p55PIK特异性抑制剂N24通过抑制血管生成治疗炎症性肠病的研究

Angiogenesis play an importation role in the development of IBD. Anti-angiogenesis is an important way for the treatment of IBD. However, it is lack of effective clinical angiogenesis inhibitors for the treatment of IBD at present. Our preliminary experiment found that the expression of p55PIK in colon tissue and the expression of VEGF-A in IBD patients increased significantly. p55PIK could stimulate the secretion of VEGF-A in colonic mucosa cells, and then promoted the proliferation, migration and tube formation of endothelial cells. N24, the inhibitor of p55PIK, could inhibit thus. Our previous animal experiments showed that N24 could significantly reduce the pathological changes of IBD. Based on this, we propose the hypothesis: N24 could treat IBD through the inhibition of angiogenesis. To test this hypothesis, we will explore the mechanisms of how N24 suppress angiogenesis and treat IBD through the level of molecular, clinical tissue samples and animal models. It will probably provide new ideas for the development of angiogenesis inhibitors to IBD in the future.

血管生成在炎症性肠病的发生发展中发挥重要作用，抗血管生成是治疗炎症性肠病的重要途径。目前临床上尚缺乏有效的治疗炎症性肠病的血管抑制剂。我们的预实验发现炎症性肠病患者结肠组织中p55PIK和血清中VEGF-A的表达明显升高，p55PIK可以促进结肠粘膜细胞分泌VEGF-A，继而促进内皮细胞的增值、迁移和成管，p55PIK的抑制剂N24可以抑制此过程。前期的动物实验显示N24可以明显减轻IBD的病理改变。基于此，我们提出假说：N24可以通过抑制血管生成治疗炎症性肠病。为了验证这一假说，我们通过分子细胞、临床组织标本和动物模型等水平多方面探讨N24抑制血管生成的机制和治疗炎症性肠病的作用和机制，这将可能为今后开发针对炎症性肠病的血管抑制剂提供新的思路。

炎症性肠病的治疗是临床上的一个难点，目前还没有针对炎症性肠病的理想用药。血管生成在炎症性肠病的发生发展过程中发挥重要作用，抑制血管生成是治疗炎症性肠病的重要途径。我们在细胞水平研究发现p55PIK的抑制剂N24可以通过负向调控内皮细胞的HIF-1α/VEGFA表达从而抑制内皮细胞的增殖、迁移和成管能力。我们提出假说：N24可以通过抑制血管生成从而对炎症性肠病发挥治疗性作用。在动物实验中我们建立了裸鼠炎症性肠病的模型。我们在动物实验中发现N24可以通过抑制血管生成发挥明显的治疗炎症性肠病的作用。本项目首次提出N24可能通过抑制血管生成继而治疗炎症性肠病，我们的研究成果可能为临床研究炎症性肠病的治疗药物提供新的思路。