Toll样受体（TLR）在介导天然免疫反应抵御感染过程中发挥重要功能。TLR信号的过度激活会引发败血症等多种炎症相关疾病，因此其激活被严格调控。我们的前期研究结果及最近文献报道表明Dab2具有抑制TLR介导的炎症反应的重要功能，但是Dab2功能如何被调控尚不清楚。我们首次发现Dab2 Ser471位点响应多种TLR配体刺激发生磷酸化，而且将Ser471突变成不能磷酸化的Ala导致Dab2的抑炎功能显著受损，表明Ser471磷酸化对Dab2抑制TLR介导的炎症反应至关重要。本项目将开展以下研究：1.鉴定TLR信号激活过程中Dab2 Ser471磷酸化的上游激酶；2.阐明Dab2磷酸化对TLR信号激活的调控作用和分子机制；3.在小鼠模型中分析Dab2 Ser471磷酸化对炎症的调控作用。本项目完成将首次揭示磷酸化修饰调控Dab2抑炎功能的作用和分子机制，为炎症相关疾病的治疗提供新靶点和新策略。

Toll-like receptors (TLRs) are critical in mediating innate immune responses and protecting against infections. Uncontrolled TLR-mediated inflammation is associated with many inflammatory diseases such as endotoxin shock, therefore the activation of TLR signaling is tightly restricted. Our preliminary results and recent reports demonstrated that endocytic adaptor protein Dab2 has an important role in suppressing TLR-mediated inflammation. However, little is known about how Dab2 function is regulated during inflammation. We found for the first time that Dab2 Ser471 was phosphorylated in response to multiple TLR ligands, and that mutation of Ser471 to non-phosphorylatible Ala impaired Dab2’s function as a suppressor of TLR-mediated inflammatory responses. We then hypothesize that phosphorylation of Ser471 is critical for Dab2 to suppress TLR-mediated inflammation. To test this hypothesis, we will investigate: 1) the upstream kinase(s) that mediate Dab2 Ser471 phosphorylation; 2) the regulatory role and mechanism of Ser471 phosphorylation in TLR-mediated inflammation; and 3) the in vivo function of Dab2 Ser471 phosphorylation in a mouse model of endotoxin shock. The completion of this study would define a novel mechanism by which Dab2 phosphorylation regulates TLR-mediated inflammation, and provide new targets and better therapeutic strategies for treatment of inflammatory diseases.