Enteric bacterial modulation of Vitamin D Receptor signaling in colitis

描述（由申请人提供）：维生素D受体（VDR）是一种核受体，介导1，25-二羟基维生素D（1，25（OH）2D 3）（维生素D的激素形式）的大多数已知功能。VDR在胃肠道炎症中起重要作用。VDR基因多态性与炎症性肠病（IBD）易感性相关。VDR基因代表IBD的候选易感基因。此外，VDR缺陷小鼠更容易受到细菌感染。VDR IL-10双基因敲除小鼠发生更严重的IBD，涉及整个肠道。然而，大多数关于维生素D、VDR和炎症的研究都集中在免疫调节上，很少强调评估VDR在肠上皮细胞中的作用。内源性肠道细菌在IBD的发病机制中起着至关重要的作用。然而，目前尚不清楚肠道VDR信号如何响应肠道和致病性细菌的刺激。本研究旨在探讨VDR消融对肠上皮细胞NF-κ B活化的影响及其机制，以及肠道致病菌对VDR表达的影响。我们假设VDR表达通过抑制促炎性NF-κ B信号通路决定肠上皮细胞如何对致病性细菌触发物作出反应。具体而言，我们建议1）定义VDR在体外由病原菌刺激的细胞中负调节肠NF-κ B活性的分子机制，2）定义VDR信号传导在实验性沙门氏菌结肠炎小鼠模型中的抗炎功能。这些研究将为VDR抑制肠道炎症的抗炎机制提供新的见解。我们的研究也将为IBD的治疗建立一个新的靶点-VDR信号通路。 公共卫生相关性：维生素D和维生素D受体（VDR）在胃肠道炎症中发挥重要作用。本研究将探讨VDR在肠道炎症中的作用和机制，以及肠道细菌在VDR表达中的作用。我们的研究将为炎症性肠病的治疗建立一个新的靶点-VDR信号通路。

DESCRIPTION (provided by applicant): Vitamin D receptor (VDR) is a nuclear receptor that mediates most known functions of 1,25-dihydroxyvitamin D (1,25(OH)2D3), the hormonal form of vitamin D. VDR plays an essential role in gastrointestinal inflammation. Polymorphisms in the VDR gene are associated with susceptibility to inflammatory bowel disease (IBD). The VDR gene represents a candidate susceptibility gene for IBD. Moreover, VDR-deficient mice are more susceptible to bacterial infection. VDR IL-10 double knockout mice develop more severe IBD that involves the whole intestinal tract. However, the majority of studies of vitamin D, VDR, and inflammation are focused on immunoregulation, with little emphasis on assessing the effects of VDR in intestinal epithelial cells. Endogenous enteric bacteria play a crucial role in the pathogenesis of IBD. However, it is unknown how intestinal VDR signaling responds to commensal and pathogenic bacterial stimulation. This study will investigate the effects and mechanism of VDR ablation on NF-kappaB activation in intestinal epithelia and the role of pathogenic enteric bacteria on VDR expression. We hypothesize that VDR expression determines how intestinal epithelial cells respond to pathogenic bacterial triggers by inhibiting the proinflammatory NF-kappaB signaling pathways. Specifically, we propose to 1) define the molecular mechanism of VDR negatively regulating intestinal NF-kappaB activity in cells stimulated by pathogenic bacteria in vitro and 2) define the anti-inflammatory function of VDR signaling in experimental Salmonella-colitis mouse models. These studies will provide new insight into the anti-inflammatory mechanism of VDR in inhibiting intestinal inflammation. Our studies will also establish a new target-VDR signaling for treatment of IBD. PUBLIC HEALTH RELEVANCE: Vitamin D and vitamin D receptor (VDR) play an essential role in gastrointestinal inflammation. This study will investigate the effects and mechanism of VDR in intestinal inflammation and the role of gut bacteria in VDR expression. Our studies will establish a new target-VDR signaling for treatment of inflammatory bowel disease.