Cellular and Environmental Regulation of Protein Absorption and Utilization in the Early Intestine

早期肠道蛋白质吸收和利用的细胞和环境调节

基本信息

批准号：
10312009
负责人：
Michel Bagnat
金额：
$ 49.64万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10312009
关键词：
Affect Amino Acids Animals Apical Biological Models Biology Celiac Disease Cell Polarity Custom Data Development Diarrhea Diet Dietary Proteins Digestion Digestive Physiology Disease Endocytosis Energy-Generating Resources Enterocytes Epithelial Cells Essential Amino Acids Exhibits Food Food Hypersensitivity Gastrointestinal tract structure Genetic Gnotobiotic Goals Growth Harvest Homeostasis Human Immune Tolerance Immunity Impairment Ingestion Innate Immune Response Innate Immune System Intestines Irritable Bowel Syndrome Larva Lead Life Liquid substance Lysosomes Malabsorption Syndromes Malignant Neoplasms Malnutrition Mammals Mediating Membrane Proteins Metabolic Modeling Molecular Mus Neonatal Nutrient Nutrition Disorders Nutritional Outcome Passive Immunity Peptide Hydrolases Peptides Pharmacology Phase Physiology Play Population Process Proteins Publishing Regulation Rodent Role Source Surface Testing Vacuole Vertebrates Work Zebrafish absorption base cell type detection of nutrient dietary gut microbiota host microbiota host-microbe interactions ileum improved insight intestinal epithelium intrinsic factor-cobalamin receptor member microbial microbiota mouse genetics mouse model mutant neonatal human neonatal mice novel strategies novel therapeutic intervention nutrient absorption nutrition receptor tool uptake

项目摘要

The neonatal intestine has a low capacity for digesting proteins in the lumen, and instead relies on the enterocytes for uptake and intracellular processing of ingested proteins. This nutritional mechanism is conserved among vertebrates including zebrafish, and is performed by a population of specialized lysosome-rich enterocytes (LREs) in the mid-intestine that exhibit high endocytic activity. Recent studies have begun to uncover genetic factors controlling LRE development and function. However, our understanding of the molecular mechanisms underlying LRE physiology and its regulation by host-microbe interactions has been hindered by the lack of specific molecular tools and the limited experimental accessibility of mammalian models. Using zebrafish, we recently uncovered a conserved molecular machinery that mediates efficient receptor-dependent and fluid phase uptake of proteins by LREs. Moreover, we found that LRE function is required for survival during nutrient restriction in zebrafish, and that zebrafish reared in the absence of microbiota display reduced LRE activity. Using zebrafish and mouse models, our proposed studies will test the central hypothesis that that LREs play essential and conserved roles in early vertebrate intestinal function. Specifically, that LREs mediate: 1- efficient uptake of dietary protein via receptor mediated and fluid phase endocytosis; 2- protein utilization and animal growth and survival under nutritional restriction; 3- host-microbe interactions controlling nutrient uptake and transcellular transport of bacterial products. Improved understanding of these conserved molecular mechanisms governing LRE function will lead to new approaches for modifying intestinal physiology to promote optimal nutrition, immune tolerance, and normal intestinal development in vertebrates including humans.

新生儿肠的消化能力较低，而依赖于肠上皮细胞来摄取和细胞内摄入的蛋白质。这种营养机制在包括斑马鱼在内的脊椎动物中是保守的，并且由表现出较高内吞活性的中肠中的专门富含溶酶体的肠肠细胞（LRE）进行。最近的研究已开始发现控制LRE发育和功能的遗传因素。然而，由于缺乏特定的分子工具和哺乳动物模型的实验可及性有限，我们对LRE生理学基础机制及其对宿主 - 微生物相互作用的调节的理解及其对宿主 - 微生物相互作用的调节。使用斑马鱼，我们最近发现了一种保守的分子机制，该机制介导了LIS介导蛋白质的有效受体依赖性和流体阶段摄取。此外，我们发现在斑马鱼中养分限制期间生存需要LRE功能，并且在没有微生物群的情况下饲养的斑马鱼表现出降低的LRE活性。使用斑马鱼和小鼠模型，我们提出的研究将检验以下中心假设，即在早期脊椎动物肠功能中起着必不可少的和保守的作用。具体而言，液压介导的：1-通过受体介导的和液相内吞作用的1-有效摄取饮食蛋白； 2-营养限制下的蛋白质利用和动物生长以及生存； 3-可控制细菌产物营养摄取和跨细胞运输的宿主微型型相互作用。对这些保守的分子机制的理解得以提高，将为修改肠道生理学的新方法，以促进包括人类在内的脊椎动物中促进最佳营养，免疫耐受性和正常肠道发育。