Functional role of PGAM5 in epithelial homeostasis and colorectal cancer

PGAM5 在上皮稳态和结直肠癌中的功能作用

• 批准号: 414209099
• 负责人: Professor Dr. Christoph Becker
• 金额: --
• 依托单位: Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/414209099?language=en
• 关键词: Functional; role; PGAM5; epithelial; homeostasis

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.

结直肠癌（CRC）是全球第二大癌症死亡原因。除了自发发生的结直肠癌（特别是老年患者）之外，炎症性肠病（IBD）患者患结直肠癌的风险也会增加。 CRC 和 IBD 均通过知之甚少的机制发生在遗传易感个体中，并涉及肠上皮稳态失调。我们已经确定 PGAM5 分子是肠道稳态和细胞存活的新关键因素。 PGAM5 是一种线粒体磷酸酶，可能作为连接多种细胞死亡途径与线粒体应激和动力学的平台。PGAM5 缺陷的动物更容易发生上皮细胞死亡和肠道组织稳态丧失。值得注意的是，我们的初步研究结果和初始蛋白质组学数据表明 PGAM5 在 CRC 发展中的作用。我们的数据表明 PGAM5 在人类和小鼠 CRC 中均强烈上调。 PGAM5 缺陷的癌细胞表现出 Wnt/β-连环蛋白信号显着减少。因此，根据我们的初步数据，我们假设 PGAM5 在 CRC 和肠道稳态​​中发挥重要作用。然而，PGAM5发挥这些功能的分子机制以及参与这些过程的信号通路仍有待明确。为了更好地了解 PGAM5 在肠道组织稳态和结直肠癌发展中的功能作用，我们寻求使用 CRC 实验小鼠模型来研究 PGAM5，并确定 PGAM5 在肠上皮细胞中的相关途径和相互作用伙伴。在四个工作包中，我们将首先确定 PGAM5 在肠上皮细胞稳态以及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PGAM5调控的基因和通路。最后，在转化方法中，我们将使用患者组织和复杂的异种移植模型来评估我们的发现与人类结直肠癌的相关性。我们的最终目标是更好地了解 PGAM5 在组织稳态和结直肠癌中的功能。我们有信心揭示影响 CRC 中 PGAM5 表达或功能是否可能具有治疗效果。