特发性肺纤维化（IPF）发病机制尚未阐明，目前无有效防治措施，是严重威胁人类健康的重要疾病。8-羟基鸟嘌呤DNA糖苷酶（OGG1）因具有DNA修复、抗凋亡及调控免疫的作用而备受关注。我们前期研究表明：OGG1参与调控小鼠肺纤维化进程和肺泡上皮细胞EMT过程，并对自噬产生影响，但具体机制不清。我们通过酵母双杂交等发现OGG1与Smad3相互作用，而TGF-β1/Smad3是潜在治疗肺纤维化的分子靶标。因此，我们提出“OGG1可能通过结合Smad3，协同激活通路下游基因转录，影响EMT、自噬及肺纤维化发生”这一新的分子机制。本研究拟利用OGG1敲除小鼠肺纤维化模型和原代肺泡上皮细胞EMT模型探讨：1）OGG1/Smad3的结合位点和调控的靶基因；2）OGG1/Smad3的生物学功能；3）OGG1协同TGF-β1信号通路如何影响自噬和EMT。以上机制的阐明，为今后研发IPF治疗靶点提供理论依据。

The pathogenesis of idiopathic pulmonary fibrosis (IPF), a serious disease which threats human health, has not been elucidated. However, there is no effective treatment for it. Recently, 8-oxoguanine DNA glycosylase（OGG1） is well known on the role of DNA repair, anti-apoptosis, and the regulation of the immune system, etc. Our preliminary results show that: OGG1 plays an important role in the regulation of pulmonary fibrosis in mouse and EMT in alveolar epithelial cells, and also impact on autophagy. However, the mechanism of OGG1 in EMT of pulmonary fibrosis is still unclear. We recently verified that OGG1 interacts with Smad3 protein using Yeast two-hybrids and GST-pull down. It was reported that TGF-β1/Smad3 signaling pathway are potential molecular targets on the therapy of pulmonary fibrosis. Based on the above results, we propose a new molecular mechanism: OGG1/Smad3, which activates the target gene transcription in the downstream of Smad3, plays an influence in EMT, autophagy and pulmonary fibrosis. We will explore this by experiments in pulmonary fibrosis model of OGG1 knockout mouse or EMT model of alveolar epithelial cells. We propose three inter-related specific aims: 1) To determine the specific binding sites and downstream target gene of OGG1 and Smad3 interaction; 2) To determine the function of OGG1/Smad3; 3) To determine how OGG1 affect the process of autophagy and EMT via cooperating TGF-β1 signaling pathway. Above-mentioned mechanism can be clarified effectively, and it will provide experimental basis for the future treatment of IPF as a therapeutic target.