Regulation of Na-Nutrient Co-Transport

描述(申请人提供)：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，并伴随营养不良和体重下降。长期以来，人们一直认为，一旦发生慢性肠道炎症，吸收不良和腹泻是不可避免的结果。然而，在这项提案的前一个资金周期中，我们证明了吸收不良和腹泻不是慢性肠道炎症的不可挽回的最终结果，而是积极调节的过程。我们重点研究了钠-葡萄糖共转运(SGLT1)和钠-氨基酸共转运(NAT)的调控，它们不仅对营养物质的同化很重要，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共同细胞外调节途径。然而，在下游，前列腺素E2(PGE2)介导SGLT1的抑制，白三烯D4(LTD4)介导NACT的抑制。我们还证明在慢性肠炎时，SGLT1的抑制机制是辅助转运体数量减少的次要机制，而NAT的抑制机制是辅助转运体亲和力改变的次要机制。在证明了SGLT1和NACT在慢性炎症性肠炎中独特的细胞外调节后，下一步合乎逻辑的是这项建议的总体目标：确定细胞内的调节机制和SGLT1和NACT在慢性肠炎过程中的分子变化。具体地说，我们将确定在慢性肠炎期间调节SGLT1和NAT的细胞内G蛋白、第二信使和蛋白激酶途径。然后，我们将破译SGLT1和NACT在慢性炎症肠道中各自的细胞内途径所介导的独特的分子变化。这些研究的成功完成将为这一提议的整体假说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SGLT1和NACT的独特变化。这一知识将为治疗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。

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.