The Role of Ceramides in the Intestinal Stem Cell

神经酰胺在肠干细胞中的作用

• 批准号: 10623315
• 负责人: Bruce Alexander Edgar
• 金额: $ 51.21万
• 依托单位: UNIVERSITY OF UTAH
• 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/10623315
• 关键词: Ablation; Adenocarcinoma; Amino Acids; Anabolism; Architecture; Automobile Driving; CRISPR interference; CRISPR-mediated transcriptional activation; Cancerous; Carbohydrates; Cell Survival; Cells; Cellular Metabolic Process; Ceramides; Chronic; Cues; Data; Detergents; Diet; Dietary Fats; Drosophila genus; Dyslipidemias; Enzymes; Epithelium; FABP1 gene; Fatty Acid-Binding Protein 1; Fatty Acids; Gastrointestinal Neoplasms; Gastrointestinal tract structure; Genes; Genetic; Genetic Transcription; Glucose; Growth; High Fat Diet; Human; Hyperplasia; Individual; Inflammation; Intestines; Knockout Mice; Lesion; Link; Lipids; Macronutrients Nutrition; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mediating; Metabolic; Metabolism; Midgut; Mus; Natural regeneration; Nutrient; Nutritional; Obesity; Organoids; PPAR alpha; Palmitates; Palmitoyl Coenzyme A; Permeability; Physical condensation; Play; Proliferating; Risk; Role; Science; Serine; Signal Transduction; Sphingolipids; Structure; Testing; Tissues; Transgenic Mice; Tumor Burden; Tumorigenicity; Work; base; cancer therapy; cell behavior; conditional knockout; crypt cell; deprivation; detection of nutrient; dietary; epithelium regeneration; fatty acid oxidation; fly; gastrointestinal; glucose metabolism; gut health; improved; intestinal epithelium; intestinal villi; lipid metabolism; mouse model; novel; novel therapeutic intervention; obesogenic; oxidation; pharmacologic; programs; protein metabolism; response; scaffold; serine palmitoyltransferase; stem cell proliferation; stem cells; stemness; tissue regeneration; tumor; tumorigenesis; uptake

SUMMARY Exposing cells to excessive amounts of lipid and other nutrients promotes the accumulation of sphingolipids such as ceramides, which alter tissue metabolism to help cells adapt to the abundance of excessive, detergent-like fatty acids (Chaurasia et al., Science, 2019). Studies described herein reveal that ceramides play particularly prominent roles in the gastrointestinal tract, where they increase fatty acid uptake into intestinal stem cells to promote regeneration of the intestinal epithelium. Using organoid, fly, and mouse models, we will dissect the mechanisms linking these sphingolipids to the control of intestinal stem cell metabolism, proliferation, and differentiation. Moreover, we will explore the contribution of sphingolipids as signals of lipid excess that drive gastrointestinal tumorigenesis and invasiveness. Findings obtained from these studies could uncover new nutrient-sensing machinery that modulates intestinal stem cell proliferation and leads to new pharmacological approaches for manipulating sphingolipids to improve gut health.

总结 将细胞暴露于过量的脂质和其他营养物质会促进鞘脂的积累， 作为神经酰胺，它改变组织代谢，帮助细胞适应过量的，清洁剂样的 脂肪酸（Chaurasia等人，Science，2019）.本文所述的研究表明，神经酰胺特别起作用， 在胃肠道中发挥重要作用，增加肠道干细胞对脂肪酸的摄取， 促进肠上皮再生。使用类器官、苍蝇和小鼠模型，我们将解剖 将这些鞘脂与控制肠干细胞代谢、增殖和 分化此外，我们将探讨鞘脂作为脂质过剩信号的贡献， 胃肠道肿瘤发生和侵袭性。从这些研究中获得的结果可以揭示新的 营养感应机制，调节肠道干细胞增殖，并导致新的药理学 操纵鞘脂以改善肠道健康的方法。