急性肺损伤（ALI）是多种因素导致的进行性、急性、缺氧性呼吸功能不全，抑制LPS/TLR-4介导的固有免疫反应能够有效控制ALI的发生发展。SIGIRR是具有负调控作用的TLR-IL-1R受体超家族成员，但SIGIRR的负调控机制尚未阐明。本课题组前期发现SIGIRR高表达于人正常肺泡上皮细胞，对LPS诱导的ALI具有显著抑制作用，且SIGIRR能够与肿瘤坏死因子受体相关因子6（TRAF6）发生直接相互作用从而抑制TRAF6的泛素化，本项目拟阐明SIGIRR对TRAF6活性的直接影响。首先分析SIGIRR和TRAF6的相互作用位点，观察SIGIRR对TRAF6寡聚化和泛素化的影响，检测LPS/TLR-4信号通路对SIGIRR和TRAF6相互作用的影响，观察SIGIRR对ALI的治疗作用是否与其直接抑制TRAF6的寡聚化和泛素化有关，最终进一步揭示SIGIRR负性调控炎症的分子机制。

Acute lung injury (ALI) is an acute hypoxic respiratory dysfunction resulted from multiple factors. Suppression of LPS/TLR-4 mediated innate immune response has great effectiveness on the control of ALI. SIGIRR, a member of TLR-IL-1R receptor superfamily, can negatively regulate multiple LR-IL-1R receptor-mediated signaling transduction, while the negative regulatory mechanism of SIGIRR has not been fully elucidated. We have found that SIGIRR is highly expressed in normal human alveolar epithelial cells and can inhibit LPS-induced ALI, and that SIGIRR can directly interact with TRAF6 and inhibit the ubiquitination of TRAF6, which is critical to NF-κB activation. The present research intends to clarify the effects and mechanisms of SIGIRR on oligomerization and autoubiquitination of TRAF6 in LPS-induced ALI. We will first analyse the interaction sites of SIGIRR and TRAF6 and the effects of SIGIRR on TRAF6 oligomerization and autoubiquitination, then detect the effects of LPS/TLR-4 signaling pathway on SIGIRR and TRAF6 interaction, and observe whether the therapeutic effects of the SIGIRR on ALI in animal model depends on its direct inhibition of the oligomerization and autoubiquitination of TRAF6. The implementation of the research will be helpful to reveal the molecular mechanisms of negative regulation roles of SIGIRR on the innate immune response.