The Role of Ceramides in the Intestinal Stem Cell

神经酰胺在肠干细胞中的作用

基本信息

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
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/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

项目摘要

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.

概括暴露细胞过量脂质和其他营养素会促进鞘脂的积累。作为神经酰胺，改变组织代谢以帮助细胞适应丰富的过度，清洁剂样脂肪酸（Chaurasia等，Science，2019年）。本文描述的研究表明，神经酰胺尤其发挥在胃肠道中的突出作用，在那里它们增加了脂肪酸吸收到肠道干细胞中促进肠上皮的再生。使用器官，飞行和鼠标模型，我们将剖析将这些鞘脂与控制肠道干细胞代谢，增殖和控制的机制分化。此外，我们将探索鞘脂的贡献，作为脂质多余的信号胃肠道肿瘤发生和侵袭性。从这些研究中获得的发现可能会发现新的调节肠道干细胞增殖并导致新药理的营养感应机制操纵鞘脂以改善肠道健康的方法。