Regulation of Na-Nutrient Co-Transport

钠-营养盐协同运输的调节

• 批准号: 8011606
• 负责人: Uma Sundaram
• 金额: $ 10万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-05 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011606
• 关键词: Affinity; Amino Acids; Arachidonic Acids; Assimilations; Body Weight decreased; Cells; Chronic; Crohn' s disease; Cyclic AMP-Dependent Protein Kinases; Diarrhea; Dinoprostone; Electrolytes; Fluids and Secretions; Funding; GTP-Binding Proteins; Glucose; Human; Immune; In Vitro; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestinal Absorption; Intestines; Knowledge; Leukotriene D4; Liquid substance; Malabsorption Syndromes; Malnutrition; Mediating; Modality; Molecular; Morbidity - disease rate; Nitric Oxide; Nutrient; Oryctolagus cuniculus; Pathway interactions; Patients; Phosphorylation; Process; Protein Kinase; Protein Kinase C; Regulation; Research Personnel; Secondary to; Stream; Transport Process; Villus; absorption; base; brush border membrane; cell growth regulation; enteritis; glycosylation; in vivo; mast cell; novel; programs; stem; symporter; trafficking; uptake

DESCRIPTION (provided by applicant): The morbidity of inflammatory bowel disease (IBD) stems from its effect on electrolytes, nutrients and fluid absorption; thus, patients with IBD sustain malabsorption and diarrhea with attendant malnutrition and weight loss. It has long been held that once chronic intestinal inflammation has occurred, malabsorption and diarrhea are the inevitable results. However, in the previous funding cycle of this proposal we demonstrated that malabsorption and diarrhea are not the irrevocable end results of chronic intestinal inflammation, but actively regulated processes. We focused on the regulation of Na-glucose co-transport (SGLT1) and Na-amino acid co-transport (NAcT), which are not only important for nutrient assimilation, but also the absorption of Na. We determined that upstream mast cells, inducible nitric oxide, and arachidonic acid were common pathways of extra cellular regulation of these 2 co-transporters. However, further downstream while prostaglandin E2 (PGE2) mediated the inhibition of SGLT1, leukotriene D4 (LTD4) mediated the inhibition of NAcT. We also demonstrated that the mechanism of inhibition of SGLT1 was secondary to a decrease in co-transporter numbers while that of NAcT was secondary to altered co-transporter affinity during chronic enteritis. Having demonstrated the unique extra cellular regulation of SGLT1 and NAcT in the chronically inflamed intestine, the next logical step is the overall aim of this proposal: Determine the intracellular mechanism of regulation and the molecular alterations of SGLT1 and NAcT during chronic enteritis. Specifically, we will determine intracellular G protein, 2nd messenger and protein kinase pathways, which regulate SGLT1 and NAcT during chronic enteritis. Then we will decipher the unique molecular alterations of SGLT1 and NAcT mediated by the respective intracellular pathways in the chronically inflamed intestine. Successful completion of these studies will provide novel and valuable information for the overall hypothesis of this proposal: Unique intracellular mechanisms of regulation result in the unique changes in SGLT1 and NAcT in the chronically inflamed intestine. This knowledge will provide the basis for new and more efficacious treatment modalities for the most common morbidities of IBD specifically, malabsorption, diarrhea and malnutrition.

描述（由申请人提供）：炎症性肠病（IBD）的发病率源于其对电解质，营养和液体吸收的影响；因此，IBD患者以伴随的营养不良和体重减轻而维持吸收不良和腹泻。长期以来一直认为，一旦发生慢性肠道炎症，不可避免的结果是不可避免的结果。但是，在该提案的先前融资周期中，我们证明了吸收不良和腹泻不是慢性肠道炎症的不可撤销的最终结果，而是积极调节的过程。我们专注于调节Na-葡萄糖共传输（SGLT1）和Na-氨基酸共转移（NACT），这不仅对营养同化，而且对NA的吸收也很重要。我们确定上游肥大细胞，可诱导的一氧化氮和花生四烯酸是这2个同伴的额外细胞调节的常见途径。但是，在下游进一步的前列腺素E2（PGE2）介导了SGLT1的抑制，白细胞D4（LTD4）介导了NACT的抑制作用。我们还证明，抑制SGLT1的机制是继发摄像机数量的减少，而NACT的抑制作用是慢性肠炎期间共同转运蛋白亲和力的继发机制。在长期发炎的肠道中显示了SGLT1和NACT的独特额外细胞调节后，下一个逻辑步骤是该建议的总体目的：确定调节的细胞内机制以及慢性肠炎期间SGLT1和NACT的分子改变。具体而言，我们将确定细胞内G蛋白，第二信使和蛋白激酶途径，它们在慢性肠炎期间调节SGLT1和NACT。然后，我们将破译SGLT1的独特分子改变和由慢性发炎的各个细胞内途径介导的NACT。这些研究的成功完成将为该提案的总体假设提供新颖而有价值的信息：调节的独特细胞内机制导致SGLT1和NACT在长期发炎的肠道中的独特变化。这些知识将为IBD最常见的病因，特别是吸收不良，腹泻和营养不良的最常见病态提供新的和有效的治疗方式的基础。