miR-21 and lung fibrosis

描述（由申请人提供）：特发性肺纤维化（IPF）是最有害的肺纤维化形式之一，目前尚无明确有效的治疗方法。尽管IPF的病因尚不清楚，但有证据表明IPF患者肺成纤维细胞中几种主要分子通路失调，包括凋亡/生存通路以及TGF-¿、Akt和MAPK信号通路。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和IPF患者的肺中表达上调。靶标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TGF-¿、PI3K和MAPK信号的关键负调控因子。这一信息，连同我们的初步数据，表明miR-21可能在IPF的发生和进展中发挥重要的整合作用。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anti-miR-21探针隔离miR-21可以降低博来霉素诱导的肺纤维化的严重程度，这有力地支持了这一假设。在这项提议中，我们的目标是1)表征miR-21在人肺成纤维细胞、博来霉素诱导肺纤维化小鼠肺和IPF患者肺中的表达；2)阐明miR-21在博来霉素诱导肺纤维化过程中的作用；3)阐明miR-21调控肺纤维化的机制；4)描述miR-21在调节IPF患者肺成纤维细胞的离体病理特性中的作用。

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.