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

• 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
• 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

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，而是依赖于肠上皮细胞对摄入的蛋白质进行摄取和细胞内加工。这种营养机制在包括斑马鱼在内的脊椎动物中是保守的，并且由中肠中表现出高内吞活性的特化的富含溶酶体的肠细胞（LRE）的群体执行。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，我们对LRE生理学及其通过宿主-微生物相互作用调节的分子机制的理解受到缺乏特定分子工具和哺乳动物模型实验可及性有限的阻碍。我们最近利用斑马鱼发现了一种保守的分子机制，该机制介导LRE对蛋白质的高效受体依赖性和液相吸收。此外，我们发现LRE功能是斑马鱼在营养限制期间生存所必需的，并且在没有微生物群的情况下饲养的斑马鱼显示LRE活性降低。使用斑马鱼和小鼠模型，我们提出的研究将测试中心假设，即LRE在早期脊椎动物肠道功能中发挥重要和保守的作用。具体而言，LRE介导：1-通过受体介导的和液相内吞作用有效摄取膳食蛋白; 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营养摄取和细菌产物的跨细胞运输。对这些控制LRE功能的保守分子机制的进一步理解将导致用于修改肠道生理学以促进脊椎动物（包括人类）的最佳营养、免疫耐受和正常肠道发育的新方法。