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.

抽象的 这是一个新应用，旨在研究肠道 NHE8 对粘膜止血的新作用。我们 在这一领域取得了重大发现，是第一个克隆和表征其表达和运输的实验室 2005年的动力学。我们描述了NHE8出生后表达的变化，定义了它通过生长的调节 因子和激素，并且（对于本提案很重要）描述了其在杯状细胞中的丰富表达 和结肠隐窝。我们培育了 NHE8 缺陷小鼠 (NHE8KO) 并展示了令人着迷的表型 包括肠道粘膜完整性受损（杯状细胞和潘氏细胞缺陷、对细菌的易感性增强） 粘膜损伤、微生物失调、细菌粘附增加和粘液层破坏），对男性 不孕症和干眼综合症的发展。本报告中提出的这些以及其他初步观察结果 该提议使我们假设这种转运蛋白在粘膜稳态中发挥多效性作用，并且其 IBD 中表达的减少会导致肠道炎症和结直肠癌的易感性。测试 根据这个假设，我们制定了以下目标： 目标 1：确定 NHE8 参与杯状细胞功能的机制 目标 2：表征人类 UC 患者中 NHE8 的表达以及微生物和 其丢失引起的炎症后果 目标 3：确定 NHE8 在肿瘤发生中的作用 我们期望计划中的研究将具有变革性，并导致创建一个新的范式： 探讨上皮 Na+/H+ 交换（尤其是 NHE8）在肠道健康中的作用。