The influence of HIF-prolyl hydroxylase-2 during colitis and inflammation-associated colorectal carcinogenesis in mice

炎症性肠病(IBD)是一种病理严重、治疗选择有限的疾病。虽然IBD的根本原因仍不清楚，但其根本缺陷涉及肠上皮屏障功能的丧失。此外，IBD也会极大地增加患结直肠癌(CRC)的风险。重要的是，相对于正常的健康组织，这些炎症和/或肿瘤部位是低氧的，以前已经证明这种情况可能对疾病的最终结果有害。在这些复杂过程中的中心角色是HIF脯lyl羟基酶(PhDS)；氧感受器不仅被证明调节缺氧诱导因子(HIF)，而且还干扰NFkB和TGFb途径。虽然已经证明，在葡聚糖硫酸钠(DSS)诱导的IBD小鼠模型中，一般的PHD抑制可以起到保护作用，但我们的初步数据强烈表明，不同细胞系中PHD2缺乏的小鼠比它们的WT后代更容易受到影响。在这个项目中，我们建议揭开这种敏感性的细胞和分子背景。因此，我们将利用我们在艾美诺太计划期间培育的不同的单条件和双条件基因敲除小鼠(PHD2/HIFA)或通过卓有成效的合作获得的小鼠(EPO-TG6)。除了HIF，作为主要的下游介质，我们还将使用不同的体内和体外方法关注上述其他途径。在化学/炎症诱导的结直肠癌(AOM/DSS)模型中，我们能够检测到在其肠道上皮细胞中缺乏PHD2的小鼠的肿瘤发展减少。这些初步实验的结果与我们早先的发现一致，表明该酶具有促肿瘤的性质。因此，这个项目的第二条线将集中在肿瘤启动和繁殖过程中PHD2效应的解体。此外，鉴于我们计划在Heisenberg计划期间开展跨学科研究合作(详情请参阅Heisenberg申请)，我们还将能够使用来自溃疡性结肠炎和结肠炎相关异型增生和癌症患者的令人印象深刻的样本收集。因此，这将使我们有机会将我们在不同小鼠模型中的发现与人类的结肠相关病理联系起来。

Inflammatory bowel disease (IBD) is a disorder with severe pathology and limited therapeutic options. Although the underlying causes of IBD remain largely undefined, the fundamental defect involves a loss of intestinal epithelial barrier function. Furthermore, IBD is a condition that also greatly increases the risk of colorectal cancer (CRC).Importantly, these inflamed and/or tumor sites are hypoxic relative to normal healthy tissue, and it has been shown before that this condition can be detrimental to the final outcome of the disease. Central players in these complex processes are the HIF prolyl hydroxylases (PHDs); oxygen sensors that have not only been shown to regulate hypoxia inducible factor (HIFs), but also interfere in the NFkB and TGFb pathway. Although it has been demonstrated that general PHD-inhibition can be protective in a mouse model of dextran sodium sulphate (DSS)-induced IBD, our preliminary data strongly suggest that mice deficient for PHD2 in different cell lineages are much more susceptible than their WT littermates.With this project we propose to unravel the cellular and molecular background of this sensitivity. Therefore, we will make use of our unique collection of different single and double conditional knock-out mice (PHD2/HIFas) that we developed during the Emmy Noether program or mice obtained through fruitful collaborations (EPO-Tg6). Next to HIF, as the main downstream mediator, we will also focus on the other aforementioned pathways using different in vivo and ex vivo approaches.In a model of chemically/inflammatory induced CRC (AOM/DSS), we were able to detect reduced tumor development in mice lacking PHD2 in their intestinal epithelial cells. The results of these initial experiments are in line with our earlier findings showing the pro-tumoral nature of the enzyme. The second line of this project will therefore be focused on the unraveling of the PHD2 effect during tumor initiation and propagation.Moreover, in view of the interdisciplinary research collaboration we plan to develop during the Heisenberg program (please see the Heisenberg application for details), we will also be able to use an impressive collection of samples from patients with ulcerative colitis and colitis-associated dysplasia and cancer. Thus, this will give us the opportunity to link our findings in the different mouse models to colon-related pathologies in humans.