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NHE8在粘膜止血中的新作用。我们 已经在该领域发现了重大发现，是第一个克隆并表征其表达和运输的实验室 动力学于2005年。我们描述了NHE8产后表达的变化，定义了其通过生长的调节 因子和激素，并且（对于此提案而言）描述了其在杯状细胞中的丰富表达 和结肠隐窝。我们开发了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（Go​​blet和Paneth细胞中的缺陷）范围内，对 粘膜损伤，微生物营养不良，细菌粘附增加和粘液层的破坏），对雄性 干眼症综合征的不育和发展。这些和其他初步观察 提案使我们假设该转运蛋白在粘膜稳态中扮演多效性角色，并且它 IBD的表达降低会导致肠道炎症和对结直肠癌的敏感性。测试 这个假设，我们制定了以下目的： AIM 1：确定NHE8参与Goblet细胞功能的机制 AIM 2：特征在人类UC患者和微生物中的NHE8表达以及 炎症后果的损失 目标3：确定NHE8在肿瘤发生中的作用 我们希望计划的研究将具有变革性，并导致创建新的范式 - 尤其是NHE8上皮Na+/H+交换的作用，在肠道健康中。