肠道微生态对肠炎癌相关免疫细胞表观遗传修饰的调节

Gut immune system play a critical role in the development of colitis-associated carcinoma. Recent studies have also shown that commensal bacteria are necessary for gut immune responses and inflammation under normal physiological and pathological conditions. However, the molecular basis for immune cell differentiation, expansion, activation to different effective cells after exposed to different gut microbiota, are not yet fully explored. Our preliminary studies have found that gut CD103+dendritic cells, RORt+cells and M2-like macrophages individually accumulated in the gut tissues of LRRC19 deficient mice, gut epithelial cells-restricted REG3 and REG3 transgeneic mice, which have remarkably resistance to colitis-associated tumorigenesis. Our and other results also point at the possible involvement of unique epigenetic modification and involvement of lincRNAs via chromatin remodeling in response to different environments. All of these led us to hypothesize that the complex milieu of epigenetic changes could sense the gut microbiota environment typical to altered gut bacteria and metabolitics, and regulate the differentiation of immune cells, which are associated with complications and colitis carcinoma progression. Therefore, our general objective is to explore the mechanisms underlying the linkage between gut microbiota, epigenetic modification, differentiation of the specific immune cells and gut carcinoma that could lead us to the development of epigenetic intervention modalities to impede disease progression. More specifically, we aim to: 1) Establish gut carcinoma models which are related to the altered gut microbiota; 2) Characterize specific immune cell populations which are involved in the development of colitis carcinoma; 3) Analyze the specific gut bacteria, which are related to development of gut carcinoma; 4) Identify the epigenetic associated factors that play a critical role in the development of colitis carcinoma associated immune cells; 5) Determine the mechanisms controlling expression and activity of the these epigenetic modification factors involved in the differentiation of gut immune cells, and 6) Combining clinical samples, assess the effect of “epigenetic treatments” on the differentiation and function of immune cells and gut carcinoma stage. Our results are expected to highlight the epigenetic modifications playing a role in gut specific immune cell populations during colitis carcinoma and enable defining the critical roles of gut microbiota in these processes, which is expected to form a solid ground for the development of new potential strategies towards recuperation of gut carcinoma.

肠特定免疫细胞群在肠微生态相关肠炎癌的发生发展过程中起关键作用，但人们很少知道肠微生态如何调控这些免疫细胞群。前期研究发现与肠炎癌相关的CD103+树突细胞，RORrt细胞和M2巨噬细胞在不同遗传修饰鼠肠组织中大量积累。该项目将围绕这些细胞，通过系统分析它们的表观遗传修饰特点，解读肠道微生物及其代谢物对这三类免疫细胞群的调控作用。强调以下目的: 1）建立肠微生态对肠炎癌发生发展干预的相关动物模型及功能评价; 2）特征与肠炎癌发生发展相关的免疫细胞群与亚群; 3）分析与肠炎癌免疫细胞群分化和功能有关的肠道细菌及其代谢物; 4）鉴定肠炎癌相关免疫细胞群表观遗传调控关键因素并解析其调控机理; 5）结合临床样本综合评价肠免疫细胞表观遗传修饰相关因素对肠炎癌发生发展的影响。研究结果不仅能够揭示非可控性肠炎癌恶性转化的分子机制与调控规律，也为发展新的肠炎癌预防炎癌预防和治疗策略奠定基础。

肠道微生态与肠炎癌发生发展有密切关系，肠道免疫系统在肠炎癌发生发展过程中起关键作用。由于肠道细菌及其代谢产物在肠炎癌相关免疫细胞分化过程中发挥重要作用，我们解析了肠道细菌及其代谢产物对肠炎癌相关免疫细胞细胞极化过程中的表观遗传调控机理，这是解开肠道微生态对肠肿瘤发生发展作用的关键。特征了与肠炎癌相关免疫细胞群，寻找控制这些免疫细胞分化和功能的关键甲基转移酶，去甲基化酶及相关表观遗传调控因素，重点解析了肠道微生态信号对肠炎癌相关免疫细胞分化相关表观遗传调控因素的调控作用。所做的研究能够揭示非可控性肠炎癌恶性转化的分子机制与调控规律，也为发展新的肠炎癌预防和治疗策略奠定基础。