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Mechanisms Driving Metabolic Shifts in the Intestinal Epithelium

驱动肠上皮代谢变化的机制

基本信息

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
项目类别：
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

项目摘要

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).

肠上皮细胞的代谢状态不一致。代谢变化伴随着