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.
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.
|Wang, Jun; Thingholm, Louise B; SkieceviÄienÄ—, Jurgita et al. (2016) Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat Genet 48:1396-1406|
|(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222|
|Munoz, Sean; Guzman-Rodriguez, Mabel; Sun, Jun et al. (2016) Rebooting the microbiome. Gut Microbes 7:353-363|
|Sun, Jun (2016) VDR/vitamin D receptor regulates autophagic activity through ATG16L1. Autophagy 12:1057-8|
|Shang, Mei; Sun, Jun (2016) Vitamin D/VDR, probiotics, and gastrointestinal diseases. Curr Med Chem :|
|Lu, Rong; Wu, Shaoping; Zhang, Yong-Guo et al. (2016) Salmonella Protein AvrA Activates the STAT3 Signaling Pathway in Colon Cancer. Neoplasia 18:307-16|
|Zhang, Yongguo; Wu, Shaoping; Ma, Jun et al. (2015) Bacterial protein AvrA stabilizes intestinal epithelial tight junctions via blockage of the C-Jun N-terminal kinase pathway. Tissue Barriers 3:e972849|
|Wu, Shaoping; Yoon, Sonia; Zhang, Yong-Guo et al. (2015) Vitamin D receptor pathway is required for probiotic protection in colitis. Am J Physiol Gastrointest Liver Physiol 309:G341-9|
|Zhang, Yong-guo; Wu, Shaoping; Lu, Rong et al. (2015) Tight junction CLDN2 gene is a direct target of the vitamin D receptor. Sci Rep 5:10642|
|Wu, Shaoping; Zhang, Yong-Guo; Lu, Rong et al. (2015) Intestinal epithelial vitamin D receptor deletion leads to defective autophagy in colitis. Gut 64:1082-94|
Showing the most recent 10 out of 36 publications