泛素化酶WWP1在肠道炎性微环境中调控肠上皮细胞凋亡及恶性转化的作用机制研究

炎症相关的肠上皮细胞凋亡抵抗及恶性转化是结直肠癌发生的重要机制之一，其分子调控通路和关键靶点有待阐明。WWP1是一种与多种肿瘤发生相关的泛素化酶,我们前期报导了WWP1在结直肠癌组织中高表达并参与结直肠癌的进展，但其在结直肠癌发生中的作用未知。据此我们在不同的WWP1敲除小鼠中分别进行AOM/DSS肠道炎症造模，发现WWP1全身敲除和肠上皮细胞特异性敲除均可导致肠上皮细胞凋亡增加且肿瘤形成减少。后续预实验提示WWP1可能通过结合Smad7调控TGF-β通路进而影响肠上皮细胞凋亡和肿瘤形成。据此，本课题拟系统性利用基因敲除细胞与小鼠等模型，以期阐明WWP1在炎性微环境中调控肠上皮细胞凋亡抵抗及恶性转化的作用机制,验证肠上皮细胞中WWP1的相互作用蛋白和泛素化调控机制及下游关键作用通路和靶点，并初步探索靶向抑制WWP1对干预结直肠癌发生的效果，进而为结直肠癌发生提出新的机制和揭示新的治疗靶点。

Inflammation-related intestinal epithelial cell apoptosis resistance and malignant transformation is one of the most important mechanisms of colorectal cancer, but its molecular mechanism and target proteins remain unclarified. WWP1 is a ubiquitinating enzyme associated with various tumors. In our previous study, we found that WWP1 was highly expressed in colorectal cancer and participated in tumor progression, but its role in the development of colorectal cancer is unknown. Therefore, we constructed AOM/DSS model to simulate the chronic intestinal inflammation in different WWP1 knockout mice. We found that both WWP1 systemic knockout and intestinal epithelial cell-specific knockout could lead to increased intestinal epithelial cell apoptosis and reduced tumor formation. Further studies suggested that WWP1 might regulate TGF-β signaling pathway and intestinal epithelial cell apoptosis by binding with Smad7. Therefore, by using gene knockout cells and mice and other in vivo and in vivo models, we aim to clarify the role of WWP1 in intestinal epithelial cell apoptosis resistance and malignant transformation in the inflammatory microenvironment, and to verify the target proteins of WWP1 in intestinal epithelial cells, and to propose new mechanisms and therapeutic targets for colorectal cancer.