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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

基本信息

批准号：
9980395
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
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980395
关键词：
Adult Affect Allografting Apical Bacterial Adhesion Basic Science Butyrates Cell Line Cell physiology Clinical Colitis associated colorectal cancer Colonic Neoplasms Colorectal Cancer Data Defect Development Distal Down-Regulation Drug or chemical Tissue Distribution Dry Eye Syndromes Electrolytes Epithelial Epithelial Cells Epithelium Family Functional disorder Gastrointestinal Diseases Gastrointestinal tract structure Gene Expression Gnotobiotic Goblet Cells Growth Factor Gut Mucosa Health Hemostatic function Homeostasis Human Impairment Inflammation Inflammatory Inflammatory Response Injury Intestines Kinetics LGR5 gene Lead Life Liquid substance MAP Kinase Gene Male Infertility 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 Testing Tissues Translational Research Ulcerative Colitis WNT Signaling Pathway absorption colonic crypt cytokine design dysbiosis fascinate gastrointestinal epithelium gut microbiome gut microbiota inflammatory disease of the intestine intestinal epithelium mRNA Expression male member microbial mouse model novel novel strategies ocular surface postnatal protein expression reproductive tract stem cells transplant model tumor tumorigenesis

项目摘要

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