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

炎症性肠病（IBD）是一种病理严重且治疗选择有限的疾病。尽管IBD的潜在病因仍未明确，但其基本缺陷涉及肠上皮屏障功能的丧失。此外，IBD也是一种大大增加结直肠癌（CRC）风险的疾病。重要的是，这些发炎和/或肿瘤部位相对于正常健康组织是缺氧的，并且之前已经证明这种情况可能对疾病的最终结果有害。这些复杂过程的核心参与者是HIF脯氨酸羟化酶（PHDs）；氧传感器不仅可以调节缺氧诱导因子（hif），还可以干扰NFkB和TGFb通路。虽然已经证明一般的博士抑制对右旋糖酐硫酸钠（DSS）诱导的IBD小鼠模型具有保护作用，但我们的初步数据强烈表明，不同细胞系中缺乏PHD2的小鼠比它们的WT幼崽更容易受到影响。通过这个项目，我们打算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项目中开发的不同的单和双条件敲除小鼠（PHD2/HIFas）或通过富有成效的合作获得的小鼠（EPO-Tg6）的独特收集。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CRC （AOM/DSS）模型中，我们能够检测到肠道上皮细胞中缺乏PHD2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，这个项目的第二部分将集中在揭示PHD2在肿瘤发生和传播过程中的作用。此外，鉴于我们计划在Heisenberg项目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、结肠炎相关发育不良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.