REGULATION OF INTESTINAL NA ABSORPTION

描述（由申请人提供）：更好地了解哺乳动物小肠中两种主要Na吸收途径Na：H交换（NHE 3）和Na-葡萄糖共转运（SGLT 1）的调节对于开发多种常见医学病症（例如，消化道疾病、高血压、糖尿病、肥胖症）的更有效治疗是必要的。NHE 3通过Na：H和Cl：HCO 3交换的双重操作介导偶联的NaCl吸收，而SGLT 1对于吸收绒毛细胞刷状缘膜（BBM）上的Na和葡萄糖的同化是重要的。一氧化氮（NO）是生物学上最重要的调节因子之一， 活性分子，尚不清楚。我们报道，在体内和体外抑制组成型NO（cNO）导致抑制SGLT 1，但刺激NHE 3。相反，刺激cNO导致SGLT 1的刺激和NHE 3的抑制。因此，我们的数据表明，BBM NHE 3和SGLT 1可能是补偿调节NO维持细胞Na稳态。这导致了我们的新的总体假设，即主要的Na吸收途径NHE 3和SGLT 1可能通过NO相互调节，以维持上皮细胞中的细胞Na稳态。解决这一假设的总体目标是确定SGLT 1或NHE 3的永久沉默如何刺激其他转运蛋白，并确定可能由cNO介导的细胞和分子机制。这项研究的结果将为SGLT 1和NHE 3是否以及如何直接相互调节提供重要和新的机制见解。这些产生的新见解可以形成开发新策略的基础，以促进缺乏的电解质和营养素吸收，并在疾病状态下抑制电解质和营养素吸收，这样做是有利的。

DESCRIPTION (provided by applicant): Better insight into the regulation of the two primary Na absorptive pathways in the mammalian small intestine, Na:H exchange (NHE3) and Na-glucose co-transport (SGLT1), is necessary to develop more efficacious treatments for a variety of common medical conditions (e.g. diarrheal diseases, hypertension, diabetes, obesity). NHE3 mediates coupled NaCl absorption via the dual operation of Na:H and Cl:HCO3 exchange while SGLT1 is important to assimilate Na and glucose on the brush border membrane (BBM) of absorptive villus cells . The regulation of both by nitric oxide (NO), one of the most biologically active molecules, was unclear. We reported that in vivo and in vitro inhibition of constitutive NO (cNO) resulted in the inhibition SGLT1 but the stimulation of NHE3. In contrast, stimulation of cNO resulted in the stimulation of SGLT1 and inhibition of NHE3. Thus, our data indicate that BBM NHE3 and SGLT1 may be compensatorily regulated by NO to maintain cellular Na homeostasis. This then led to our novel overall hypothesis that the major Na absorptive pathways, NHE3 and SGLT1, regulate one another to maintain cellular Na homeostasis in epithelial cells likely via NO. The overall aim that will address this hypothesis will be to determine how permanent silencing of SGLT1 or NHE3 stimulates the other transporter and define the cellular and molecular mechanisms likely mediated by cNO. The results of this study will provide significant and new mechanistic insight into whether and how SGLT1 and NHE3 directly regulate one another. These resulting novel insights may form the basis for developing novel strategies to promote electrolyte and nutrient absorption where deficient and inhibit the same in disease states where it would be advantageous to do so.