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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
5R03DK089010-02
Application #
8112427
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2010-07-20
Project End
2012-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
2
Fiscal Year
2011
Total Cost
$26,531
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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