剪接体蛋白Eftud2调控UC癌变相关巨噬细胞功能的机制研究

Ulcerative colitis (UC) is chronic inflammatory bowel disease with unknown etiology. Accumulating evidence has shown that the risk of cancer is increased dramatically in UC patients. Macrophage is well accepted to represent a key player during the progression from colitis to cancer. However, the mechanisms by which intestinal inflammatory microenvironment modulates the proinflammatory/pro-tumor function of macrophage remain poorly understood. Based on the previous studies, we give the hypothesis: in the milieu of intestinal inflammation, microbiota-derived components (e.g. LPS) regulate alternative splicing of mRNA of signaling proteins by enhancing the expression and function of splicing regulator Eftud2 in macrophages, and thereby up-regulate the expression of proinflammatory and protumorigenic factors and promote UC malignant transformation. In this study, integrating the experiments in vitro and in vivo, we will elucidate the effect of Eftud2 on macrophage function and underlying machanisms, clarify the molecular events in the regulation of Eftud2 expression by Toll signaling, and ultimately demonstrate our hypothesis in multiple-layers. In conclusion, our work not only provide new insights into immune mechanisms underlying UC malignant transformation, but also contribute to discovery of potential therapeutic targets.

溃疡性结肠炎（UC）是一种病因不明的慢性肠道炎症性疾病。研究发现，UC的迁延不愈大大增加宿主细胞癌变的风险。巨噬细胞被认为是UC癌变进程中发挥至关重要作用的免疫细胞群。然而，关于肠道炎症微环境如何调控巨噬细胞的促炎/促瘤功能这一重要的科学问题目前仍不甚清楚，亟待解答。本课题组在前期研究的基础上，提出以下科学假设：在肠炎微环境中，移位细菌的致炎组分（如LPS）通过增强巨噬细胞内剪接体蛋白Eftud2的表达和功能，调控相关信号通路蛋白mRNA的可变剪接，上调促炎/促瘤因子的表达，促进UC癌变。本项目拟通过体内外实验，阐明剪接体蛋白Eftud2对巨噬细胞促炎/促瘤效应的影响，揭示Eftud2调控巨噬细胞功能的作用机制，解析Toll信号调节Eftud2表达的分子机理，多个层面论证我们的设想。本课题的研究将从RNA可变剪接这一新的角度深入了解UC癌变的免疫学机制，而且将有助于发现潜在的干预靶点。

溃疡性结肠炎（UC）是一种病因不明的慢性肠道炎症性疾病。研究发现，UC的迁延不愈大大增加宿主细胞癌变的风险。巨噬细胞被认为是UC癌变进程中发挥至关重要作用的免疫细胞群。然而，关于肠道炎症微环境如何调控巨噬细胞的促炎/促瘤功能这一重要的科学问题目前仍不甚清楚，亟待解答。本项目利用慢性肠炎恶性转化的小鼠模型，在分子、细胞、动物层面揭示了剪接体蛋白Eftud2在UC癌变中起着重要的促进作用。具体机理如下：在肠炎微环境中，移位细菌的致炎组分（如LPS）通过增强巨噬细胞内剪接体蛋白Eftud2的表达和功能，调控相关信号通路蛋白（如MyD88、MD-2、TLR4）mRNA的可变剪接，增强TLR4信号通路，上调促炎/促瘤因子（如IL-6、TNF-a、IL-1b等）的表达，促进UC癌变。这一发现从RNA可变剪接这一新的角度加深了人们对UC癌变的认识，而且Eftud2可能是潜在的干预靶点。