Metabolic regulation of intestinal stem cell homeostasis

肠道干细胞稳态的代谢调节

基本信息

批准号：
10189530
负责人：
Jared P Rutter
金额：
$ 45.5万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10189530
关键词：
Acetyl Coenzyme A Agar Amino Acids Animal Model Animals Architecture Automobile Driving Biochemical Pathway Biological Models Cancer Model Carbon Cell Compartmentation Cell Culture Techniques Cell Differentiation process Cell model Cell physiology Cells Citric Acid Cycle Colon Colon Adenocarcinoma Colon Carcinoma Colonic Neoplasms Colorectal Cancer Consumption Cytoplasm Data Diet Drosophila genus Drosophila melanogaster Energy Metabolism Enzymes Exhibits Gene Expression Genetic Genetic Models Genetic study Glycolysis Health Histones Hyperplasia Impairment Instruction Intestines LGR5 gene Laboratories Malignant Neoplasms Mammalian Cell Mediating Metabolic Metabolic Control Metabolic Pathway Metabolism Mitochondria Mus Organoids Oxides Pharmacology Phenotype Physiological Play Positioning Attribute Production Pyruvate Pyruvate Metabolism Pathway Regulation Role Signal Transduction Solid Neoplasm Testing Warburg Effect Work aerobic glycolysis beta catenin cancer cell fatty acid oxidation fly gain of function inhibitor/antagonist intestinal homeostasis loss of function mouse model oxidation programs pyruvate carrier response stem cell biomarkers stem cell division stem cell fate stem cell homeostasis stem cell proliferation stem cell self renewal stem cells stemness tumor tumor growth tumor initiation tumor progression tumor xenograft tumorigenesis

项目摘要

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.

概括许多癌症和干细胞表现出与大多数终末分化不同的代谢程序细胞，其中较小部分的糖酵解产物丙酮酸被转运到线粒体中并且被氧化。通过最近的一项合作研究，Rutter 和 Thummel 实验室最近发现转运蛋白的身份，称为线粒体丙酮酸载体（MPC），它介导线粒体丙酮酸进入。取得这一突破后，我们现在可以检验最初提出的假设大约 40 年前，MPC 的缺失是线粒体丙酮酸氧化减少的一部分原因在癌症中观察到。我们已经生成了重要的初步数据来支持结肠的这一假设癌症，我们的数据表明肠道干细胞可能表现出相同的现象。我们建议采用一种多系统方法，类似于最初发现 MPC 的方法，该方法使用肠道类器官培养、果蝇和癌症小鼠模型的强大优势肠道稳态。利用这种方法，我们打算检验线粒体丙酮酸的假设氧化对于维持适当的干细胞稳态是必要且充分的，并且可以发挥指导性作用在结肠肿瘤发生中的作用。我们将通过三个具体目标来实现这一目标，这些目标定义了 MPC 在指导肠道干细胞命运和肿瘤发生倾向中的调节和功能以及定义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用于理解核心代谢途径如何直接影响代谢的启动和进展的框架结肠肿瘤。