整合素相互作用蛋白Kindlin-2在肺纤维化中的作用及分子机制

Pulmonary fibrosis (PF) is a group of intractable diseases commonly in clinical working. Included in PF, idiopathic interstitial pneumonias (IIP) are cryptogenic and the pathogenesis is unknown. Epithelial- Mesenchymal Transition (EMT) may play a role in development and progression of PF. Our preliminary work found that integrin interacting protein Kindlin-2 may participated in EMT process regulating, interacted with β-catenin, the key molecular in Wnt signaling pathway, and as well with Smad3 which is crucial in TGFβ1 signaling pathway. Smad3 may be activated by Kindlin-2 in this process. The results above indicated that Kindlin-2 may play an important role in the regulation of PF. We found that Kindlin-2 expressed in nuclei of hyperplastic alveolar type Ⅱ cells and fibroblasts in human pulmonary fibrosis tissues. In human lung type Ⅱ alveolar epithelial cell line cultured in vitro, we will investigate the regulating effect and molecular mechanism of Kindlin-2 in PF. Our research, starting from the open lung biopsies of clinical patients, combined with cell lines and animal models, will explore the interaction and regulation of Kindlin-2 with TGFβ1 and Wnt signaling pathways,and in EMT process, thus to find out the function of Kindlin-2 in pathogenesis of PF, and provide a new potential target of development, progression and therapy of PF.

肺纤维化是临床常见且难治的一组疾病，其中特发性间质性肺炎病因及发病机制不明。上皮间质转化（EMT）是肺纤维化发生发展的机制之一。我们前期工作表明整合素相互作用蛋白Kindlin-2调控EMT并与Wnt信号通路的关键分子β-catenin及TGFβ1通路中的关键分子Smad3相互作用并激活Smad3，提示Kindlin-2可能参与调控肺纤维化并在其中发挥重要作用。我们发现人肺纤维化标本中可见Kindlin-2在增生的Ⅱ型肺泡上皮细胞及成纤维细胞中呈核表达。本申请中，我们将在体外培养的Ⅱ型肺泡上皮细胞中研究Kindlin-2对肺纤维化的调控作用及其分子机制；从肺纤维化患者活检标本入手，结合体外细胞实验及动物模型，研究Kindlin-2与EMT、TGFβ1及Wnt通路之间的相互作用及其调控关系，从而揭示Kindlin-2在肺纤维化发病机制中的作用，为肺纤维化发生、发展及治疗提供新的潜在靶标。