Enteric bacterial modulation of Vitamin D Receptor signaling in colitis

描述（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)2D3）的大多数已知功能，维生素D的激素形式。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基因是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双敲除小鼠会发生更严重的IBD，并累及整个肠道。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，很少重视评估VDR对肠上皮细胞的影响。内源性肠道细菌在IBD发病机制中起着至关重要的作用。然而，肠道VDR信号如何响应共生菌和致病菌刺激尚不清楚。本研究将探讨VDR消融对肠上皮细胞NF-kappaB活化的影响及机制，以及致病性肠道细菌对VDR表达的影响。我们假设VDR的表达通过抑制促炎NF-kappaB信号通路来决定肠上皮细胞对致病菌触发的反应。具体而言，我们建议：1)明确VDR在体外致病菌刺激下负性调节肠道NF-kappaB活性的分子机制；2)明确VDR信号在实验性沙门氏菌-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认识。我们的研究也将建立一个新的靶点- vdr信号治疗IBD。

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.