(申请人提供)：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，特征是严重的肺炎和明显的肺泡损伤。过去几十年积累的证据有力地表明，由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，而且反映了宿主先天和获得性免疫反应的强度或大小。我们实验室对了解先天性和获得性免疫反应在IAV清除感染肺中的作用以及相关的肺部炎症和损伤的发展一直很感兴趣(持续了30多年)。这一探索性的R21应用的基础是一组最近的偶然发现，表明在他IAV感染的肺中瘦素/瘦素受体信号是肺部炎症和损伤程度的重要调节因素，因此IAV感染的严重程度。这项应用旨在通过SNP分析在实验(小鼠)模型中和通过在人类中的推断获得关键的额外数据，这是未来更详细地分析瘦素/瘦素受体信号所必需的 在IAV感染中。为此，我们提出了以下具体目标：1.确定瘦素及其受体信号在IAV感染严重程度和转归中的作用，并确定瘦素在感染肺中作用的细胞靶点(S)；2.确定瘦素受体信号通路(S)介导疾病促进IAV感染后增强的宿主反应。拟议分析的成功完成为减轻IAV感染的严重程度提供了新的治疗策略的可能性。

 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.