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.

新生儿肠道消化管腔中蛋白质的能力较低，而是依赖肠上皮细胞摄取蛋白质并进行细胞内处理。这种营养机制在包括斑马鱼在内的脊椎动物中是保守的，并且是由肠道中部一群专门的富含溶酶体的肠上皮细胞（LRE）执行的，这些细胞表现出高内吞活性。最近的研究已经开始揭示控制 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 生理学及其通过宿主-微生物相互作用的调节的分子机制的理解受到了阻碍。最近，我们利用斑马鱼发现了一种保守的分子机制，可以介导 LRE 对蛋白质的高效受体依赖性和液相摄取。此外，我们发现斑马鱼在营养限制期间生存需要 LRE 功能，并且在缺乏微生物群的情况下饲养的斑马鱼表现出 LRE 活性降低。我们提出的研究将使用斑马鱼和小鼠模型来检验中心假设，即 LRE 在早期脊椎动物肠道功能中发挥重要且保守的作用。具体而言，LRE 介导： 1- 通过受体介导和液相内吞作用有效摄取膳食蛋白质； 2- 营养限制下的蛋白质利用和动物生长和存活； 3- 宿主-微生物相互作用控制细菌产物的营养吸收和跨细胞运输。对这些控制 LRE 功能的保守分子机制的进一步了解将带来改变肠道生理学的新方法，以促进包括人类在内的脊椎动物的最佳营养、免疫耐受和正常肠道发育。