Metabolic regulation of intestinal stem cell homeostasis

肠道干细胞稳态的代谢调节

• 批准号: 10463558
• 负责人: Jared P Rutter
• 金额: $ 44.59万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463558
• 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; 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

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一种代谢程序，该程序与大多数终端分化不同 细胞，其中较小的糖酵解产物丙酮酸的比例被转运到线粒体和 氧化。通过最近的合作研究，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），该载体介导了线粒体 丙酮酸进入。实现了这一突破之后，我们现在可以检验假设，首先提出 大约40年前，MPC的损失是降低线粒体丙酮酸氧化的一部分的基础 在癌症中观察到。我们已经产生了大量的初步数据，以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，类似于启用MPC初始发现的方法 肠道器官培养，果蝇的强大优势以及癌症的小鼠模型和 肠内稳态。利用这种方法，我们打算检验线粒体丙酮酸的假设 氧化是必要的，足以维持适当的干细胞稳态，并且可以发挥作用 在结肠肿瘤发生中的作用。我们将通过定义机械基础的三个特定目的来做到这一点 MPC在指导肠道干细胞命运和肿瘤发生倾向的调节和功能 以及定义这些机制在完整动物模型中的影响。此信息将建立一个新的 了解核心代谢途径如何直接影响启动和发展的框架 结肠肿瘤。

项目成果

Functional analysis of Aarf domain-containing kinase 1 in Drosophila melanogaster.

果蝇中含有 Aarf 结构域的激酶 1 的功能分析。

• DOI: 10.1002/dvdy.66
• 发表时间: 2019
• 期刊: Developmental dynamics : an official publication of the American Association of Anatomists
• 作者: Wisidagama,DonaR;Thomas,StefanM;Lam,Geanette;Thummel,CarlS
• 通讯作者: Thummel,CarlS

Stressed to death: Mitochondrial stress responses connect respiration and apoptosis in cancer.

• DOI: 10.1016/j.molcel.2022.07.012
• 发表时间: 2022-09-15
• 期刊: MOLECULAR CELL
• 影响因子: 16
• 作者: Winter, Jacob M.;Yadav, Tarun;Rutter, Jared
• 通讯作者: Rutter, Jared