肺成纤维细胞（LF）自噬抑制是LF增殖与肺纤维化发生的前提。申请者发现脂多糖（LPS）能引起LFThy-1表达缺失并抑制LF自噬，但机制未明。整合素αvβ3分子变构与Thy-1表达缺失相关，申请者推测LPS可诱导LFThy-1表达缺失，改变整合素αvβ3构象，使其活化并激活PI3K-Akt-mTOR通路从而抑制LF自噬。本课题在胶原蛋白三维培养环境下研究LPS抑制LF自噬的机制，通过抑制或过表达Thy-1和整合素、阻断PI3K-Akt-mTOR通路，明确Thy-1表达缺失、整合素αvβ3活化和PI3K-Akt-mTOR通路活化的作用。同时建立LPS诱导小鼠肺纤维化模型，采用CRISPR/Cas9技术构建肺组织特异性Thy-1过表达小鼠，使用自噬诱导剂促进肺组织自噬过程以抑制LF增殖和肺纤维化。本研究有望从生物大分子间相互作用的角度完善LPS诱导肺纤维化的机理，为探索该病的防治手段奠定基础。

The inhibited autophagy of lung fibroblast is the precondition for lung fibroblast proliferation and pulmonary fibrosis. Our previous studies revealed that lipopolysaccharide (LPS) could induce Thy-1 gene deletion and autophagy inhibition in lung fibroblast, but the underlying mechanism remains unknown. Thy-1 deletion was reported to change the conformational alternation of integrin αvβ3. Here we hypothesize that LPS-induced deletion of Thy-1 can cause the conformational change of integrinαvβ3, which result in inhibited autophagy of lung fibroblast though activation of PI3K-Akt-mTOR pathway. In this study, under the condition of three-dimensional polymerized collagen matrices, we aim to elucidate the possible mechanism of LPS-induced inhibition of lung fibroblast autophagy and to clarify the role of Thy-1 deletion, integrinαvβ3 activation and PI3K-Akt-mTORsignaling pathway activation play in this process though inhibiting/over-expressing Thy-1gene/integrinαvβ3 or blocking PI3K-Akt-mTOR pathway. Meanwhile, based on the mouse model of LPS-induced pulmonary fibrosis, we plan to up-regulate Thy-1 expression by establishing the pulmonary-specific Thy-1 gene knock-in mouse though CRISPR/Cas9 genome-editing technique, and to promote autophagy by autophagy inducer administration in order to inhibit lung fibroblast proliferation and pulmonary fibrosis. This study is expected to explore the mechanism of LPS-induced pulmonary fibrosis from the perspective of synergistic interaction between bio-macromolecules and to lay the foundation for its countermeasures explorer.