Functional role of PGAM5 in epithelial homeostasis and colorectal cancer

结直肠癌（CRC）是全球癌症死亡的第二大原因。除了CRC自发发展，特别是在老年患者中，炎症性肠病（IBD）患者患结直肠癌的风险增加。CRC和IBD都发生在遗传易感个体中，其机制知之甚少，并涉及肠上皮稳态失调。我们已经确定了PGAM 5分子作为一种新的肠道稳态和细胞存活的关键因素。PGAM 5是一种线粒体磷酸酶，可能作为一个平台，将几种细胞死亡途径与线粒体应激和动力学联系起来，PGAM 5缺陷的动物更容易发生上皮细胞死亡和肠道组织稳态的丧失。值得注意的是，我们的初步研究结果和初步蛋白质组学数据表明PGAM 5在CRC的发展中起作用。我们的数据表明，PGAM 5在人类和小鼠CRC中均强烈上调。PGAM 5缺陷型癌细胞显示Wnt/β-连环蛋白信号传导显著减少。基于我们的初步数据，我们因此假设PGAM 5在CRC和肠道稳态中起重要作用。然而，PGAM 5发挥这些功能的分子机制和参与这些过程的信号通路尚未确定。为了更好地了解PGAM 5在肠道组织稳态和结直肠癌发展中的功能作用，我们试图使用结直肠癌实验小鼠模型研究PGAM 5，并确定肠上皮细胞中PGAM 5的相关通路和相互作用伙伴。在四个工作包中，我们将首先确定PGAM 5在肠上皮细胞稳态和自发性和炎症依赖性结直肠癌实验模型中的功能作用。我们将进一步确定肠上皮细胞和癌细胞中PGAM 5调控的基因和途径。最后，在一个翻译的方法，我们将评估我们的研究结果的相关性，人类结直肠癌患者的组织和异种移植模型。我们的最终目标是更好地了解PGAM 5在组织稳态和结直肠癌中的功能。我们有信心揭示影响PGAM 5在CRC中的表达或功能是否可能是治疗有效的。

Colorectal cancer (CRC) is the second leading cause of death from cancer worldwide. Aside from CRC developing spontaneously, especially in elderly patients, there is an increased risk for colorectal cancer in patients with inflammatory bowel disease (IBD). Both CRC and IBD occur in genetically susceptible individuals through poorly understood mechanisms and involve dysregulation of intestinal epithelial homeostasis. We have identified the molecule PGAM5 as a novel key factor of gut homeostasis and cell survival. PGAM5 is a mitochondrial phosphatase which might serve as a platform connecting several cell death pathways to mitochondrial stress and dynamics.PGAM5-deficient animals were more susceptible to epithelial cell death and loss of gut tissue homeostasis. Of note, our preliminary findings and initial proteomics data suggest a role of PGAM5 in the development of CRC. Our data demonstrate that PGAM5 is strongly up-regulated in both human and mouse CRC. PGAM5-deficient cancer cells showed a significant reduction in the Wnt/ beta-catenin signaling. On the basis of our preliminary data, we therefore hypothesize that PGAM5 plays an important role in CRC and gut homeostasis. However, the molecular mechanism by which PGAM5 exerts these function and the signaling pathway involved in these processes are yet to be defined. In order to better understand the functional role of PGAM5 in gut tissues homeostasis and colorectal cancer development, we seek to study PGAM5 using experimental mouse models for CRC and to identify relevant pathways and interaction partners of PGAM5 in intestinal epithelial cells. In four work packages we will first identify the functional role of PGAM5 in intestinal epithelial cell homeostasis and in experimental models of spontaneous and inflammation-dependent colorectal cancer. We will further determine PGAM5 regulated genes and pathways in intestinal epithelial cells and cancer cells. Finally, in a translational approach we will evaluate our findings for the relevance to human colorectal cancer using patient tissues and a sophisticate xenograft model. Our ultimate goal is an improved understanding of the function of PGAM5 in tissue homeostasis and colorectal cancer. We are confident to uncover whether influencing PGAM5 expression or function in CRC might be therapeutically effective.