microRNAs调控网络在炎症性肠病恶性转化中作用及其机制研究

Inflammatory bowel disease (IBD) is a chronic, non-resolving intestinal inflammatory disease, which increases the risk of colon cancer. Given the growing of the incidence and mortality of IBD associated cancer in recent years, attempts are needed to identify the molecular mechanisms involved in IBD transformation. Although studies have been focused on the involvement of protein-coding genes in this process, the molecular nature underlying IBD transformation is still poorly defined. In our previous studies, we found that small non-coding RNAs--microRNA (miRNA) functioned as important regulators in immune response, IBD and colorectal cancer, indicating a possible role in IBD transformation. Therefore, by establishing the animal model of IBD associated cancer induced by azoxymethane (AOM) and dextran sulfate sodium salt (DSS), and employing miRNA sequencing, proteomics- and bioinformatics- associated technologies, this project is designed to investigate the alterations of miRNA profile in different phases of IBD transformation and to figure out the functional role of candidate miRNAs in this process. By delineating the regulatory network of miRNAs in IBD transformation, we will attempt to set up novel evaluation systems which can be clinically used in early diagnosis and prognosis of IBD transformation, thus to improve the prevention and treatment of IBD associated cancer.

炎症性肠病是肠道非可控性炎症的主要类型，也是大肠癌的最常见诱因之一。炎症性肠病恶性转化的发生率及死亡率逐年增加，因此对其发生及转化的分子与调控机制认识具有重要意义。以往的研究聚焦在在关键分子及其信号通路上，但未能解释其在非可控性炎症恶性转化中的调控作用。我们前期研究发现microRNAs(miRNAs)在炎症性肠病和肠癌的表达中具有相关性，提示其可能在疾病恶性转化中发挥作用。基于此，本课题拟以动物模型及临床样品为研究对象，应用miRNA平行测序、蛋白组学、转基因动物及生物信息学等技术和方法，探讨炎症性肠病恶性转化不同阶段miRNAs的变化规律及功能，借以发现一批关键miRNAs形成的网络调控系统及其在肠炎向肠癌转化过程中的作用，揭示肠炎恶性转化的分子机制；并尝试建立可运用于临床恶性转化早期诊断及转归预测的综合指标评价体系，为疾病早期诊断、干预策略和防治模式提供新的视野和切入点。

慢性炎症是多种肿瘤发生的关键诱因之一。炎症性肠病是肠道非可控性炎症的主要类型，目前炎性肠病癌化的发生率及死亡率逐年增加，因此对其发生及转化的分子与调控机制的认识具有重要意义。以往的研究聚焦在关键蛋白编码基因的失调上，我们构建了持续炎症恶性转化的小鼠模型，发现小分子蛋白非编码RNA，microRNAs在炎症性肠病和肠癌的表达中具有相关性，其中microRNA-15/16 (miR-15/16)在炎症至肿瘤期的结直肠组织中表达持续下调，miR-15/16可通过调控B细胞等调节性免疫细胞的局部浸润，影响CD8+ T细胞的增殖，抑制肠炎癌转化，研究结果从miRNA调控局部免疫稳态的新视角阐释了肠炎癌化的机理，拓展了对炎癌转化的机制认识，靶向miR-15/16及下游调节性B细胞，可能成为控制肠炎恶性转化的早期临床干预策略。