Regulation of intestinal NaCl absorption

肠道 NaCl 吸收的调节

• 批准号: 10655307
• 负责人: Uma Sundaram
• 金额: --
• 依托单位: HUNTINGTON VETERANS AFFAIRS MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655307
• 关键词: APPBP2 gene; Affect; Affinity; Animal Model; Anions; Arachidonic Acids; Bicarbonates; Brush Cell; Cells; Chronic; Chronic diarrhea; Colon; Complication; Country; Coupled; Crohn' s disease; Data; Diarrhea; Dinoprostone; Disease model; Electrolytes; Epithelial Cells; Epithelium; Foundations; Funding; Genetic Transcription; Glucose; Goals; Homeostasis; Human; Immune; Immunotherapy; Impairment; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Intestinal Diseases; Intestinal Mucosa; Intestines; Life; Link; Liquid substance; Malabsorption Syndromes; Malnutrition; Mediating; Modality; Modeling; Molecular; Morbidity - disease rate; Mucous Membrane; Mus; Nutrient; Oral Rehydration Therapy; Organoids; Oryctolagus cuniculus; Outcome; Pathway interactions; Phosphorylation; Physiological; Play; Prevalence; Process; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Regulation; Role; SLC26A3 gene; Secondary to; Small Intestines; Ulcerative Colitis; Veterans; Villus; absorption; brush border membrane; clinically relevant; common symptom; crypt cell; design; diarrheal disease; disability; disabling symptom; enteritis; gut inflammation; immunoregulation; in vivo; inhaled nitric oxide; insight; intestinal epithelium; intestinal villi; mast cell; monolayer; mouse model; novel; operation; putative anion transporter 1; side effect; therapeutically effective; trafficking

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.

在这个国家和退伍军人中最常见的慢性腹泻病是炎症性肠病 （IBD；例如克罗恩病）。腹泻是 IBD 最常见且最致残的疾病。可用的 IBD 腹泻的治疗效果欠佳、非特异性且充满许多副作用。腹泻于 这些情况是由于吸收性绒毛细胞吸收电解质（例如 Na、Cl）和液体吸收不良造成的 分泌隐窝细胞的分泌增强。免疫炎症介质（例如前列腺素），已知 在慢性发炎的肠道粘膜中升高，是改变其活性的最重要因素 上皮电解质转运蛋白。虽然 IBD 中电解质转运的免疫调节概念是相当合理的。 被广泛接受，特别是许多免疫炎症途径中的哪一个可以调节耦合的 NaCl IBD 患者的吸收导致腹泻的情况尚不清楚。现有的范例是耦合 NaCl 吸收通过 Na:H (NHE3) 和 Cl:HCO3 交换 (DRA) 的双重操作发生。但我们的研究在 多个 IBD 模型显示 NHE3 不受影响，提出了一个重要问题：还有哪些 Na 吸收途径可能与 DRA 一起受到影响，导致 NaCl 吸收不良，从而导致 IBD 最常见和致残的症状是腹泻。其他潜在的主要Na吸收 可能与 Cl:HCO3 交换耦合的过程是绒毛细胞上的 Na-葡萄糖共转运 (SGLT1) BBM。 SGLT1 不仅对于主要营养物质葡萄糖的吸收至关重要，而且在 通过为每个葡萄糖吸收两个 Na 来维持整体液体和电解质稳态。的确， 两种 IBD 动物模型和人类 IBD 的初步数据同时证明了 SGLT1 的抑制作用 与 DRA，尽管通过不同的机制。此外，初步研究表明，关键的前列腺素 免疫炎症介质，可能是慢性肠炎期间 SGLT1 的特异性调节剂。这些 观察结果得出了范式转变的结论，即在慢性发炎的肠道中，这并不是 通过 NHE3/DRA 的传统耦合 NaCl 吸收受到影响，而是一种新颖的 DRA/SGLT1 耦合 吸收途径可能受到抑制而导致 IBD 腹泻。在此背景下，总体 这一竞争性更新提案的假设是改变了新型 DRA/SGLT1 耦合的 NaCl 吸收， 可能受 PG 调节，导致 IBD 腹泻。因此，本提案的总体目标是阐明 慢性炎症中免疫炎症介质调节SGLT1和DRA的分子机制 肠道发炎。我们将全面、互补地研究分子和生理调控 慢性肠炎兔体内 SGLT1 和人小肠类器官 2-D 离体 SGLT1 的变化 单层。拟议研究的结果将为造成这种现象的原因提供新的机制见解 IBD 肠道中电解质（氯化钠）和营养物质（葡萄糖）的吸收受损以及临床产量 相关数据对于为最常见的疾病设计有效且具体的疗法非常重要 IBD的并发症，慢性腹泻。