竞争性内源RNA RP11-311C24.1调控特发性肺纤维化的作用及分子机制

特发性肺纤维化（IPF）是一种慢性进行性肺部疾病，临床缺乏有效治疗药物。申请者对三百余例IPF患者进行了肺移植手术治疗，发现肺泡Ⅱ型上皮细胞（AEC II）缺陷是导致IPF发生发展的关键因素，且PTEN基因的缺失可通过PI3K/Akt通路加速AEC II的衰老而促进肺纤维化；进一步发现，竞争性内源RNA RP11-311C24.1（简称RP11）在IPF肺组织中显著低表达，并可能通过竞争性结合miRNA-181d-5p参与PTEN的调控。据此，本项目将利用临床肺组织样本和肺纤维化小鼠模型，发现RP11在AEC II衰老中的作用方式及相关调控分子机制；利用内皮细胞和成纤维细胞等与纤维化密切相关的细胞，发现RP11在不同类型细胞中的表达特征及其竞争性结合的miRNA，阐明RP11在不同细胞中如何作为竞争性内源RNA影响靶基因及相关通路，为进一步理解IPF发病机制以及选择诊疗靶点提供理论依据。

Idiopathic pulmonary fibrosis (IPF) is a kind of chronic progressive lung disease, which lacks effective drugs. More than 300 patients with IPF were treated with lung transplantation, and it was found that the defect of alveolar type II epithelial cells (AEC II) was the key factor leading to the development of IPF; the deletion of PTEN gene could accelerate the aging of AEC II through PI3K/Akt pathway and promote the development of pulmonary fibrosis; furthermore, LncRNA RP11-311c24.1 (RP11 for short) is significantly underexpressed in IPF lung tissue, and may participate in PTEN regulation through competitive binding to miRNA-181d-5p. According to this, we will use human lung tissue samples and pulmonary fibrosis model to discover the role of RP11 in ACE II aging and regulatory molecular mechanism; use endothelial cells and fibroblasts closely related to fibrosis and other cell types to discover the expression characteristics and the specific ceRNA regulatory network in different types of cells. To clarify how RP11 affects target genes and related pathways through ceRNA regulatory network in different cells can provide theoretical basis for further understanding the pathogenesis of IPF and the selection of treatment targets.