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

摘要 这是一项新的应用，旨在研究肠道NHE 8对粘膜止血的新作用。我们 在该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年的动力学。我们已经描述了出生后NHE 8表达的变化，定义了其通过生长调节 因子和激素，并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NHE 8缺陷小鼠（NHE 8 KO），并展示了迷人的表型 范围从受损的肠粘膜完整性（杯状细胞和潘氏细胞的缺陷，增强的易感性， 粘膜损伤、微生物生态失调、细菌粘附增加和粘液层破坏）， 不育和干眼症的发展。本报告中提出的这些和其他初步意见 这一提议使我们假设这种转运蛋白在粘膜内稳态中起多效性作用， IBD中的表达降低有助于肠道炎症和对结肠直肠癌的易感性。测试 根据这一假设，我们制定了以下目标： 目的1：确定NHE 8参与杯状细胞功能的机制 目的2：表征人UC患者中的NHE 8表达以及微生物和细胞因子的表达。 其损失的炎症后果 目的3：确定NHE 8在肿瘤发生中的作用 我们希望计划中的研究将是变革性的，并导致建立一个新的范式， 上皮Na+/H+交换，特别是NHE 8在肠道健康中的作用。

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.