Regulation of intestinal NaCl absorption

肠道 NaCl 吸收的调节

• 批准号: 10368181
• 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/10368181
• 关键词: APPBP2 gene; Affect; Affinity; Animal Model; Anions; Arachidonic Acids; Bicarbonates; Brush Cell; Cells; Chronic; Chronic diarrhea; Complication; Country; Coupled; Crohn' s disease; Data; Diarrhea; Dinoprostone; Electrolytes; Epithelial; Epithelial Cells; Foundations; Funding; Genetic Transcription; Glucose; Goals; Homeostasis; Human; Immune; Immunotherapy; Impairment; Inflammation Mediators; Inflammatory; Inflammatory Bowel 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最常见和残疾的发病率。可用 IBD腹泻的治疗方法是次优的，非特异性的，并且具有许多副作用。腹泻 这些条件是电解质（例如Na，cl）和吸收性绒毛细胞和流体吸收不良的结果 秘密加密细胞增强了分泌。免疫炎症介质（例如前列腺素），已知 长期发炎的肠粘膜中升高是改变活性的最高因素 上皮电解质转运蛋白。虽然IBD中电解质传输的免疫调节的概念是公平的 公认的，特别是多种免疫炎症途径中的哪一个可以调节NaCl耦合 吸收引起IBD的腹泻知之甚少。现有的范式是耦合的NaCl 通过Na：H（NHE3）和Cl：HCO​​3 Exchange（DRA）的双重操作进行抽象。但是我们的研究 多个IBD模型表明NHE3不受影响，提出了一个重要的问题，即其他NA 吸收途径可能与DRA同时影响，从而导致NaCl吸收不良导致导致 IBD，腹泻的最常见和残疾症状。其他潜在的主要NA吸收剂 可能与Cl：HCO​​3交换的过程是绒毛细胞上的Na-葡萄糖共循环（SGLT1） BBM。 SGLT1不仅是主要营养葡萄糖的抽象，而且在 通过对每个葡萄糖吸收两个NA来维持总体液体和电解质稳态。的确， IBD和人类IBD中的两个动物模型中的初步数据表现出对SGLT1的抑制作用，并行 使用DRA，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期间SGLT1的特定调节剂。这些 观察结果导致了范式转移的结论，在长期发炎中，这不是 传统的耦合NaCl滥用通过受影响的NHE3/DRA，而是一种新颖的DRA/SGLT1耦合 可以抑制会导致IBD腹泻的吸收途径。鉴于此背景，总体 这种竞争性更新建议的假设是改变了新型的DRA/SGLT1耦合NaCl滥用， 可能由PGS调节，导致IBD的腹泻。这是该提议的总体目标是阐明 慢性介体在长期通过免疫炎症介质调节SGLT1和DRA的分子机制 发炎的肠发。我们将全面，完整地研究分子和物理调节 兔子中的体内sglt1的慢性肠炎和体内小肠癌中的体内 单层。拟议的研究的结果将提供新的机械见解 IBD肠中电解质（NaCl）和营养（葡萄糖）的滥用受损，并在临床上产生 相关数据对于为最常见的有效疗法设计有效的特定疗法至关重要 IBD的并发症，慢性腹泻。