肠胶质细胞在溃疡性结肠炎炎症-肿瘤序列演进过程中的作用及其机制研究

Ulcerative colitis (UC) is a high risk factor associated with colorectal cancer. Our previous study showed that although the number of entric glial cell was decreased in ulcerative colitis, EGC still played key role in maintaining the enteric mucosa barrier integrity via secreting the glia-derived-neurotrophic- factor,which plays a role in anti-inflammation and anti-apopotosis of epithelial cells.It is reported that ablation of EGC in mice results in and can mimic the manifestations of human ulcerative colitis, which includes hemorrhage, ulcer and infiltration of inflmmatory cells in colon.The proliferation of colonic carcinoma cells is inhibited by decreased EGC network in colonic carcinoma tissues and EGC in vitro.It is infered that EGC is gradually diminished but may exert protective effects on the whole process from ulcerative colitis, atypical hyperplasia to colon carcinoma.To verify our hypothesis we plan to perform a series of experiments as follows.First we investigate the dynamic changes of EGC in mice model of colitis-associated-cancer,which is induced by intraperitoneal injection of AOM before free drinking water with 2% dextran sulfate sodium,Then we will isolate enteric glial cells and co-culture them with either epithelial cells or colonic carcinoma cells to determine the effect of EGCs on the growth of these cells. We will further observe whether or how EGCs influence the growth of xenograft tumors in nude mice.All together,our study will elucidate the mechanism underlying the pathogenesis of ulcerative colitis and its cancerization,idetify the role of enteric glia in the proceeding of ulcerative colitis from inflammation to cancer,and provide a clue for the prevent and therapy of ulcerative colitis and colonic cancer.

溃疡性结肠炎是结肠癌的高危因素之一。我们的前期研究显示，肠胶质细胞(EGC)在急性溃疡性结肠炎时其数目减少，但是可通过分泌肠胶质细胞源性神经生长因子抗炎，抗上皮细胞凋亡而维护肠粘膜屏障完整。结合文献报道，抹除（Ablate）小鼠EGC引发肠组织出血、溃疡、炎性细胞浸润等类人类炎症性肠病表现，结肠癌组织中EGC网络显著减少及体外EGC可抑制结肠癌细胞增殖。我们推测在溃疡性结肠炎炎症-不典型增生-癌症序列演进过程中EGC发挥保护性作用，只是数目逐渐减少。我们拟构建AOM/DSS结肠炎相关结肠癌小鼠模型动态观察EGC变化；通过小鼠腹腔注射EGC培养上清观察EGC对炎-癌进程的影响；分离EGC分别与肠上皮细胞，小鼠结肠癌细胞共培养，并通过裸鼠移植瘤实验体内外探讨EGC的作用及其机制。旨在阐明溃疡性结肠炎癌变的机制，明确EGC在炎症-癌变过程中的作用，为溃疡性结肠炎及其癌变的防治提供新的选择。

溃疡性结肠炎是结肠癌的高危因素之一。申请人前期研究显示，肠胶质细胞(EGC)在急性溃疡性结肠炎时其数目减少，但是可通过分泌肠胶质细胞源性神经生长因子抗炎，抗上皮细胞凋亡而维护肠粘膜屏障完整。这些结果初步表明EGC在溃疡性结肠炎炎症-不典型增生-癌症序列演进过程中发挥重要作用。本项目在前期工作基础上，通过构建AOM/DSS结肠炎相关结肠癌小鼠模型并动态观察EGC在结肠炎炎症-肿瘤序列演进过程中的作用，发现EGC可降低血清炎症细胞因子水平，升高血清NGF、GDNF水平，其机制可能与其抑制IKKβ/NF-κB有关。此外，可能通过调控PTEN-PI3K/AKT途径抑制上皮细胞凋亡，增加ZO-1表达从而降低肠粘膜通透性，减缓炎症-不典型增生-癌变的进程。此外，通过将EGC与IEC-6细胞共培养发现EGC可以促进肠上皮细胞的增殖，抑制其凋亡，并且通过促进紧密连接蛋白ZO-1和E-cadherin的表达维护肠粘膜屏障的完整性。从而进一步阐述EGC在炎-癌演进过程中的作用及其机制，丰富、补充溃疡性结肠炎、结直肠癌的发病机制研究，为其预防、治疗筛选提供了新的靶点。项目资助已经发表论文5篇，接收待刊出2篇，在审2篇。含SCI一篇，三篇SCI文章在外审中。培养硕士生4名，其中3名已经取得硕士学位，1名在读。项目投入经费75万元，支出53.793663万元，各项支出基本与预算相符。剩余经费21.206337万元，剩余经费计划用于本项目后续研究支出。