Metabolic Control of Hair Follicle Stem Cell Homeostasis and Tumorigenesis

毛囊干细胞稳态和肿瘤发生的代谢控制

基本信息

批准号：
10361228
负责人：
Heather Christofk
金额：
$ 41.55万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2018-03-12 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10361228
关键词：
Adult Biological Assay Cancer Biology Cell Proliferation Cell division Cells Cellular Metabolic Process Data Development Enzymes Epidermis Etiology Evolution Exhibits Gene Expression Profiling Genetically Engineered Mouse Glycolysis Hair Hair follicle structure Homeostasis Human Immune In Situ In Vitro Individual Investigation Lactate Dehydrogenase Light Maintenance Malignant - descriptor Malignant Neoplasms Mass Spectrum Analysis Metabolic Metabolic Control Metabolic Pathway Metabolism Modeling Multipotent Stem Cells Mutation Normal tissue morphology Oncogenic Oxidative Phosphorylation Pathology Pharmacology Phenocopy Play Process Regulation Role Squamous cell carcinoma TP53 gene Testing Time Tissues Tumor Suppressor Proteins Tumor-Associated Process Warburg Effect Work adult stem cell base cancer cell cell transformation cell type enzyme activity epidermis cell experimental study genetic manipulation glucose metabolism in vivo loss of function metabolic profile metabolomics migration mouse model new therapeutic target novel progenitor response self-renewal stem cell biology stem cell homeostasis stem cells tumor tumor initiation tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT The current project builds on our previous efforts to define and characterize cancer cells of origin within the epidermis. We demonstrated that hair follicle stem cells are cells of origin for squamous cell carcinoma, and that the inherent quiescence of these cells acts as a tumor suppressor mechanism. The current proposal seeks to understand the role metabolism plays in both maintaining HFSCs, and also in their ability to initiate tumorigenesis. Our preliminary data suggests that HFSCs possess a unique mode of metabolism, and we seek to understand if this metabolic state is necessary to maintain these cells as quiescent, multipotent stem cells. We will extend our characterization of HFSCs to include metabolomics approaches and determine whether alteration of metabolic pathways disrupts their self-renewal or differentiation. Furthermore, with our inducible tumor initiation model, we will be able to characterize the full extent of any metabolic transitions that occur in vivo for the first time. We expect that these experiments will uncover novel mechanisms that regulate HFSC biology, and perhaps even point towards new targeted therapeutics for HFSC initiated tumors.

项目概要/摘要当前的项目建立在我们之前定义和表征癌细胞起源的努力的基础上表皮。我们证明毛囊干细胞是鳞状细胞癌的起源细胞，并且这些细胞固有的静止状态起到了肿瘤抑制机制的作用。目前的提案试图了解新陈代谢在维持 HFSC 以及启动 HFSC 的能力中所扮演的角色肿瘤发生。我们的初步数据表明 HFSC 具有独特的代谢模式，我们试图了解这种代谢状态是否是维持这些细胞作为静止、多能干细胞所必需的细胞。我们将扩展 HFSC 的表征，包括代谢组学方法并确定代谢途径的改变是否会破坏它们的自我更新或分化。此外，通过我们的诱导肿瘤起始模型，我们将能够表征任何代谢转变的全部范围首次发生在体内。我们期望这些实验将揭示调节的新机制 HFSC 生物学，甚至可能指向针对 HFSC 引发的肿瘤的新靶向疗法。