Inflammatory bowel disease (IBD) involves the interplay of multiple biological factors, among which nonimmune cells represent an underrated but crucial component of disease pachogenesis. In particular; mucosal endothelial cells play a key role in chronic inflammation through angiogenesis, a complex process mediated by the coordinated involvement of multiple cells types and a variety of sol nble mediators, which can be grouped into four major categories: a) growth factors, that directly promote endothelial cell proliferation and migration, b) integrins, adhesion molecules that allow communication of endothelial cells with other cells and the extracellular matrix (ECM), c) leukocytes, cytokines and chemokines, that drive immune-mediated endothelial cell activation, and d) proteolytic enzymes and ECM proteins, that are responsible for the tissue remodeling necessary to formation of new vessels. Sate-of-the-art knowledge on tie role of angiogenesis in cancer, autoimmunity and chronic inflammation, and our own preliminary data, obtained by studying tissues and cells from IBD patients and mice with experimental colitis, provide solid evidence supporting the concept that angiogenesis plays a vital role in initiation and perpetuation of intestinal inflammation. This proposal will investigate mechanisms of angiogenesis in IBD by testing the following central hypothesis: Angiogenesis is a critical component of IBD and contributes to disease pathogenesis. This hypothesis will be tested by four specific aims: 1) Obtain evidence of increased vascularization and endothelial cell activation in IBD mucosa; 2) Define the dominant angiogenic factors produced in IBD, their origin, and biological activity; 3) Characterize endothelial cell-mediated changes in the ECM that promote angiogenesis; 4) Investigate the therapeutic effects of anti-angiogenic compounds in animal models of IBD. Blocking angiogenesis may interrupt the chronic cycle of immune-nonimmune cell interactions occurring in IBD and result in clinical improvement, as suggested by clinical trials in humans and animals suffering from neoplastic, autoimmune and inflammatory disorders. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069854-04
Application #
7485809
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
2005-09-15
Project End
2010-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
4
Fiscal Year
2008
Total Cost
$301,485
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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