Regulation of Na-Nutrient Co-Transport

描述（由申请方提供）：炎症性肠病（IBD）的发病率源于其对电解质、营养物质和液体吸收的影响;因此，IBD患者持续吸收不良和腹泻，伴随营养不良和体重减轻。长期以来，人们一直认为，一旦发生慢性肠道炎症，吸收不良和腹泻是必然的结果。然而，在该提案的前一个资助周期中，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。我们重点研究了钠-葡萄糖共转运（SGLT 1）和钠-氨基酸共转运（NAcT）的调控，这两个转运蛋白不仅对营养物质的同化作用很重要，而且对钠的吸收也很重要。我们确定，上游肥大细胞，诱导型一氧化氮和花生四烯酸是这两种共转运蛋白的细胞外调节的共同途径。然而，在前列腺素E2（PGE 2）介导SGLT 1抑制的下游，白三烯D4（LTD 4）介导NAcT抑制。我们还证明了SGLT 1的抑制机制继发于协同转运蛋白数量的减少，而NAcT的抑制机制继发于慢性肠炎期间协同转运蛋白亲和力的改变。已经证明了SGLT 1和NAcT在慢性炎症肠道中的独特细胞外调节，下一步是该提案的总体目标：确定慢性肠炎期间SGLT 1和NAcT的细胞内调节机制和分子改变。具体来说，我们将确定细胞内G蛋白，第二信使和蛋白激酶途径，调节SGLT 1和NAcT在慢性肠炎。然后，我们将破译SGLT 1和NAcT在慢性炎症肠道中由各自的细胞内途径介导的独特分子改变。这些研究的成功完成将为该提案的总体假设提供新的和有价值的信息：独特的细胞内调节机制导致慢性炎症肠道中SGLT 1和NAcT的独特变化。这些知识将为IBD最常见的疾病，特别是吸收不良，腹泻和营养不良提供新的和更有效的治疗方式的基础。

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.