Regulation of intestinal NaCl absorption

在这个国家和退伍军人中最常见的慢性腹泻疾病是炎症性肠病 (IBD；例如克罗恩病)。腹泻是IBD最常见的致残性疾病。可用的 IBD腹泻的治疗是次优的，非特异性的，并且充满了许多副作用。腹泻在中国 这些情况是电解质(如钠、氯)和吸收绒毛细胞和液体吸收不良的结果 分泌性隐窝细胞分泌增强。免疫炎症介质(如前列腺素)，已知 在慢性炎症的肠黏膜中升高是改变血管活性的重要因素 上皮电解质转运体。而IBD电解质转运的免疫调节概念 公认的是，特别是许多免疫炎症途径中的哪一种可以调节偶联的氯化钠 吸收导致IBD腹泻的机制还知之甚少。现有的范例是耦合的氯化钠 吸收通过Na：H(NHE3)和Cl：HCO3交换(DRA)的双重作用发生。但我们在中国的研究 多个IBD模型显示NHE3未受影响，这引发了一个重要的问题，即还有哪些Na 吸收途径可能与DRA一起受到影响，导致耦合的氯化钠吸收不良导致 IBD最常见和最令人无力的症状是腹泻。另一种潜在的主要钠吸收 可能与氯：HCO3交换有关的过程是绒毛细胞上的钠-葡萄糖共转运(SGLT1) BBM。SGLT1不仅在主要营养物质葡萄糖的吸收中起着关键作用，而且在 通过为每个葡萄糖吸收两个钠来维持液体和电解质的整体动态平衡。的确， 在两种IBD动物模型和人类IBD模型中的初步数据显示SGLT1平行抑制 与DRA合作，尽管是通过不同的机制。此外，初步研究表明，前列腺素，关键 免疫炎症介质可能是慢性肠炎时SGLT1的特异性调节因子。这些 观察，导致了范式转换的结论，在慢性炎症的肠道中，它不是 受影响的NHE3/DRA对氯化钠的传统耦合吸收，而是一种新的DRA/SGLT1耦合 可能被抑制而导致IBD腹泻的吸收途径。在这种背景下，总体上 该竞争更新提议的假设是改变的新的DRA/SGLT1耦合了氯化钠吸收， 可能受PGs调节，导致IBD腹泻。因此，这项提案的总体目标是澄清 慢性阻塞性肺疾病免疫炎症介质对SGLT1和DRA调节的分子机制 肠子发炎。全面、互补研究分子和生理调控 SGLT1在慢性肠炎兔体内和人小肠有机化合物2-D中的体外研究 单层。拟议的研究结果将提供新的机制洞察力的原因 IBD肠道对电解质(氯化钠)和营养物质(葡萄糖)的吸收受损，临床表现为 相关数据，对于为最常见的疾病设计有效和特定的治疗方法将是重要的 IBD并发症、慢性腹泻。

The most common chronic diarrheal disease in this country and in veterans is inflammatory bowel disease (IBD; e.g. Crohn’s disease). Diarrhea is the most common and disabling morbidity of IBD. The available treatments for diarrhea of IBD are suboptimal, non-specific and fraught with many side effects. Diarrhea in these conditions is a result of electrolyte (e.g. Na, Cl) and fluid malabsorption by absorptive villus cells and enhanced secretion by secretory crypt cells. Immune inflammatory mediators (e.g. prostaglandins), known to be elevated in the mucosa of the chronically inflamed intestine, are paramount factors altering the activity of epithelial electrolyte transporters. While the concept of immune regulation of electrolyte transport in IBD is fairly well accepted, specifically which of the many immune inflammatory pathways may regulate coupled NaCl absorption to cause diarrhea in IBD is poorly understood. The existing paradigm is that coupled NaCl absorption occurs via the dual operation of Na:H (NHE3) and Cl:HCO3 exchange (DRA). But our studies in multiple IBD models showing that NHE3 is unaffected, raised an important question of what other Na absorptive pathway may be affected in tandem with DRA that results in coupled NaCl malabsorption leading to the most common and disabling symptom of IBD, diarrhea. Of the other potential major Na absorptive processes that may be coupled to Cl:HCO3 exchange is Na-glucose co-transport (SGLT1) on the villus cell BBM. SGLT1 is pivotal not only for the absorption of the major nutrient glucose, but also plays a critical role in maintaining overall fluid and electrolyte homeostasis by absorbing two Na for each glucose. Indeed, preliminary data in two animal models of IBD and in human IBD demonstrated inhibition of SGLT1, in parallel with DRA, albeit via different mechanisms. Further, preliminary studies showed that prostaglandins, key immune inflammatory mediators, may be specific modulators of SGLT1 during chronic enteritis. These observations, have led to the paradigm shifting conclusion, that in the chronically inflamed intestine it is not the conventional coupled NaCl absorption via NHE3/DRA that is affected, but rather a novel DRA/SGLT1 coupled absorptive pathway that may be inhibited to cause diarrhea in IBD. Given this background, the overall hypothesis of this competing renewal proposal is that altered novel DRA/SGLT1 coupled NaCl absorption, likely regulated by PGs, causes the diarrhea in IBD. Thus, the overall goal of this proposal is to elucidate the molecular mechanisms of regulation of SGLT1 and DRA by immune-inflammatory mediators in the chronically inflamed intestine. We will comprehensively and complementarily study molecular and physiological regulation of SGLT1 in vivo in rabbits with chronic enteritis and ex vivo in human small intestinal organoid 2-D monolayers. Outcome of the proposed studies will provide novel mechanistic insights into the cause of impaired absorption of both electrolytes (NaCl) and nutrient (glucose) in the IBD intestine and yield clinically relevant data which will be important to design effective and specific therapies for the most common complication of IBD, chronic diarrhea.