REGgamma蛋白酶体系统介导肠道炎症与恶性结肠肿瘤的机制研究

As unresolving inflammatory diseases, inflammatory bowel diseases have an increased incidence in our country. Due to recurrent inflammation, risks to develop intestinal cancers are gradually rising. Yet there is no sufficient ways to eradicate such disease. Colitis associated cancer (CAC) is one of the most malicious neoplasias, occupying the third highest rank along with sporatic colon cancers. Facing the world-class health problem, scientists need to focus on how to control inflammation in both basic and translational research. Our bioinformatics analysis indicate that the proteasome activator REGgamma is highly expressed in ulcerative colitis compared with controls (p<0.0001). Pilots studies have established the link between REGgamma and colonic inflammation as well as CAC. Preliminary evidence suggests that the REGgamma-proteasome forms a regulatory circuit with NFkappaB to control progression of inflammatory bowel disorders and CAC. In this proposal, we plan to use bioinformatics, molecular, cellular and animal approaches to elucidate the mechanisms how the REGgamma-proteasome mediates inflammtory signals to promote CAC. A regulatory network connecting bowel inflammation and conlon cancers will be elaborated. Successful execution of the proposed study will define REGgamma as a novel therapeutic target for inhibition of colitis and CAC in personalized therapy.

非可控性炎性肠病在我国发病率逐年上升，由于反复发作，患者癌变风险不断升高，严重影响生活质量，目前尚无根治办法。结肠癌是常见的消化道恶性肿瘤之一，全世界结肠癌的发病率处于恶性肿瘤的第三位。因此结肠炎症恶变已经成为世界性的一个健康难题。如何从源头控制炎性肠病的进展已成为目前基础和临床研究的重点。本课题组前期采用生物信息学方法发现蛋白酶体激活因子REGgamma 在溃疡性结肠炎中显著高表达（P<0.0001)。在模式动物中初步确立了REGgamma与急性肠炎及其相关肿瘤发生发展的关系，并进一步发现了REGgamma与NF-KB通路的交互调控影响炎症的可能机制。本项目将结合生物信息学、分子生物学与炎症-肿瘤模式动物研究，重点探讨REGgamma蛋白酶体介导肠道炎症信号促进肿瘤干细胞增殖、导致肿瘤发生发展的机制，研究并绘制REGγ介导肠道炎症信号通路增强结肠癌发生发展的信号调控网络图谱。

非可控性炎性肠病在我国发病率逐年上升，由于反复发作，患者癌变风险不断升高，严重影响生活质量，目前尚无根治办法。结肠癌是常见的消化道恶性肿瘤之一，全世界结肠癌的发病率处于恶性肿瘤的第三位。因此结肠炎症恶变已经成为世界性的一个健康难题。如何从源头控制炎性肠病的进展已成为目前基础和临床研究的重点。本课题发现组前期采用生物信息学方法发现蛋白酶体激活因子REGgamma 在溃疡性结肠炎中显著高表达（P<0.0001)。在模式动物中初步确立了REGgamma与急性肠炎及其相关肿瘤发生发展的关系，并进一步发现了REGgamma与NF-KB通路的交互调控影响炎症的可能机制。本项目结合生物信息学、分子生物学与炎症-肿瘤模式动物研究，确定REGgamma通过调节Hippo-YAP信号通路参与结肠癌的发病机制。并绘制了REGgamma介导肠道炎症信号通路增强结肠癌发生发展的信号调控网络图谱，为明确REGgamma参与结肠癌病理发生发展的基础和临床机制研究提供了重要的线索。