Metabolic regulation of intestinal stem cell homeostasis

总结 许多癌症和干细胞表现出与大多数终末分化的细胞不同的代谢程序， 细胞，其中较小部分的糖酵解产物丙酮酸盐被转运到线粒体中， 被氧化了通过最近的一项合作研究，Rutter和Thummel实验室最近发现了 转运蛋白的身份，称为线粒体丙酮酸载体（MPC），其介导线粒体丙酮酸转运。 丙酮酸进入取得这一突破后，我们现在可以检验第一次提出的假设， 大约40年前，MPC的丢失是线粒体丙酮酸氧化减少的一部分的基础 在癌症中观察到。我们已经产生了重要的初步数据，以支持这一假设，结肠 我们的数据表明，肠道干细胞可能表现出同样的现象。我们建议 采用多系统方法，类似于启用MPC的初始发现的方法，该方法使用 肠道类器官培养、黑腹果蝇和小鼠癌症模型的强大优势， 肠内稳态利用这种方法，我们打算测试线粒体丙酮酸的假设， 氧化是必要的，足以维持适当的干细胞稳态， 在结肠癌发生中的作用。我们将通过三个具体目标来实现这一点，这些目标定义了 MPC在指导肠干细胞命运和肿瘤发生倾向中的调节和功能， 并确定这些机制在完整动物模型中的影响。这些信息将建立一个新的 理解核心代谢途径如何直接影响疾病的发生和发展的框架 结肠肿瘤

Summary Many cancer and stem cells exhibit a metabolic program that is distinct from most terminally differentiated cells, wherein a smaller fraction of the glycolytic product pyruvate is transported into the mitochondria and oxidized. Through a recent collaborative study, the Rutter and Thummel laboratories recently discovered the identity of the transporter, known as the Mitochondrial Pyruvate Carrier (MPC), which mediates mitochondrial pyruvate entry. Having made this breakthrough, we are now in position to test the hypothesis, first proposed about 40 years ago, that loss of the MPC underlies a portion of the decreased mitochondrial pyruvate oxidation observed in cancers. We have generated significant preliminary data in support of this hypothesis for colon cancers, and our data suggests that intestinal stem cells might exhibit the same phenomenon. We propose to employ a multi-system approach, similar to the one that enabled the initial discovery of the MPC, that uses the powerful strengths of intestinal organoid culture, Drosophila melanogaster, and mouse models of cancer and intestinal homeostasis. Utilizing this approach, we intend to test the hypothesis that mitochondrial pyruvate oxidation is necessary and sufficient to maintain appropriate stem cell homeostasis and can play an instructive role in colon oncogenesis. We will do this through three specific aims that define the mechanistic basis for the regulation and function of the MPC in instructing intestinal stem cell fate and the propensity of oncogenesis as well as define the impact of those mechanisms in intact animal models. This information will establish a new framework for understanding how core metabolic pathways can directly impact the initiation and progression of colon tumors.