细胞衰老是肺纤维化的重要发病机制，主要由DNA损伤、氧化应激及端粒酶缺失损耗等引起。热休克蛋白90（HSP90）作为细胞内重要的分子伴侣，参与氧化应激、损伤修复等重要病理生理过程。我们前期研究发现细胞外HSP90α经激活AKT/ERK等信号通路，参与肺纤维化；进一步在肺纤维化模型中观察到细胞衰老现象，特异性拮抗细胞外HSP90α可抑制衰老标志蛋白P16/P21高表达。文献报道，在纤维化模型中可引起Thy-1等DNA高甲基化。故我们拟构建肺纤维化模型，经二代测序检测Thy-1等DNA甲基化水平，利用CRISPR基因敲除技术、DNA甲基转移酶抑制剂及人重组HSP90α等，证实细胞外HSP90α可能经其受体LRP-1诱导Thy-1等DNA甲基化，引起细胞衰老，促进肺纤维化的发生发展；进而利用抗HSP90αmAb干预肺纤维化模型，观测其对肺纤维化进程的影响，本研究将为肺纤维化的诊治提供新的视点。

Cellular senescence is an important pathogenesis of pulmonary fibrosis, which mainly caused by DNA damage, oxidative stress and loss of telomerase. Heat shock protein 90 (HSP90), as a key intracellular chaperone, is involved in critical pathophysiological processes such as oxidative stress and injury repair. Our previous study indicated that extracellular HSP90α activated AKT / ERK signaling pathways involved in pulmonary fibrosis. Furtherly, we observed cellular senescence in the pulmonary fibrosis models.In parallel,utilized specific antibody to antagonise the extracellular HSP90α, which could inhibit the expression of cellular senescence markers P16 / P21 . Some researches reported that Thy-1 methylation can be observed in the pulmonary fibrosis models . Based on these, we plan to establish models of pulmonary fibrosis in vivo/vitro, use next-generation sequencing(NGS) to test Thy-1 and other relevant DNA methylation. We will take advantage of CRISPR gene knockout technology,DNA methyltransferase inhibitors and human recombinant HSP90α, to make a confirm that extracellular HSP90α can induce Thy-1 and other relevant DNA methylation through LRP-1 receptor, to cause cellular senescence which trigger the development of pulmonary fibrosis. Going further, we will make sure whether anti-HSP90α mAb can affect the progression of pulmonary fibrosis. This study will provide us a new perspective for the diagnosis and treatment of pulmonary fibrosis.