Development of Intestinal Ion Transport

描述（由申请人提供）：这是一项竞争性更新申请，旨在继续研究钠-氢交换剂3（NHE 3）在胃肠道中的作用。NHE属于一个转运蛋白家族，参与Na+和H+的电中性交换。NHE 3是主要的Na+/H+交换剂，负责大部分电解质跨胃肠道的转运，并且其被炎性介质和肠道致病菌抑制被认为是炎症相关腹泻的主要机制。然而，我们最近发表的和初步的数据已经证明了NHE 3在胃肠道中的新作用。这些涉及其对上皮完整性的贡献，在肠道炎症中改变免疫反应，以及塑造肠道微生物群及其相互作用 与粘膜接触。NHE 3缺乏导致粘膜细菌粘附和易位增加，并导致严重的IBD样生态失调。另一方面，抗生素和再衍生到无螺杆菌的超净屏障环境中消除了炎症表型。此外，NHE 3缺乏导致受损的细胞粘附，尽管所产生的屏障缺陷通过肠粘膜中的调节性免疫应答而部分补偿。目前的建议旨在扩展这些观察结果，以解决以下假设：肠道NHE 3介导的Na+/H+交换通过调节细胞相互作用和结肠微生物群有助于肠道稳态。已经制定了三个具体目标来解决这一假设：（1）确定NHE 3和肠道微生物群之间的关系;（2）确定NHE 3在肠细胞粘附中的作用;（3）确定粘膜调节免疫应答在NHE 3-/-小鼠上皮缺陷补偿中的作用。拟议的研究将有助于解释NHE 3抑制决定上皮屏障缺陷程度的机制，并有助于炎症，疾病进展和结果的最终程度。 公共卫生相关性：NHE 3是主要的Na+/H+交换剂，负责大部分钠和水穿过胃肠道的转运，并且其在炎症期间的抑制代表炎症相关性腹泻的主要机制。来自我们实验室的新数据表明，NHE 3抑制导致的其他后果可能导致肠道微生物群、细胞相互作用的深刻改变，并导致最终的上皮屏障缺陷。这些研究具有重要的基础性意义。 和临床相关性，因为它们不仅可以解释Na+/H+交换在肠道炎症期间的作用，而且还可以指导未来针对各种肠道炎症状况的临床方法。

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. PUBLIC HEALTH RELEVANCE: NHE3 is the predominant Na+/H+ exchanger responsible for the majority of sodium and water transport across the gastrointestinal tract, and its inhibition during inflammation represents the primary mechanism of inflammation-associated diarrhea. Novel data from our laboratory suggest additional consequences resulting from NHE3 inhibition, which may lead to profound alteration of intestinal microbiota, cellular interactions, and contribute to the ultimate epithelial barrier defect. The proposed studies are of significant basic and clinical relevance as they may not only explain the role of Na+/H+ exchange during intestinal inflammation but they may also guide future clinical approaches to a variety of inflammatory conditions of the gut.