Mechanisms Driving Metabolic Shifts in the Intestinal Epithelium

驱动肠上皮代谢变化的机制

• 批准号: 10623339
• 负责人: MICHAEL P. VERZI
• 金额: $ 40.61万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623339
• 关键词: 3-Dimensional; Adult; Automobile Driving; Binding; Binding Proteins; Binding Sites; Biogenesis; Biological Assay; Cell Line; Cell Respiration; Cells; Cellular Metabolic Process; Chromatin Loop; Colon Carcinoma; Data; Development; Diet; Dietary Fats; Disease; ERR1 protein; Electron Transport; Energy-Generating Resources; Enhancers; Enterocytes; Environment; Epithelial Cells; Epithelium; Exposure to; Fatty Acids; Gene Expression; Gene Expression Regulation; Genes; Genetic Models; Genetic Transcription; Genome; Glycolysis; Goals; HNF4A gene; Health; High Fat Diet; Homeostasis; Human; Infection prevention; Intestinal Diseases; Intestines; Knock-out; Knockout Mice; Link; Literature; Longevity; Malignant Neoplasms; Mediating; Metabolic; Metabolic Control; Metabolism; Mitochondria; Muscle; Natural regeneration; Nuclear Receptors; Organogenesis; Organoids; Oxidative Phosphorylation; Oxygen; Pathologic; Play; Process; Proteomics; Regulation; Reporting; Research; Respiration; Role; Shapes; Source; Stress; Testing; Therapeutic; Tissues; Up-Regulation; Villus; Work; YY1 Transcription Factor; cell regeneration; cell type; cofactor; dietary; dietary excess; enzyme activity; epigenomics; epithelium regeneration; estrogen-related receptor; fatty acid oxidation; fetal; insight; intestinal epithelium; metabolomics; mouse model; mutant mouse model; new technology; novel; nutrient absorption; obesity risk; obesogenic; oxidation; paralogous gene; promoter; regenerative; repaired; response; response to injury; stem; stem cell division; stem cells; stemness; tissue regeneration; transcription factor; tumorigenesis

Cells of intestinal epithelium do not exhibit a uniform metabolic state. Metabolic shifts accompany transitions during adult stem-crypt-villus homeostasis. Metabolic shifts also occur in response to injury and in colon cancer. The long term goal of this research is to define targetable metabolic regulatory processes to treat diseases and disorders of the intestine. The immediate goal of this proposal is to define the regulatory mechanisms that govern metabolic shifts during the epithelial cell lifespan. OX-PHOS gene expression levels are high in intestinal stem cells, low in crypts, and highest in villus. Dynamic expression of OX-PHOS genes parallels the metabolic transitions of the epithelium. However, the mechanisms regulating cellular metabolism during epithelial cell transitions in the intestine are unclear. We have generated new mouse models that identify transcription factors contributing to epithelial metabolism. Aim 1 of the proposed studies will drill down to identify how the transcription factor, YY1, promotes expression of genes that drive the electron transport chain. We will test the hypothesis that YY1 regulates enhancer-promoter chromatin looping to promote expression of these key genes required for mitochondrial respiration. We will also test the hypothesis that YY1 function differs in intestinal stem cells versus in their progeny in crypts or in villus enterocytes. State-of-the-art epigenomic and proteomic assays will be employed in the context of novel mouse models. We expect these regulatory mechanisms are important to drive metabolic shifts that occur upon exposure to low oxygen environments during tissue damage/regeneration or in oncogenesis. Therefore, we will also investigate these regulatory mechanisms in regenerative foci after tissue damage to discern whether YY1 controls the metabolic shifts that accompany tissue regeneration. Aim 2 will look at regulation of an important energy source for mitochondrial respiration – fatty acid oxidation. We will test the hypothesis that HNF4 transcription factors promote fatty acid oxidation to support intestinal stem cell renewal. A combination of metabolomics, epigenomics, and organoid-based assays will be employed, using novel mouse models. We will further test the hypothesis that the Estrogen-Related Receptor is an important and novel partner factor of HNF4, and that together, HNF4 and ESRRA shape the response of the intestinal epithelium in response to a change in dietary fat. To our knowledge, these studies would provide the first link between the core intestinal transcription factor regulatory networks and the metabolic state required for intestinal stemness. Excess dietary fat increases risk for obesity and colon cancer. Our studies will move the field forward in linking how diet and metabolites can intersect with the transcriptional regulatory mechanisms of the intestinal epithelium. Together, these studies will reveal how metabolic transitions are regulated in the intestine during normal homeostasis, as well as under pathological situations (epithelial regeneration or under high-fat diet).

肠上皮细胞不表现出统一的代谢状态。代谢变化伴随 成体茎-隐窝-绒毛稳态过程中的转变。代谢变化也会因受伤而发生 结肠癌。这项研究的长期目标是确定有针对性的代谢调节过程来治疗 肠道疾病和紊乱。该提案的直接目标是定义监管 控制上皮细胞寿命期间代谢变化的机制。 OX-PHOS 基因表达水平在肠干细胞中较高，在隐窝中较低，在绒毛中最高。 OX-PHOS 基因的动态表达与上皮的代谢转变平行。然而， 肠道上皮细胞转变期间调节细胞代谢的机制尚不清楚。我们 已经建立了新的小鼠模型，可以识别有助于上皮代谢的转录因子。 拟议研究的目标 1 将深入研究转录因子 YY1 如何促进 驱动电子传递链的基因的表达。我们将检验 YY1 调节的假设 增强子-启动子染色质环化以促进线粒体所需的这些关键基因的表达 呼吸。我们还将检验 YY1 功能在肠干细胞中与其在肠道干细胞中不同的假设。 隐窝或绒毛肠细胞中的后代。将采用最先进的表观基因组和蛋白质组检测 在新型小鼠模型的背景下。我们预计这些监管机制对于推动 在组织损伤/再生期间或在暴露于低氧环境时发生的代谢变化 肿瘤发生。因此，我们还将研究组织后再生灶中的这些调节机制。 损伤来辨别 YY1 是否控制伴随组织再生的代谢变化。 目标 2 将着眼于线粒体呼吸重要能源——脂肪酸的调节 氧化。我们将检验 HNF4 转录因子促进脂肪酸氧化的假设，以支持 肠道干细胞更新。代谢组学、表观基因组学和基于类器官的检测相结合 雇用，使用新颖的小鼠模型。我们将进一步检验雌激素相关受体的假设 是 HNF4 的一个重要且新颖的伙伴因子，HNF4 和 ESRRA 共同塑造了以下反应： 肠上皮对膳食脂肪变化的反应。据我们所知，这些研究将提供 核心肠道转录因子调控网络与代谢状态之间的第一个联系 肠干性所必需的。膳食脂肪过多会增加肥胖和结肠癌的风险。我们的研究将 推动该领域向前发展，将饮食和代谢物如何与转录调控相结合 肠上皮的机制。这些研究将共同​​揭示代谢转变是如何发生的 在正常稳态以及病理情况下（上皮细胞）在肠道中受到调节 再生或高脂肪饮食下）。