Development of Intestinal Ion Transport

描述(由申请人提供)：这是一个竞争性的续期申请，旨在继续研究钠氢交换器3(NHE3)在胃肠道中的作用。Nhe属于参与Na+和H+电子中和交换的运输蛋白家族。NHE3是主要的Na+/H+交换器，负责大部分电解质通过胃肠道的运输，炎症介质和肠道致病菌对NHE3的抑制被认为是炎症性腹泻的主要机制。然而，我们最近公布的初步数据表明，NHE3在胃肠道中扮演着新的角色。这些包括对上皮完整性的贡献，改变肠道炎症中的免疫反应，以及塑造肠道微生物区系及其相互作用。 与粘膜的关系。NHE3缺乏导致粘膜细菌黏附和移位增加，并导致严重的IBD样生物失调。另一方面，抗生素和重新衍生成无幽门螺杆菌的超清洁屏障环境可以消除炎症表型。此外，NHE3缺乏会导致细胞黏附受损，尽管由此产生的屏障缺陷可以被肠粘膜中的调节性免疫反应部分补偿。目前的提议旨在扩大这些观察结果，以解决以下假设：肠道NHE3介导的Na+/H+交换通过调节细胞相互作用和结肠微生物区系来促进肠道内环境的稳定。为了解决这一假说，已经形成了三个特定的目标：(1)确定NHE3与肠道微生物区系的关系；(2)确定NHE3在肠道细胞黏附中的作用；(3)确定粘膜调节性免疫反应在NHE3-/-小鼠上皮缺陷补偿中的作用。这项拟议的研究将有助于解释NHE3抑制决定上皮屏障缺陷程度的机制，并有助于最终的炎症程度、疾病进展和结果。

DESCRIPTION (provided by applicant): This is a competing renewal application to continue studies on the role of sodium- hydrogen exchanger 3 (NHE3) in the gastrointestinal tract. NHE belong to a family of transport proteins involved in the electroneutral exchange of Na+ and H+. NHE3 is the predominant Na+/H+ exchanger responsible for the majority of electrolyte transport across the gastrointestinal tract, and its inhibition by inflammatory mediators and enteropathogenic bacteria is believed to be the primary mechanism of inflammation- associated diarrhea. However, our recently published and preliminary data have demonstrated novel roles for NHE3 in the GI tract. These involve its contribution to epithelial integrity, modifying immune responses in intestinal inflammation, and in shaping the intestinal microbiota and its interactions with the mucosa. NHE3 deficiency leads to increased mucosal bacterial adherence and translocation, and to profound IBD- like dysbiosis. On the other hand, antibiotics and rederivation into a Helicobacter-free ultraclean barrier environment eliminates the inflammatory phenotype. Moreover, NHE3 deficiency results to impaired cellular adhesion, although the resulting barrier defect is partially compensated by regulatory immune responses in the intestinal mucosa. The current proposal is aimed at expanding upon these observations to address the following hypothesis: intestinal NHE3-mediated Na+/H+ exchange contributes to the intestinal homeostasis via modulating cellular interactions and colonic microbiota. Three specific aims have been formulated to address this hypothesis: (1) to determine the relationship between NHE3 and intestinal microbiota; (2) to determine the role of NHE3 in intestinal cell adhesion; and (3) to determine the role of mucosal regulatory immune responses in the compensation of epithelial defect in NHE3-/- mice. The proposed research will help explain the mechanisms by which NHE3 inhibition determines the extent of the epithelial barrier defect and contributes to the ultimate degree of inflammation, disease progression and outcome.