申请者集中探索免疫细胞利用整合素调控粘附迁移、炎症反应及免疫相关疾病的新型分子机制。已经构建了以ADAP和SKAP55为核心的增强整合素粘附的信号通路，并揭示ADAP调控HIV-1转录、细胞间传播的机制，提出靶向ADAP对HIV-1防治发挥重要意义。进一步，筛查出感染后的巨噬细胞升高VEGFR-3的表达，形成负反馈环路，抑制TLR4-NF-kB活化，避免败血症的发生。已发表SCI论文17 篇，影响因子累计165分，包括以（共同）责任/第一作者在Immunity、NI、 JEM、PNAS等期刊发表10篇论文。拟进一步探讨调控整合素活化的新型信号分子如何参与T细胞迁移、自身免疫性疾病的发生以及巨噬细胞负性调控炎症的功能；并创新性探索T细胞分泌的细胞因子促进肌肉干细胞增殖和损伤修复的新机理。本项目期望实现将基础研究与防治自身免疫性疾病、重症感染或促进肌肉修复等转化医学有机的联合。

The applicant has long-term interests to identify new molecules that regulate integrin activation to modulate T-cell adhesion/migration, inflammation and immune-related diseases. The applicant has demonstrated the ADAP-SKAP55 module in the ‘inside-out’ signaling to regulate integrin activation and T cell adhesion. Further, the applicant has identified that ADAP increases HIV-1 transcription via CD28 pathway and enhances cell-cell viral transmission via integrin adhesion. This suggests that targeting ADAP would control multiple steps of HIV-1 infection. More importantly, integrin CD11b has been demonstrated to enhance macrophage phagocytosis and inhibit inflammation. The applicat identified that the expression levels of VEGFR-3 and its ligand VEGF-C are increased in macrophages after Gram- bacterial infection. As noted previously, VEGFR-3 could activate integrins. The applicant’s findings suggest that VEGFR-3 inhibits TLR4-NF-kB pathway to reduce excessive inflammation and protect the host from bacterial infection induced-septic shock. Therefore, VEGFR-3/VEGF-C represents a new ‘self-control’ mechanism to negatively control TLR4-NF-kB pathway. Together, the applicant published 17 SCI research articles, including 10 papers as the (co)-corresponding/first author in Immunity, Nat Immunol, J Exp Med, PNAS et al. The impact factors of these publications reach 165 points. In the future, the applicant would (1) identify the new molecules that activate integrins for T cell adhesion and the development of multiple sclerosis; (2) or for negative regulation of TLR4 pathway and inflammatory response in macrophages; (3) identify how the cytokine cocktails secreted by activated T cells could facilitate muscle stem cell expansion in vitro and promote muscle repair in vivo. The applicant expects to transform basic research work into clinical treatment against autoimmune diseases, severe infectious diseases or improve tissue repair.

申请者集中探索免疫细胞利用整合素调控粘附迁移、炎症反应及免疫相关疾病的新型分子机制。已经构建了以ADAP和SKAP55为核心的增强整合素粘附的信号通路，并揭示ADAP调控HIV-1转录、细胞间传播的机制，提出靶向ADAP对HIV-1防治发挥重要意义。进一步，筛查出感染后的巨噬细胞升高VEGFR-3的表达，形成负反馈环路，抑制TLR4-NF-kB活化，避免败血症的发生。已发表SCI论文17篇，影响因子累计165分，包括以（共同）责任/第一作者在Immunity、NI、JEM、PNAS等期刊发表10篇论文。拟进一步探讨调控整合素活化的新型信号分子如何参与T细胞迁移、自身免疫性疾病的发生以及巨噬细胞负性调控炎症的功能；并创新性探索T细胞分泌的细胞因子促进肌肉干细胞增殖和损伤修复的新机理。本项目期望实现将基础研究与防治自身免疫性疾病、重症感染或促进肌肉修复等转化医学有机的联合。