特发性肺纤维化（IPF）与氧化应激密切相关。P66shc在促进线粒体氧化应激产生中起关键作用，其在IPF中的作用尚无研究。我们前期工作表明IPF患者p66shc表达增高，TGF-β1和表观遗传修饰可调节p66shc的表达。TGF-β1/Smad p53参与纤维化病变的形成,p66shc为p53下游效应基因。推测TGF-β1/Smad p53可能通过对p66shc的表观遗传修饰，参与肺纤维化的发病机制。本课题拟利用活检标本、体外培养肺成纤维细胞和动物模型，进一步了解p66shc在IPF中的表达，及TGF-β1/Smad p53信号通路，是否转录调控p66shc DNA启动子区域的去甲基化和组蛋白乙酰化修饰，上调p66shc的表达，产生氧化应激，促进成纤维细胞的分化和肺纤维化的形成，从而揭示p66shc在IPF形成中的作用和机制。为IPF防治开辟新途径。

Idiopathic pulmonary fibrosis (IPF) is closely correlated with oxidative stress. P66shc plays a pivotal role in oxidative stress of mitochondrion. It's role in IPF remains unknown. Our preliminary work found that the expression of p66shc was elevated in fibroblast of patients with IPF,TGF-β1 and epigenetic modification can modulate the expression of p66shc.It has been demonstrated that p53 can transcriptionally regulate the expression of p66shc and TGF-β1/Smad p53 palys a role in fibrosis disease.So we hypothesize that TGF-β1/Smad p53 may regulae the expression of p66shc through epigenetic mechanism and participate in the pathogenesis of pulmnary fibrosis.The aims of this research are,using lung biopsies of clinical patients, cultured fibroblast and animal models, evaluating the role of p66shc in IPF, investigating if TGF-β/Smad p53 signal pathway can upregulate p66shc expression through DNA promotor demethylation and histone acetylation, provoke oxidative stress and the differentiation of lung fibroblast, eventually result in the formation of pulmonary fibrosis. The completion of this study could provide a new avenue for the treatment of IPF.