Toll样受体(TLR)对固有免疫及获得性免疫均具有重要的调节作用。TLR信号通路调节机制的研究对于阐明机体免疫反应产生的机理，寻找免疫调节治疗的新途径具有重要科学意义和应用价值。我们前期在青年基金项目资助下，围绕TLR信号通路调控这一重要科学问题展开研究，发现了hnRNP-U、TRIM38、TRIP等多个调节因子并阐明了其作用机制。后续实验发现TLR4可诱导磷酸酶PTPN4的表达；siRNA抑制PTPN4表达，LPS介导的IFN-β表达明显增强，而TLR2/3/7/8和RIG-I介导信号通路均未受影响，提示PTPN4特异性调控TLR4信号通路。本研究利用动物模型(PTPN4基因敲除小鼠)、细胞模型(巨噬细胞及HEK293细胞等)和多种分子技术（免疫共沉淀、细胞因子抗体芯片、报告基因分析等）探讨PTPN4是否参与TLR信号通路调控并揭示其分子机制，为疫苗研制和药物设计提供更为理想的靶点。

Toll like receptors (TLRs) play crucial roles in both innate immunity and adaptive immunity. Investigation of the regulatory mechanisms of TLR signaling has important scientific significance and application value in elucidating the mechanism of the immune responses and developing novel ways of immunomodulatory therapy. Under the support of Youth Project of the National Natural Science Foundation, we focused on the modulation of TLR signal transduction, a fundamental scientific issue in immunology, and carried out a series of researches. We reported that multiple molecules including heterogeneous nuclear ribonucleoprotein U (hnRNP-U), E3 ligases tripartite motif-containing protein 38 (TRIM38) and TRAF-interacting protein (TRIP) were involved in the regulation of TLR signaling and clarified their molecular mechanism. In the follow-up experiments, we found the expression of tyrosine-protein phosphatase non-receptor type 4 (PTPN4) was substantially induced with stimulation of LPS (a TLR4 ligand) in thioglycolate-elicited mouse primary peritoneal macrophages. siRNA knockdown of endogenous PTPN4 expression enhanced TLR4-mediated IFN-β expression, while PTPN4 knockdown had no effects on TLR2/3/7/8- and RIG-I-mediated signal transduction. These data suggest that PTPN4 may be specifically involved in the regulation of TLR4 signaling. In this following proposal, we plan to use PTPN4 knockout mice, various cells including macrophages and HEK293 cells combining with varieties of molecular techniques, such as co-immunoprecipitation, cytokine antibody array, dual-luciferase reporter assay etc., to explore the functions of PTPN4 in the regulation of TLR signaling, reveal the possible molecular mechanisms and supply ideal target for novel vaccine development and drug design.