Crohn's disease (CD) is a debilitating condition with no known cure. The precise cause(s) of CD remain undefined. Increasing evidence suggests that CD may be initiated by a dysregulated innate immune response against """"""""unknown"""""""" antigens in a genetically-susceptible host. The central hypothesis of this Program Project application is that CD results from a abnormality in Innate immune responses to luminal antigens. Our preliminary data suggests that a dysregulation in N0D2 signaling and intestinal permeability may precede the development of chronic ileitis. These effects are associated with abnormal dendritic and macrophage function and excessive activation of the adaptive immune system. The resulting proinflammatory effects leads to the chronic inflammatory response characteristic of CD. The overall objective of this Program Project is to understand the mechanisms of innate immune dysfunction in CD pathogenesis, with the ultimate goal of developing new therapeutic strategies for this devastating disease. The Program Project will be directed by Dr. Pablo Cominelll and will consist of 4 projects and 2 cores. Project 1, headed by Dr. Fabio Cominelli, will test the hypothesis that a deficit in N0D2 signaling and MDP responses is responsible for SAMP CD-like ileitis. Project 2, headed by Dr. Derek Abbott, will focus on the alternative hypothesis that an exaggeration in N0D2 signaling may result in chronic intestinal inflammation. Project 3, headed by Dr. Klaus Ley, will investigate the role of myeloid cells in mediating chronic ileitis. Project 4, headed by Dr. Theresa Pizarro, will study epithelial-immune cell interactions, specifically the interplay between the intestinal epithelium, dendritic cells, and T regulatory cells. These projects are supported by an Administrative Core, which provides administrative support and coordinates the enrichment program. A Mouse/Histology Core will centralize the production and breeding of mice with experimental CD and provide centralized pathologic and histological analysis. The long-term goal of this Program Project is to understand key pathogenic mechanisms of innate immunity in experimental CD, which can be immediately translated to the human condition.

Public Health Relevance

CD affects more than 500,000 individuals In the US and incurs significant costs to society. Understanding the precise mechanisms and immune defects that cause the disease will allow us to develop better therapies and begin to develop a cure for this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK091222-04
Application #
8716735
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (J1))
Program Officer
Hamilton, Frank A
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
$1,327,589
Indirect Cost
$359,951
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
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Bamias, Giorgos; Pizarro, Theresa T; Cominelli, Fabio (2016) Pathway-based approaches to the treatment of inflammatory bowel disease. Transl Res 167:104-15
Grivennikov, Sergei I; Cominelli, Fabio (2016) Colitis-Associated and Sporadic Colon Cancers: Different Diseases, Different Mutations? Gastroenterology 150:808-10
Rodriguez-Palacios, Alexander; Aladyshkina, Natalia; Retuerto, Mauricio et al. (2016) Clinical Effects of Gamma-Radiation-Resistant Aspergillus sydowii on Germ-Free Mice Immunologically Prone to Inflammatory Bowel Disease. J Pathog 2016:5748745
Chirieleison, Steven M; Kertesy, Sylvia B; Abbott, Derek W (2016) Synthetic Biology Reveals the Uniqueness of the RIP Kinase Domain. J Immunol 196:4291-7

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