miR-21 and lung fibrosis

描述(申请人提供)：特发性肺纤维化(IPF)是最有害的肺纤维化形式之一，目前还没有明显有效的治疗方法。虽然IPF的病因仍是个谜，但有证据表明IPF患者肺成纤维细胞中的几个主要分子通路调节失调，包括凋亡/生存通路以及转化生长因子-β、Akt和MAPK信号转导。在我们的初步研究中，我们发现miR-21在博莱霉素诱导的肺纤维化小鼠的肺组织和IPF患者的肺组织中表达上调。靶点预测和先前的研究表明，miR-21调节PDCD4、Smad7、Spry1和PTEN的表达。这些蛋白是细胞增殖和存活以及转化生长因子β、PI3K和MAPK信号转导的关键负性调节因子。这一信息与我们的初步数据一起表明，miR-21可能在IPF的发生和发展中作为整合子发挥重要作用。因此，miR-21似乎是开发治疗IPF的新疗法的潜在靶点。我们的初步数据显示，通过抗miR-21探针隔离miR-21可以减轻博莱霉素诱导的肺纤维化的严重程度，这有力地支持了这一假说。在这项研究中，我们旨在1)研究miR-21在人肺成纤维细胞、博莱霉素性肺纤维化小鼠肺组织和肺纤维化患者肺组织中的表达；2)阐明miR-21在体内博莱霉素诱导的肺纤维化中的作用；3)阐明miR-21调控肺纤维化的机制；4)阐明miR-21在调节IPF患者肺成纤维细胞体外病理特性中的作用。

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is one of the most pernicious forms of lung fibrogenesis and currently has no clearly effective treatments. Whereas the etiology of IPF remains enigmatic, there is evidence of dysregulations of several major molecular pathways in lung fibroblasts of IPF patients, including apoptosis/survival pathways as well as TGF-¿, Akt, and MAPK signaling. In our preliminary studies, we found that the expression of miR-21 is upregulated in the lungs of mice with bleomycin-induced lung fibrosis and in the lungs of patients with IPF. Target predictions as well as previous studies demonstrate that miR-21 regulates the expression of PDCD4, Smad7, Spry1, and PTEN. These proteins are critical negative regulators of cell proliferation and survival as well as TGF-¿, PI3K, and MAPK signaling. This information, together with our preliminary data, suggests that miR-21 may play an important role as an integrator in initiation and progression of IPF. Therefore, miR-21 appears to be a potential target for developing novel therapeutics to treat IPF. Our preliminary data showing that sequestering miR-21 by anti-miR-21 probes diminishes the severity of bleomycin induced lung fibrosis lend a strong support to this hypothesis. In this proposal, we aim to 1) characterize miR-21 expression in human lung fibroblasts, in the lungs of mice with bleomycin induced pulmonary fibrosis and in the lungs of patients with IPF; 2) delineate the role of miR-21 in vivo during bleomycin induced lung fibrosis; 3) delineate the mechanisms by which miR-21 regulates lung fibrosis; 4) delineate the role of miR-21 in modulating the ex vivo pathological properties of lung fibroblasts from IPF patients.