Enteric bacterial modulation of Vitamin D Receptor signaling in colitis

结肠炎中维生素 D 受体信号传导的肠道细菌调节

基本信息

批准号：
8112427
负责人：
Jun Sun
金额：
$ 2.65万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-20 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8112427
关键词：
1,25 (OH) vitamin D Ablation Anti-Inflammatory Agents Anti-inflammatory Bacteria Bacterial Infections Binding Calcium Cells Colitis Defensins Electrolytes Enteral Enterobacteriaceae Enzymes Epithelial Epithelial Cells Escherichia coli Gene Targeting Genetic Polymorphism Homeostasis Hormonal Human I Kappa B-Alpha Immune response In Vitro Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Interleukin-10 Intestines Knock-out Knockout Mice Mediating Microbe Molecular Mus NF-kappa B Nuclear Receptors Outcome Pathogenesis Play Predisposition Receptor Gene Receptor Signaling Regulation Role Salmonella Serum Signal Pathway Susceptibility Gene Tight Junctions Vitamin D Vitamin D3 Receptor Wild Type Mouse antimicrobial peptide base blood pressure regulation cathelicidin cytokine gastrointestinal immunoregulation in vivo inhibitor/antagonist insight intestinal epithelium mouse model p65 pathogenic bacteria public health relevance receptor expression salmonella colitis

项目摘要

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.

描述（由申请人提供）：维生素D受体（VDR）是一种核受体，介导了1,25-二羟基维生素D（1,25（OH）2D3）的最著名功能，维生素D的激素形式D. VDR在胃肠道炎症中起着重要作用。 VDR基因中的多态性与炎症性肠病（IBD）的易感性有关。 VDR基因代表了IBD的候选敏感性基因。此外，缺乏VDR的小鼠更容易受到细菌感染的影响。 VDR IL-10双基因敲除小鼠会产生更严重的IBD，涉及整个肠道。但是，大多数维生素D，VDR和炎症的研究都集中在免疫调节上，很少强调评估VDR在肠上皮细胞中的影响。内源性肠细菌在IBD的发病机理中起着至关重要的作用。然而，尚不清楚肠道VDR信号如何对共生和致病细菌刺激做出反应。这项研究将研究VDR消融对肠上皮中NF-kappab激活的影响和机制，以及致病性肠细菌对VDR表达的作用。我们假设VDR表达通过抑制促炎性NF-kappab信号通路来确定肠上皮细胞如何应对致病细菌触发。具体而言，我们建议1）定义VDR的分子机制在体外被致病细菌刺激的细胞中负调控肠NF-kappab活性，并定义实验性沙门氏菌炎小鼠模型中VDR信号传导的抗炎信号传导的抗炎功能。这些研究将为VDR抑制肠炎的抗炎机制提供新的见解。我们的研究还将建立一种用于治疗IBD的新目标VDR信号。公共卫生相关性：维生素D和维生素D受体（VDR）在胃肠道炎症中起着至关重要的作用。这项研究将研究VDR在肠道炎症中的影响和机制，以及肠道细菌在VDR表达中的作用。我们的研究将建立一个新的靶标信号，用于治疗炎症性肠病。