Mechanisms Driving Metabolic Shifts in the Intestinal Epithelium

驱动肠上皮代谢变化的机制

• 批准号: 10390788
• 负责人: MICHAEL P. VERZI
• 金额: $ 41.95万
• 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/10390788
• 关键词: 3-Dimensional; Adult; Automobile Driving; Binding; Binding Proteins; Binding Sites; Biogenesis; Biological Assay; 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; Epithelial Cells; Exposure to; Fatty Acids; Gene Expression; 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; Natural regeneration; Nuclear Receptors; Nutrient; Organogenesis; Organoids; Oxidative Phosphorylation; Oxygen; Pathologic; Play; Process; Proteomics; Regulation; Reporting; Research; Respiration; Role; Shapes; Source; Stress; Testing; Therapeutic; Tissues; Transitional Epithelium; Up-Regulation; Villus; Work; YY1 Transcription Factor; base; cell type; 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; obesity risk; obesogenic; oxidation; 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均匀的代谢状态。代谢转移参加 成人茎 - 晶状体体内稳态期间的过渡。代谢转移也发生在响应伤害和 结肠癌。这项研究的长期目标是定义目标的代谢调节过程以治疗 肠道疾病和疾病。该提案的直接目标是定义监管 在上皮细胞寿命中控制代谢转移的机制。 Ox-Phos基因表达水平高肠道干细胞，隐窝低，在绒毛中最高。 Ox-Phos基因的动态表达与上皮的代谢转变相似。但是， 在肠道上上皮细胞转变过程中应对细胞代谢的机制尚不清楚。我们 已经生成了新的小鼠模型，以识别有助于上皮代谢的转录因子。 拟议的研究的目标1将深入研究，以确定转录因子yy1如何促进 驱动电子传输链的基因的表达。我们将测试YY1调节的假设 增强剂促启动子染色质循环以促进线粒体所需的这些关键基因的表达 呼吸。我们还将检验以下假设，即YY1在肠道干细胞中的功能差异 后代在隐窝或绒毛肠肠细胞中。将雇用最先进的表观基因组和蛋白质组学测定 在新型鼠标模型的背景下。我们预计这些监管机制对于驾驶很重要 在组织损伤/再生期间暴露于低氧环境时发生的代谢转移 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 损坏YY1是否控制适应组织再生的代谢转移。 AIM 2将考虑调节线粒体呼吸的重要能源 - 脂肪酸 氧化。我们将测试HNF4转录因子促进脂肪酸氧化以支持的假设 肠干细胞更新。代谢组学，表观基因组学和基于器官的测定法的结合将是 使用新型鼠标模型。我们将进一步检验与雌激素相关受体的假设 是HNF4的重要且新颖的伴侣因素，HNF4和ESRRA共同塑造了响应 肠上皮响应饮食脂肪的变化。据我们所知，这些研究将提供 核心肠道转录因子调节网络与代谢状态之间的第一个连接 肠干所必需的。饮食过多会增加肥胖症和结肠癌的风险。我们的研究将 将田间向前移动，以链接饮食和代谢物如何与转录调节性相交 肠上皮的机理。这些研究将共同​​揭示代谢过渡的方式 在正常体内稳态和病理情况下（上皮）在肠道中受到调节 再生或在高脂饮食下）。