Intestinal inflammation involves two stages: early inflammatory phase and later resolution phase. The early phase is characterized by pathogen-induced activation of various cell types and release of numerous inflammatory mediators which then cause infiltration of leukocytes from circulation into intestinal mucosa to kill pathogens. The process also inevitably causes intestinal mucosal damage. The later phase involves proliferation of epithelial cells to repair damaged tissue. Activation and dysfunction of Intestinal microvascular endothelial cells (IMEC) during the early phase causes increased adhesion and transmigration of circulating immune cells into the mucosa. New microvessel formation (angiogenesis) which is induced by inflammatory mediators presumably has dual roles: one to increase leukocyte infiltration in the early phase and another to provide nutrients for extensive intestinal epithelial cell proliferation and tissue repair in the late phase. However, the exact functions and molecular mechanisms of IMEC in these processes are largely unknown. In addition to tumor necrosis factor-1 (TNF1), vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) and histamine are two potent microvascular permeability factors that are involved in dysfunction of microvascular endothelium. In order to profile the gene expression induced by VEGF/VPF we found that orphan nuclear receptors including Nur77, Nurr1 and Nor1 were highly induced. However nothing is known as to whether these orphan nuclear receptors play a role in intestinal inflammation though it can be induced by numerous factors such as TNF1 and LPS. In this pilot feasibility study we will focus on expression and function of Nur77 during colitis. Our preliminary results support the relevance of Nur77 in colitis. Therefore, our overall hypothesis of this proposal is that one important mechanism by which Nur77 modulates colitis is to regulate the functions of intestinal microvascular endothelium. To test our hypothesis, we will characterize the expression of Nur77 in animal models of colitis and determine whether Nur77 is involved in the formation of acute and chronic colitis. Our study will provide important insights on the role and mechanisms of novel orphan nuclear receptor Nur77 in inflammatory responses including human colitis.

Public Health Relevance

The pathophysiology of inflammatory bowel diseases is largely unknown. Our preliminary study suggests that novel orphan nuclear receptor Nur77 is involved in intestinal inflammation. We will further investigate the exact functions and mechanisms of this gene in both acute and chronic colitis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Hamilton, Frank A
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Beth Israel Deaconess Medical Center
United States
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