Lnc-PFAR调控pre-miR-141成熟激活自噬促进慢性胰腺炎纤维化的机制研究

Chronic pancreatitis (CP) describes as a progressive fibro-inflammatory disorder which eventually leads to the progression of endocrine and exocrine insufficiency. Currently, no treatment has been shown to be effective in halting the fibrogenic process. PSCs are widely distributed in the stroma of pancreas and the activation of PSCs is the key cause of pancreatic fibrosis. To explore the specific molecular target for inhibiting PSCs activation and to develop new drug will delay the development of illness. In previous study, we have investigated the differential expression of long noncoding RNAs (lncRNAs) in the pancreatic tissue of sham and CP mouse models. Our data showed that higher lnc-PFAR expression was associated with pancreatic fibrosis progression. Further study indicated that lnc-PFAR inhibited miR-141-5p expression which accelerated PSCs activation. Our previous studies have suggested that lncRNA induces autophagy activation via the post-transcriptional modification. In addition, RB1CC1 serves an adaptive role to facilitate PSCs activation and pancreatic fibrosis. In light of that, we aim to explore the main molecular mechanism of lnc-PFAR inducing RB1CC1-enhanced autophagy via inhibiting precursor miR-141 maturation. Ultimately, the PSCs are activated and pancreatic fibrosis is exacerbated. Our study will provide new train of thought to reveal the main functions of lncRNA on pancreatic fibrosis and to develop the molecule-targeted treatment in CP.

慢性胰腺炎（CP）以胰腺纤维化为主要临床表现，终将导致胰腺内外分泌功能不可逆性损伤，目前尚缺乏有效的治疗手段。胰腺星形细胞（PSCs）广泛存在于胰腺间质，PSCs活化是胰腺纤维化发生的主要诱因，寻找抑制PSCs活化的特异性分子并开发靶向药物将有助于延缓CP进展。在前期工作中，我们比较对照组与CP组小鼠胰腺组织lncRNA表达谱，发现高表达lnc-PFAR促进胰腺纤维化；进一步研究提示，lnc-PFAR通过抑制miR-141-5p表达参与PSCs活化。我们前期研究已证实lncRNA介导靶基因转录后修饰调控细胞自噬，并且，RB1CC1激活自噬促进PSCs活化及胰腺纤维化。有鉴于此，本项目旨在探讨lnc-PFAR通过抑制pre-miR-141成熟介导RB1CC1激活自噬促进PSCs活化的具体机制，为进一步阐明lncRNA促进胰腺纤维化的分子机理及开展CP的靶向治疗提供更多证据。

慢性胰腺炎（CP）以胰腺纤维化为主要特征，伴有胰腺内、外分泌功能不全，严重影响病人生活质量，长链非编码RNA作为调控纤维化的重要因素，但其在CP中的作用机制尚不明确。借助转录组测序，我们发现lnc-PFAR在活化的胰腺星形细胞（PSCs）中显著上调，进一步对其功能预测发现，其通过激活自噬参与CP进展。本研究借助体内、体外实验及临床样本，获得以下结果：第一，lnc-PFAR介导的自噬激活诱导PSCs活化。利用小鼠原代PSCs与PSCs细胞系实验，系统证实lnc-PFAR通过靶向结合pre-miR-141并抑制miR-141成熟，减少其与RB1CC1的3'UTR结合，最终激活自噬加速胰腺纤维化。第二，抑制lnc-PFAR缓解小鼠胰腺纤维化进展。通过慢病毒干预CP小鼠模型，进一步证实抑制lnc-PFAR通过降低胰腺组织自噬体形成抑制CP进展。第三，探究lnc-PFAR在评估CP病人胰腺纤维化中的临床价值。借助临床样本，证实血浆与组织lnc-PFAR高表达可作为评估胰腺纤维化的诊断靶标。本项目的研究成果不仅从全新角度揭示lnc-PFAR调控胰腺纤维化中的关键机制，更为阐明自噬在胰腺纤维化治疗中的临床价值提供更多依据，该研究为CP治疗药物靶点的开发以及进一步揭示自噬抑制剂在CP治疗中的应用与前景提供重要的实验基础。在本项目支持下，共计发表论文13篇，其中SCI论文12篇。