小RNA对肠道树突状细胞分化和活化功能的调控

Inflammatory Bowel Disease (IBD) is a disease caused by mucosal immune disorder. The incidence rate increased quickly in China these years. Up to now, the pathogenesis of IBD is far from clarified. In mucosal immune system, dendritic cell (DC) play an important role in the maintenance of intestinal mucosal homeostasis and the immune responses. Our previous work had found series of miRNAs changed in DC during colitis progression. Among them, miR-223 which showed highest abundance in DC was further demonstrated to negatively regulate colitis. Therefore, we hypothesized that other miRNAs changed significantly in DC might also modulate the intestinal mucosal immune responses. In this project, these miRNAs will be studied comprehensively. The regulatory network of miRNA in DC will be clarified by using our DC miRNA function screening system in vitro and in vivo, and the conditional knock out mice available in our lab. What’s more, we will also discuss the possibilities of clinical trial of these miRNAs. Our work will give us a better understanding of the pathogenesis of IBD, and provide new ways for the diagnosis and treatment of IBD.

炎症性肠炎（Inflammatory Bowel Disease，IBD）是由黏膜免疫功能紊乱所导致的复杂疾病，其发病率在国内呈现迅速增加的趋势。由于其病因不明且缺乏根治手段，对其致病机理及相互作用机制就成为了目前肠道免疫相关疾病的研究重点之一。在肠道黏膜系统中，树突状细胞（Dendritic Cell，DC）对维持肠道黏膜稳态及诱导免疫应答中发挥重要作用。我们前期的研究发现了一系列在肠炎发生中，肠道DC亚群中变化的miRNA分子。基于此，本项目将对这些miRNA进行系统研究。利用本申请人建立的DC中的miRNA功能体外和体内筛选平台，结合实验室已有的多种miRNA条件敲除小鼠，全面阐明miRNA在肠道DC中的调控网络及其与肠炎的关系。本项目的预期结果将有助于更好地理解IBD炎症发生和调控机制，为发展新的IBD诊断和治疗手段打下基础。

炎性肠病（Inflammatory Bowel Disease，IBD）是由黏膜免疫功能紊乱所导致的一种自身免疫疾病，多种因素相互作用，如基因遗传，肠道菌群和生活环境等方面，可能是导致黏膜免疫效应细胞功能异常的重要原因。在肠道黏膜系统中，树突状细胞（Dendritic Cell，DC）对维持肠道黏膜稳态及诱导免疫应答中发挥重要作用。MicroRNA作为一类非编码小RNA分子，在免疫稳态的调节中起关键作用。本项目通过研究发现miR-148a在肠道免疫稳态的维持中起重要作用。通过比较对照和miR-148a KO小鼠的免疫前体细胞和脾脏、肠道等免疫细胞的构成，我们发现miR-148a的缺失导致骨髓中髓-粒系前体细胞比例和脾脏中DC的比例降低。诱导肠炎后，miR-148a的缺失造成肠道中DC比例的降低和促炎巨噬细胞比例增加。与之相对应的是，miR-148a KO小鼠肠系膜淋巴结的Th17和B细胞比例增加。结果，miR-148a KO小鼠显示更严重的肠炎症状。同时，我们证实了miR-148a是DC活化的负调控基因，它的缺失还导致单核细胞更多的向巨噬细胞分化，而单核向DC分化的潜能则受到抑制。进一步机制研究表明，MAFB是miR-148a的直接靶基因。通过负调控MAFB的表达，miR-148a参与对造血分化和粘膜免疫稳态的调控。该项目发现了新的调控粘膜免疫的microRNA分子，提示miR-148a可以作为靶标对炎症性肠病进行干预。