The pathophysiology of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, has been studied extensively but. Disease mechanisms involve cross-talk amongst pathogens and various host cell types (luminal epithelial cells, enteric nerve cells, resident immune cells, fibroblasts, microvascular endothelia cells and circulating leukocytes, inter alia). Amongst these, intestinal microvascular endothelial cells (IMEC) may play a central role in the progression of the disease by modulating infiltration of circulating immune cells and providing nutrients for inflammation resolution and tissue repair. Activated IMEC secrete various pro- inflammatory mediators and express cell-cell adhesion molecules that facilitate leukocyte infiltration. In addition, increased microvessel formation (angiogenesis) during colitis could promote inflammation and impact tissue regeneration/healing. Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) has been shown to play important roles in experimental colitis. In our initial efforts to profile VEGF/VPF-induced genes in cultured human endothelial cells HUVEC, we found that the orphan nuclear receptor Nur77 was highly induced in these cells. Nur77 has been shown to play important roles in cell growth, differentiation and apoptosis. The goal of this application isto test the hypothesis that Nur77 modulates colitis by regulating the functions of intestinal microvascular endothelium: such as microvessel permeability, angiogenesis and leukocyte transendothelial migration. To this end, we have shown that Nur77 is highly induced in acute trisnitrobenzene sulfonic acid (TNBS) and dextran sulfate sodium (DSS) experimental colitis. Further, high levels of Nur77 are present in the colons of patients with IBD, when compared to non-inflamed colonic tissues. The present application will investigate how Nur77 specifically regulates endothelial functions and impacts progression of colitis. We propose that Nur77 expression in IMEC and infiltrating immune cells might play an important role in regulating acute intestinal inflammation.
Aim 1 will examine several models of colitis in mice express Nur77 exclusively in endothelial cells.
Aim 2 will determine the role of VE-cadherin-based adherens junction in colitis.
Aim 3 will dissect out regulatory mechanisms of VE-cadherin expression by Nur77. Several genetic approaches include generation of inducible endothelial specific transgenic mice to express wild-type Nur77 and dominant negative Nur77 on both wild-type and Nur77-null backgrounds. Our studies have high impact by linking Nur77 to IBD pathogenesis and indicate vascular components of inflammation that could serve as therapeutic targets.

Public Health Relevance

The pathophysiology of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, has been studied extensively but. Disease mechanisms involve cross-talk amongst pathogens and various host cell types (luminal epithelial cells, enteric nerve cells, resident immune cells, fibroblasts, microvascular endothelial cells and circulating leukocytes, inter alia). Amongst these, intestinal microvascular endothelial cells (IMEC) may play a central role in the progression of the disease by modulating infiltration of circulating immune cells and providing nutrients for inflammation resolution and tissue repair. Activated IMEC secrete various pro- inflammatory mediators and express cell-cell adhesion molecules that facilitate leukocyte infiltration. In addition, increased microvessel formation (angiogenesis) during colitis could promote inflammation and impact tissue regeneration/healing. Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) has been shown to play important roles in experimental colitis. In our initial efforts to profile VEGF/VPF-induced genes in cultured human endothelial cells HUVEC, we found that the orphan nuclear receptor Nur77 was highly induced in these cells. Nur77 has been shown to play important roles in cell growth, differentiation and apoptosis. The goal of this application isto test the hypothesis that Nur77 modulates colitis by regulating the functions of intestinal microvascular endothelium: such as microvessel permeability, angiogenesis and leukocyte transendothelial migration. To this end, we have shown that Nur77 is highly induced in acute trisnitrobenzene sulfonic acid (TNBS) and dextran sulfate sodium (DSS) experimental colitis. Further, high levels of Nur77 are present in the colons of patients with IBD, when compared to non-inflamed colonic tissues. The present application will investigate how Nur77 specifically regulates endothelial functions and impacts progression of colitis. We propose that Nur77 expression in IMEC and infiltrating immune cells might play an important role in regulating acute intestinal inflammation. Aim 1 will examine several models of colitis in mice express Nur77 exclusively in endothelial cells. Aim 2 will determine the role of VE-cadherin-based adherens junction in colitis. Aim 3 will dissect out regulatory mechanisms of VE-cadherin expression by Nur77. Several genetic approaches include generation of inducible endothelial specific transgenic mice to express wild-type Nur77 and dominant negative Nur77 on both wild-type and Nur77-null backgrounds. Our studies have high impact by linking Nur77 to IBD pathogenesis and indicate vascular components of inflammation that could serve as therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK095873-01A1
Application #
8579528
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
2013-07-01
Project End
2018-05-31
Budget Start
2013-07-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$378,450
Indirect Cost
$160,950
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215