Regulation of amino acid absorption in the mammalian small intestine

哺乳动物小肠氨基酸吸收的调节

• 批准号: 9174959
• 负责人: Uma Sundaram
• 金额: $ 47.81万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174959
• 关键词: Affect; Affinity; Amino Acids; Apoptosis; Architecture; Assimilations; Body Weight decreased; Cell Line; Cells; Chronic; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diarrhea; Disease; Electrolytes; Enterocytes; Epithelial Cells; Epithelium; Fluids and Secretions; Foundations; Glutamine; Health; Homeostasis; Human; Immune; In Vitro; Inflammation Mediators; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestinal Diseases; Intestinal Mucosa; Intestines; Leukotrienes; Lipoxygenase; Liquid substance; Malabsorption Syndromes; Malnutrition; Mediating; Modeling; Molecular; Mucous Membrane; Nutrient; Nutritional Support; Oryctolagus cuniculus; Pathway interactions; Process; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Kinase C; Rattus; Regulation; Secondary to; Small Intestines; Source; Sum; Time; Villus; Wound Healing; absorption; base; brush border membrane; cell growth regulation; crypt cell; deprivation; design; enteritis; improved; intestinal epithelium; novel; symporter

The amino acid glutamine is the primary nutrient for the intestinal enterocytes and thus, critical for the health of the epithelium. However, how glutamine is assimilated in the normal mammalian small intestine and/or in a primarily mucosal disease such as inflammatory bowel disease (IBD) is not well known. Glutamine is absorbed via Na- glutamine co-transport (NGcT) on the brush border membrane (BBM) of enterocytes. We have demonstrated that B0AT1 mediates NGcT on the BBM of villus cells. And in paradigm shift, we demonstrated the only nutrient absorptive process on the BBM of crypt cells, specifically SN2, which mediates NGcT in these cells. Further, in a rabbit model of chronic intestinal inflammation resembling IBD we demonstrated that NGcT in total was reduced. This net inhibition was a sum of B0AT1 inhibition in villus cells and SN2 stimulation in crypt cells. The mechanism of inhibition of B0AT1 was secondary to a reduction in the number of co-transporters in the villus cell BBM while the mechanism of stimulation of SN2 in crypt cells was secondary to an increase in the affinity for glutamine. Thus, glutamine assimilation which occurs via distinct transporters in villus and crypt cells is uniquely regulated in the chronically inflamed intestine. Importantly, similar results were seen in the human IBD intestine. Additional preliminary studies indicated that immune inflammatory mediators known to be produced in the chronically inflamed intestine may be responsible for these unique alterations in glutamine absorption. Given this background, the overall aim is to determine the immune mechanism of regulation of B0AT1 in villus and SN2 in crypt cells in the chronically inflamed intestine. Better understanding of the regulation of glutamine absorption in the normal and IBD intestine will provide the foundation to develop more efficacious, specific immune based nutritional therapies for IBD.

氨基酸谷氨酰胺是肠肠上皮细胞的主要养分 因此，对上皮的健康至关重要。但是，如何同化谷氨酰胺 在正常的哺乳动物小肠和/或主要是粘膜疾病中 炎症性肠病（IBD）尚不清楚。谷氨酰胺通过NA-吸收 肠肠细胞的刷边膜（BBM）上的谷氨酰胺共同传输（NGCT）。 我们已经证明，B0AT1在绒毛细胞的BBM上介导了NGCT。并在 范式转移，我们证明了BBM上唯一的营养吸收过程 地穴细胞，特别是SN2，它介导了这些细胞中的NGCT。此外，在兔子里 慢性肠道炎症模型类似于IBD，我们证明了NGCT 总数减少了。该净抑制是绒毛细胞中B0AT1抑制的总和 SN2刺激隐窝细胞。 B0AT1抑制的机制是继发于A的 绒毛细胞BBM中的共发器数量减少，而机制 刺激隐窝细胞中SN2的刺激是对亲和力增加的继发 谷氨酰胺。因此，通过绒毛中不同转运蛋白发生的谷氨酰胺同化 在慢性发炎的肠中，隐窝细胞受到唯一的调节。重要的是， 在人类IBD肠中也看到了类似的结果。其他初步研究 表明已知在慢性产生的免疫炎症介质 发炎的肠可能是谷氨酰胺的这些独特改变的原因 吸收。鉴于此背景，总体目的是确定免疫力 绒毛中B0AT1调节的机理和慢性隐窝细胞中SN2的调节机制 发炎的肠发。更好地了解谷氨酰胺吸收的调节 正常和IBD肠将为发展更有效，具体的基础提供基础 IBD的基于免疫的营养疗法。