TRIM31/mTORC1/VEGF正反馈环路通过调控子宫内膜间质细胞生物学行为介导子宫内膜异位症发病的机制

The pathophysiology of the endometriosis is incompletely understood. We analyzed the expression of TRIM family members in endometriosis using microarray data from RNA-seq and found that TRIM31 is markedly upregulated in both eutopic and ectopic endometrium. TRIM31 high expression is significantly associated with the expression of VEGF. Interestingly, VEGF positively actives TRIM31. Functional studies suggest that TRIM31 knockdown significantly impaired the proliferation and invasion ability of endometrial stromal cells in vitro. Mechanistically, according to privious study, we speculate that TRIM31 activates VEGF through mTORC1 pathway. TRIM31 knockdown repressed the transcription of several mTORC1 downstream targets. Therefore, Our study provided proof of principle to show that TRIM31/mTORC1/VEGF positive feedback loop contributes to endometriosis. The research include 1)clarifying clinical significance of TRIM31 in endometriosis. 2)demonstrating the biological behavior of TRIM31 in endometrial stromal cells. 3)revealing function of TRIM31 inducing VEGF expression dependented on mTORC1. Molecular biology experiments, animal models will be used to explore project. We hope our study will help to provide a new sight between TRIM family and the pathogenesis of endometriosis, Which provide the theoretical evidence to therapeutic targets.

子宫内膜异位症（内异症）因发病机制不明而无根治手段。TRIM31是我们通过转录组测序技术筛选出的一个在人内异症在位、异位内膜中均显著上调表达的基因。前期工作发现：TRIM31在内异症病灶中的表达与VEGF呈正相关，VEGF正反馈促进TRIM31蛋白表达；沉默TRIM31则抑制内膜间质细胞的增殖和侵袭；通过查阅文献推测mTORC1介导TRIM31调控VEGF，沉默TRIM31可抑制mTORC1下游基因表达，故提出TRIM31/mTORC1/VEGF正反馈环路参与内异症发病的科学假说。具体内容包括：1）明确TRIM31在内异症中的表达及临床意义；2）论证TRIM31在内膜间质细胞中的生物学行为；3）以mTORC1为主要切入点，揭示TRIM31调控VEGF发挥生物学功能的机制，采用手段包括分子生物学、动物模型等。本研究有助于理解TRIM家族与内异症发病的关系，为探讨其源头机制及靶向治疗提供依据。

子宫内膜异位症（EMS）是一种雌激素依赖性的慢性炎症性疾病，临床上以痛经、不孕为主要表现，影响着全球约10%的育龄期女性。炎症免疫调节障碍、血管生成是促进子宫内膜异位症发病的关键因素，寻找新的与此相关的调控因子对揭示EMS发生发展的机制具有重要意义。我们前期研究中通过生物信息学分析，发现了EMS中与炎症免疫微环境和血管生成相关的基因，其中TRIM31和KLF2是锌指蛋白，在EMS和正常子宫内膜组织中存在显著差异表达且参与炎症免疫、血管生成调控。本项目从临床样本、原代细胞、分子机制、小鼠自体移植实验等多个不同层面对TRIM31的mTOR、NF-κB信号和VEGF调控展开了深入研究，同时采用多种模型预测及检验，初步鉴定了KLF2是参与调控EMS炎症免疫和血管生成的重要基因，为认识EMS的炎症免疫、血管生成调控提供的新的线索；同时，项目组探讨了锌指蛋白ZBTB7A和RNF183在子宫内膜癌中的异常表达机制及其对子宫内膜癌细胞生物学行为、免疫浸润细胞的影响，为锌指蛋白与子宫内膜疾病发病关系提供了新的思路及候选靶标。以本项目为第一、第二标注在包括Frontiers in immunology、Cancer cell international、Frontiers in genetics SCI杂志发表研究论文3篇，协助培养妇产科硕士研究生2人。