落新妇苷酚羟基衍生物抗特发性肺纤维化作用中对TERRA信号通路的调控机制

Idiopathic pulmonary fibrosis,a diffuse pulmonary interstitial disease of unknown etiology, eventually lead to irreversible respiratory failure.The treatment for IPF is supportive, and there are currently no known therapies and drugs that alter its natural history. The previous results showed that a hydroxylated phenolic derivative of Astilbin has therapeutic effects on IPF and could improve alveolar epithelial regenerative capacity which may partly due to its ability to regulate telomere stability. The objectives of this study are to determine whether the effect of the hydroxylated phenolic derivative of Astilbin on IPF is related to its modulation of miR-101/138-EZH2-TERRA-TERT-telomere signaling pathway using miRNA chip,gene transfection, gene interference technology from the aspect of histomorphology, regulation of gene expression and bioinformatics. And all the results may provide a theoretical basis for not only developping the hydroxylated phenolic derivative of Astilbin as a first class new drug(lung fibrosis) but also making TERRA as a novel molecular target for treatment of lung fibrosis.

特发性肺纤维化( idiopathic pulmonary fibrosis，IPF)是一种病因不清、机制未明的弥漫性肺间质疾病，最终导致不可逆的呼吸功能衰竭，严重危害人类健康，目前尚无确定有效的治疗方法和药物。我们前期研究发现落新妇苷酚羟基衍生物具有抗IPF的作用，能够促进肺泡上皮细胞的损伤修复，初步明确可能与影响端粒稳态相关。本课题拟采用BLM/TGF-β1诱发的体内外肺纤维化模型，从组织形态学、基因表达调控、基因信息学等方面，利用miRNA芯片、基因转染、基因干扰等技术研究落新妇苷酚羟基衍生物抗肺纤维化作用中对miR-101/138-EZH2-TERRA-TERT-端粒信号通路的调控机制，为将其开发为抗肺纤维化的一类新药提供理论依据，同时为将TERRA开发为肺纤维化疾病新的基因靶标提供重要的理论和技术支持。

特发性肺纤维化（IPF）是一种病因和机制不清的弥漫性肺间质疾病，病死率高，且无有效的治疗方法和药物。研究肺纤维化的发病机制，开发有效防治肺纤维化的药物具有重要的临床价值。研究发现长链非编码RNA在哺乳动物进化及疾病发生中起重要调控作用，是潜在的药物作用靶点和分子治疗靶标。本项目深入研究了长链非编码RNA-telomeric UUAGGG repeat-containing RNA (TERRA)调控肺纤维化发生发展的分子机制。研究发现TERRA在IPF患者血液、损伤的肺泡上皮细胞中显著上调表达，通过抑制端粒酶活性，调控肺泡上皮细胞的损伤修复。本项目从植物土茯苓中分离纯化得到落新妇苷，并利用天然产物化学技术对其酚羟基进行优化结构改造制备酚羟基衍生物；进一步采用气管喷雾博莱霉素建立的肺纤维化动物模型、双氧水/TGF-β1建立的肺纤维化细胞模型，研究了落新妇苷及其衍生物的抗肺纤维化作用机制。实验结果证实落新妇苷及其衍生物可以改善纤维化小鼠的肺功能，改善肺泡结构，减轻体内的胶原沉积，缓解肺纤维化症状，阻止肺纤维化的进展，而且落新妇苷酚羟基衍生物的抗纤维化活性明显优于落新妇苷；机制研究发现落新妇苷显著的抗肺纤维化作用是通过调控Hedgehog-Gli信号通路进而抑制肌成纤维细胞功能实现的；而其酚羟基衍生物可通过调控TERRA-端粒酶通路发挥抑制纤维化进程的作用。该项目提供了潜在的肺纤维化治疗药物和分子靶点。