Regulation of Intestinal Na Absorption

描述（由申请方提供）：哺乳动物小肠中的主要钠吸收途径是钠-葡萄糖共转运（SGLT-I）和偶联NaCl吸收。组成型一氧化氮（cNO），已知调节许多胃肠道功能，可能会调节这些重要的钠吸收途径在正常哺乳动物小肠还没有很好地理解。我们实验室的初步研究表明，cNO以互补的方式独特地调节小肠中这两种主要的Na吸收途径，以实现细胞Na稳态。我们的初步研究表明，在生理状态下，cNO通过调节其对葡萄糖的亲和力来促进SGLT-1，而cNO通过调节其转运体数量来抑制NHE 3。在此背景下，我们假设cNO独特地调节哺乳动物小肠中的初级Na吸收途径。因此，本提案的总体目标是确定在正常哺乳动物小肠中通过一氧化氮调节Na吸收的机制。 本研究将揭示cNO在正常肠道中对必需钠吸收转运过程的主动调节和机制。它也将提供新的见解cNO介导的细胞内调节这些运输过程。此外，这些研究的结果将为解释炎症性肠病（IBD）中这些重要钠吸收途径的调节机制奠定基础。在IBD中，了解Na吸收的调节是重要的，因为已知IBD的发病率源于其对电解质、营养素和液体吸收的影响;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。更好地了解NO在正常和慢性炎症肠道中调节Na吸收转运过程的机制，将为IBD吸收不良、腹泻和营养不良的新的和更有效的治疗方式提供基础。

DESCRIPTION (provided by applicant): The primary Na absorbing pathways in the mammalian small intestine are Na-glucose co-transport (SGLT-I) and coupled NaCI absorption. How constitutive nitric oxide (cNO), known to regulate many gastrointestinal tract functions, may regulate these important Na absorbing pathways in the normal mammalian small intestine is not well understood. Preliminary studies from our laboratory indicate that cNO uniquely regulates these two primary Na absorbing pathways in the small intestine in a complementary fashion to achieve cellular Na homeostasis. Our preliminary studies indicate that in physiological states cNO facilitates SGLT-1 by modulating its affinity for glucose whereas cNO represses NHE3 by modulating its transporter numbers. Given this background we hypothesize that cNO uniquely regulates primary Na absorbing pathways in the mammalian small intestine. Thus, the overall goal of this proposal is to determine the mechanism of regulation of Na absorption by nitric oxide in the normal mammalian small intestine. This study will shed novel insight into the active regulation of and decipher the mechanisms of modulation of essential Na absorbing transport processes by cNO in the normal intestine. It will also provide new insights into the cNO mediated intracellular regulation of these transport processes. Further, the results of these studies will set the stage to decipher the mechanism of regulation of these important Na absorptive pathways in inflammatory bowel disease (IBD). In IBD understanding the regulation of Na absorption is important since, it is known that morbidity of 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. Better understanding of the mechanism of regulation of Na-absorbing transport processes by NO in the normal and chronically inflamed intestine will provide the basis for new and more efficacious treatment modalities for the malabsorption, diarrhea and malnutrition of IBD.