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

炎症性肠病（IBD）是一种具有严重病理学和有限治疗选择的疾病。虽然IBD的根本原因在很大程度上仍不明确，但基本缺陷涉及肠上皮屏障功能的丧失。此外，IBD是一种也会大大增加结直肠癌（CRC）风险的疾病。重要的是，这些炎症和/或肿瘤部位相对于正常健康组织是缺氧的，并且之前已经表明这种情况可能对疾病的最终结果有害。在这些复杂的过程中的中心球员是HIF脯氨酰羟化酶（PHD）;氧传感器，不仅被证明可以调节缺氧诱导因子（HIF），而且还干扰NF κ B和TGF β通路。虽然已经证明，一般的PHD抑制可以在葡聚糖硫酸钠（DSS）诱导的IBD小鼠模型的保护，我们的初步数据强烈表明，在不同的细胞系中的PHD 2缺陷的小鼠比他们的WT littermate.With这个项目，我们建议解开这种敏感性的细胞和分子背景。因此，我们将利用我们在Emmy Noether项目期间开发的不同单和双条件性敲除小鼠（PHD 2/HIFas）的独特集合或通过富有成效的合作获得的小鼠（EPO-Tg 6）。在化学/炎症诱导的CRC（AOM/DSS）模型中，我们能够检测到肠上皮细胞中缺乏PHD 2的小鼠肿瘤发展减少。这些初步实验的结果与我们早期的发现一致，显示了酶的促肿瘤性质。因此，本项目的第二部分将致力于揭示PHD 2在肿瘤发生和增殖过程中的作用。此外，鉴于我们计划在海森伯计划期间开展的跨学科研究合作（请参阅海森伯申请），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。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结肠相关的病理联系起来。

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.