Novel Roles of Sodium Hydrogen Exchanger 8 (NHE8) in Mucosal Homeostasis

钠氢交换器 8 (NHE8) 在粘膜稳态中的新作用

• 批准号: 9402244
• 负责人: Fayez Khalaf Ghishan
• 金额: $ 34.54万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9402244
• 关键词: Adult; Affect; Allografting; Apical; Bacterial Adhesion; Basic Science; Butyrates; Cell Line; Cell physiology; Clinical; Colitis; Colonic Neoplasms; Colorectal Cancer; Data; Defect; Development; Distal; Down-Regulation; Drug or chemical Tissue Distribution; Dry Eye Syndromes; Electrolytes; Employee Strikes; Epithelial; Epithelial Cells; Family; Functional disorder; Gastrointestinal Diseases; Gastrointestinal tract structure; Gene Expression; Gnotobiotic; Goblet Cells; Growth Factor; Health; Hemostatic function; Homeostasis; Human; Impairment; Inflammation; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Injury; Intestines; Kinetics; LGR5 gene; Lead; Life; Liquid substance; MAP Kinase Gene; Male Infertility; Modeling; Morphology; Mucin-2 Staining Method; Mucositis; Mucous Membrane; Mucous body substance; Mus; NHE2; Nutrient; Paneth Cells; Pathologic; Pathway interactions; Patients; Phenotype; Physiological; Play; Predisposition; Protein Isoforms; Proteins; RNA; Regulation; Role; Small Intestines; Sodium-Hydrogen Antiporter; Somatotropin; Stem cells; Testing; Tissues; Translational Research; Transplantation; Ulcerative Colitis; WNT Signaling Pathway; absorption; colonic crypt; cytokine; design; fascinate; gastrointestinal epithelium; gut microbiome; gut microbiota; mRNA Expression; male; member; microbial; mouse model; novel; novel strategies; ocular surface; postnatal; protein expression; reproductive tract; tumor; tumorigenesis

Abstract This is a new application designed to study the novel roles of intestinal NHE8 on mucosal hemostasis. We have made major discoveries in this field, being the first lab to clone and characterize its expression and transport kinetics in 2005. We have described changes in postnatal expression of NHE8, defined its regulation by growth factor and hormones, and (of importance for this proposal) described its abundant expression in the goblet cells and colonic crypts. We developed NHE8-deficient mice (NHE8KO) and demonstrated fascinating phenotypes ranging from the impaired gut mucosal integrity (defects in goblet and Paneth cells, enhanced susceptibility to mucosal injury, microbial dysbiosis, increased bacterial adhesion and disruption of the mucus layer), to male infertility and development of dry eye syndrome. These and additional preliminary observations presented in this proposal led us to hypothesize that this transporter plays pleiotropic roles in mucosal homeostasis and that its reduced expression in IBD contributes to intestinal inflammation and susceptibility to colorectal cancer. To test this hypothesis, we formulated the following Aims: Aim 1: Determine the mechanism of NHE8 involvement in goblet cell function Aim 2: Characterize NHE8 expression in human UC patients and the microbial and inflammatory consequences of its loss Aim 3: Determine the roles of NHE8 in tumorigenesis We expect that the planned studies will be transformative and lead to the creation of a new paradigm regard- ing the role of epithelial Na+/H+ exchange, NHE8 in particular, in gut health.

摘要 这是一种新的应用，旨在研究肠道NHE8在粘膜止血中的新作用。我们 在这一领域取得了重大发现，成为第一个克隆和表征其表达和运输的实验室 2005年的Kinetics。我们描述了NHE8在出生后表达的变化，定义了它的生长调节 因子和激素，并描述了它在杯状细胞中的丰富表达。 还有结肠隐窝。我们培育了NHE8缺陷小鼠(NHE8KO)，并展示了令人着迷的表型 从肠道粘膜完整性受损(杯状细胞和潘氏细胞缺陷，易感性增强)到 粘膜损伤、微生物失调、细菌黏附增加和粘液层破坏)，对男性 不孕不育与干眼症的发展。这些以及在本报告中提出的其他初步观察结果 这一提议使我们假设这种转运蛋白在粘膜动态平衡中起着多效性作用，而且它的 IBD中表达减少会导致肠道炎症和结直肠癌的易感性。为了测试 在这一假设下，我们提出了以下目标： 目的1：确定NHE8参与杯状细胞功能的机制 目的2：研究人类溃疡性结肠炎患者NHE8的表达特征及微生物和 它的损失带来的煽动性后果 目的3：确定NHE8在肿瘤发生中的作用 我们预计，计划中的研究将是变革性的，并导致建立一个关于以下方面的新范式： 上皮性Na+/H+交换，特别是NHE8在肠道健康中的作用。