表观遗传异常及代谢重编程协同致肺纤维化的分子机制

Pulmonary fibrosis is one of the leading causes of lung dysfunction and associates with high mortality in a variety of complex diseases. Our preliminary study revealed that the abnormal glucose and fat acid metabolism occurred in patients with scleroderma. Additionally, in the process of mouse pulmonary fibrosis, we uncovered that inflammation-induced aberrant expression of metabolic-related genes, which leads to the balance between glycolysis and fact acid metabolism, tipped toward fat acid synthesis as a consequence of metabolic reprogramming. Moreover, the metabolic reprogramming-driven activation of one carbon unit metabolism can further promote the gene methylation level and other epigenetic changes in the cells. To fulfill the requirements of cells, the whole-genome expression patterns of the cells will adaptively change, and consequently further solidify the patterns of gene expression regulation network and energy metabolism network of the cells in the pathological conditions. Therefore, in order to understand systematically the key molecular mechanisms of pulmonary fibrosis, we intend to integrate the epigenetic changes in the occurrence and development of pulmonary fibrosis, signal transduction, energy metabolism and other multi-aspect researches to dissect how the methylation and metabolic networks cooperate through the regulation of key genes, using the lung cells and pulmonary fibrotic mouse models. In addition, the above-mentioned process will be verified in patient samples with pulmonary fibrosis. Thus, through establishing a bridge linking all levels of researches, the results of this project will help us to screen and capture the molecular mechanism of pulmonary fibrosis in the process of epigenetic abnormalities and metabolic network regulation.

肺纤维化是导致多种复杂疾病患者肺功能丧失、进而致死的主要原因。申请人前期研究发现，硬皮病肺纤维化患者表现出糖脂代谢异常；在小鼠模型的肺纤维化进程中，炎症反应诱发了代谢相关基因表达水平的改变，导致代谢重编程及细胞糖脂代谢的失衡。相关研究也已表明，代谢重编程及其驱动的一碳单位代谢的活跃可能进一步促进基因的甲基化谱式异常，使细胞在全基因组表达水平发生适应性改变，促使细胞的基因表达调控网络与能量代谢网络的运行模式固化在病理状态下。因此，立足于系统理解肺纤维化疾病关键分子机制的角度，我们拟利用肺部细胞及肺纤维化小鼠模型，将肺纤维化发生与发展过程中表观遗传学及细胞能量代谢等多层次研究加以整合，以甲基化调控和代谢调控的关键基因功能为纽带建立起各层次研究的桥梁，并在肺纤维化患者样本中进行验证，以透视和捕捉肺纤维化进程中表观遗传异常及代谢重编程协同导致肺纤维化的分子机制，并为进一步的药物开发提供理论基础。

肺纤维化是一类高度致死的疾病。肺纤维化病因复杂，包括以自身免疫为特征的硬皮病，以及不明原因的特发性肺纤维化。然而，各类肺纤维化发病机制迄今仍未明确。因此，深入开展肺纤维化的机理研究、寻找安全有效的治疗措施尤为重要。.项目组从临床样本、小鼠肺纤维化模型出发，通过肺组织、血液等样本进行代谢组学和转录组学检测，并利用体内动物实验、体外细胞实验深入阐释了表观遗传异常致代谢基因改变，继而驱动代谢重编程的机制；系统评估了不同类型的代谢异常在肺纤维化中作用，并基于代谢干预策略评估了其在肺纤维化中的治疗效果，为临床转化提供依据。主要结果如下：1）发现表观修饰因子miR-106a在调节低密度脂蛋白受体（LDLR）以及膜铁转运蛋白（FPN）两种关键脂代谢和铁代谢基因中的重要作用；2）作为促纤维化因子和代谢调控因子，TGF-β信号通路活化是肺纤维化的重要标志。本项目发现miR-3606-3p靶向结合TGFBR2基因，在抑制TGF-β信号通路活性中发挥关键作用；3）发现肺纤维化中LDLR表达缺失诱发低密度脂蛋白LDL过度沉积，并揭示LDL-LDLR代谢轴通过诱导内皮、上皮凋亡和转化以及成纤维细胞活化等细胞功能紊乱继而加重肺纤维化；基于该代谢轴的他汀+PCSK9抗体联用策略可修复LDL-LDLR代谢失调，并有效缓解肺纤维化；4）发现新发铁代谢基因FGF6在调节铁超载、铁死亡中作用及机制，基于铁代谢的干预策略能够有效缓解肺纤维化发生发展。.通过本项目的实施，加深了对肺纤维化发病机制的认知，为肺纤维化治疗靶标的开发开辟了新的方向，对临床转化具有重要参考价值和借鉴意义。