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.
NHE8 is a unique Na+/H+ exchanger which has broad tissue distribution and cellular localization. The expression of NHE8 in the intestine is subject to developmental regulation under normal physiological conditions. During intestinal inflammation, NHE8 expression is severely reduced at both RNA and protein levels. Using a NHE8 deficient mouse model, we discovered novel physiological roles of NHE8 in the intestine and other tissues. Our new discoveries suggest that loss of NHE8 leads to profound alteration in intestinal stem cell Lgr5 gene expression, the intestinal microbiota distribution, goblet cell function and cytokine expression. These changes contribute to ultimate mucosal injury. The proposed studies not only may explain the role of NHE8 in mucosal integrity but also provide new approaches for understanding the physiological and pathological basis of gastroin- testinal disorders. Thus, these studies are of significant relevance in both basic research and clinical translational research.
| Xu, Hua; Ghishan, Fayez K; Kiela, Pawel R (2018) SLC9 Gene Family: Function, Expression, and Regulation. Compr Physiol 8:555-583 |
