肺泡上皮损伤及炎症微环境调控与肺纤维化发生密切相关，然而分子机制知之甚少。我们前期研究发现蛋白酪氨酸磷酸酶Shp2在调控肺泡上皮稳态及巨噬细胞活化发挥重要作用。肺泡特异性Shp2敲除小鼠表现呼吸上皮损伤并产生自发纤维化，抑制Shp2磷酸酶活性可促进巨噬细胞II型活化，加重肺纤维化进程。后续机制研究提示非受体型磷酸酶Shp2调控炎症信号特异性依赖其与不同锚定蛋白形成信号复合体(Signalosome)，其中锚定蛋白GABs家族（Gab1、Gab2）参与正向调控上游Shp2信号，而我们新筛选Hook1蛋白与Shp2催化亚基（PTP）直接结合参与负向调控酶活及下游信号传导。基于此，本项目将依托已多品系条件性基因敲除小鼠模型，系统研究肺泡微环境GABs-Shp2-Hook1信号复合体精确调控肺上皮损伤及巨噬细胞活化介导纤维化的病理生理学意义及分子机制。预期结果有望提出上皮损伤诱发肺纤维化的可逆磷酸化修饰新方式，建立肺纤维化疾病的新型动物模型，同时为探索潜在的纤维化早期干预靶点积累实验依据。

Lung alveolar epithelial injuries and inflammatory microenvironment play essential roles in promoting pulmonary fibrosis; however the molecular mechanism underlying initiation of fibrosis remains largely elusive. Shp2, a ubiquitously expressed tyrosine phosphatase has been previously demonstrated to be a critical signal transducer that integrates multiple molecular events in epithelial integrity and alternative activation of macrophage (M2). Mice with a conditionally-disrupted Shp2 in alveolus develop spontaneous fibrosis. Inactivcation of Shp2 enzyme in macrophages induceds M2, predipose mice to pulmonary fibrosis. Emerging evidences support that docking proteins diversify Shp2 signal specificity. Our experiments further suggested that GAB docking protein family (Gab1 and Gab2) direct interacting with Shp2 positively regulates Shp2 signal relay, while a recently-identified Hook1 direct binding with catalytic domain of Shp2 acts as negative modulator of Shp2 enzymatic activity in lungs. Together, those preliminary evidences suggest a novel GABs-Shp2-Hook1 signalosome in lungs may orchestrate the Shp2 signal in a fine-tune manner during epithelial injury and inflammation, and thus dysregulation of signaling in epithelial disintegrity initiates fibrogenesis. Based on those, this plan will utilize the multiple pre-engineered genetically-modified mice to finely dissect in vivo physiological relevancies of GABs-Shp2-Hook1 in regulation of epithelial injuries-initiated macrophage M2 activation and pulmonary fibrosis. Collectively, we expect this plan would optimize the diseases mode of lung fibrosis using transgenic approaches, and provide us with new insight into understanding the etiology and potential therapeutic benefits of pulmonary fibrosis.