Regulation of Intestinal Na Absorption

描述(申请人提供)：哺乳动物小肠中主要的钠吸收途径是钠-葡萄糖共转运(SGLT-I)和偶联NaCI吸收。结构型一氧化氮(CNO)调节多种胃肠道功能，但在正常哺乳动物小肠中如何调节这些重要的钠吸收途径尚不清楚。我们实验室的初步研究表明，CNO以互补的方式唯一地调节小肠中这两条主要的钠吸收途径，以实现细胞内钠的动态平衡。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通过调节其转运子数量来抑制NHE3。鉴于这一背景，我们假设CNO唯一地调节哺乳动物小肠中主要的钠吸收途径。因此，这项建议的总体目标是确定一氧化氮对正常哺乳动物小肠钠吸收的调节机制。 本研究将为CNO对正常肠道钠吸收转运过程的主动调控和机制研究提供新的思路。这也将为CNO介导的这些转运过程的细胞内调控提供新的见解。此外，这些研究的结果将为破译这些重要的钠吸收途径在炎症性肠病(IBD)中的调节机制奠定基础。在IBD中，了解钠吸收的调节很重要，因为众所周知，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，并伴随着营养不良和体重下降。更好地了解NO对正常和慢性炎症肠道钠吸收转运过程的调节机制，将为IBD吸收不良、腹泻和营养不良的新的、更有效的治疗方案提供基础。

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.