The overall goal of the Program Project is to fill a major gap in current knowledge of IBD pathogenesis by studying children with Crohn's disease and ulcerative colitis, and the progression of early to late stages of disease in animal models of gastrointestinal inflammation. The proposal is the natural outcome of a vigorous and multi-disciplinary expertise in IBD pathophysiology, intestinal immunity, mucosal cytokines, animal model of colitis and gastritis, and immune-non immune cell interaction in intestinal inflammation. The Program Project will investigate will investigate mechanistic links of early to late events of gut inflammation by testing the specific hypotheses proposed in four Research Projects. Project 1: Early IBD in children results from loss of tolerance to antigens of the commensal flora, and its persistence contributes to the chronicity of IBD. Project 2: Inflammation in murine models of IBD is initiated by mucosal T-cell responses to enterobacterial antigens, and it is perpetuated during the late stage of disease by a pro-inflammatory response maintained by mucosal immune and non immune cells. Project 3: Chronic gastrointestinal inflammation results from an aberrant immune response against antigenic stimuli derived from the normal enteric flora, and this response is modulated by immunization and the presence or absence of Helicobacter organisms. Project 4: Specific changes in the composition of the extracellular matrix of mucosal basement membrane contributes crucially to early inflammation, while altered synthesis and modulation of interstitial extracellular matrix foster progression of inflammation from the early to the late stages of disease. These proje3cts will be performed using state-of-the-art methodological strategies including evaluation of tolerance to normal enteric antigens in pediatric and adult IBD patients, immunoregulatory studies in gene-deficient mice with early and late models of intestinal inflammation, colonization by commensal and infectious bacteria in these models, DNA microarray systems for differential gene expression in intestinal inflammation, extracellular matrix gene and protein expression in human and murine models of IBD, and induction of intestinal fibrosis in normal and proteoglycan-deficient mice. The four Projects will be supported by three Service Cores: a Patient Core (A), an Animal Core (B) and an Administrative Core (C).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
1P01DK057756-01
Application #
6090252
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (J3))
Program Officer
Hamilton, Frank A
Project Start
2000-09-15
Project End
2005-09-14
Budget Start
2000-09-15
Budget End
2001-09-14
Support Year
1
Fiscal Year
2000
Total Cost
$882,828
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Danese, Silvio; Sans, Miquel; Spencer, David M et al. (2007) Angiogenesis blockade as a new therapeutic approach to experimental colitis. Gut 56:855-62
Kugathasan, S; Saubermann, L J; Smith, L et al. (2007) Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease. Gut 56:1696-705
Etling, Michele R; Davies, Sarah; Campbell, Melanie et al. (2007) Maturation of the mucosal immune system underlies colitis susceptibility in interleukin-10-deficient (IL-10-/-) mice. J Leukoc Biol 82:311-9
Day, Anthony J; de la Motte, Carol A (2005) Hyaluronan cross-linking: a protective mechanism in inflammation? Trends Immunol 26:637-43
Drakes, Maureen L; Blanchard, Thomas G; Czinn, Steven J (2005) Colon lamina propria dendritic cells induce a proinflammatory cytokine response in lamina propria T cells in the SCID mouse model of colitis. J Leukoc Biol 78:1291-300
Stallion, Anthony; Kou, Tzuyung D; Latifi, Samir Q et al. (2005) Ischemia/reperfusion: a clinically relevant model of intestinal injury yielding systemic inflammation. J Pediatr Surg 40:470-7
Manley, Mollie O; O'Riordan, Mary Ann; Levine, Alan D et al. (2005) Interleukin 10 extends the effectiveness of standard therapy during late sepsis with serum interleukin 6 levels predicting outcome. Shock 23:521-6
Matsumoto, Yuko; Blanchard, Thomas G; Drakes, Maureen L et al. (2005) Eradication of Helicobacter pylori and resolution of gastritis in the gastric mucosa of IL-10-deficient mice. Helicobacter 10:407-15
Drakes, Maureen; Blanchard, Thomas; Czinn, Steven (2004) Bacterial probiotic modulation of dendritic cells. Infect Immun 72:3299-309
Rahn, Wibke; Redline, Raymond W; Blanchard, Thomas G (2004) Molecular analysis of Helicobacter pylori-associated gastric inflammation in naive versus previously immunized mice. Vaccine 23:807-18

Showing the most recent 10 out of 17 publications