Project 2, headed by Dr. Derek Abbott, will test the alternative hypothesis that exaggerated N0D2 signaling leads to chronic intestinal inflammation. This project will investigate the dysregulation of the Nod2 gene at the molecular level. Lack of coordination between inflammatory signaling pathways influences the development of CD. We recently published that the E3 ubiquitin ligase ITCH, causes K63-linked polyubiquitination of RIP2, and this event downregulates active NOD2:RIP2 complexes. Mice in which Itch is genetically lost (itchy mice) develop inflammatory disease at mucosal surfaces (including intestinal inflammation). We have data showing that ITCH-/- mice develop gastritis, ileitis and colitis and that drugs that inhibit RIP2 tyrosine phosphorylation, such as tarceva and iressa, inhibit the exaggerated N0D2 responses. The central hypothesis of this project is that ITCH downregulates NOD2;RIP2-induced NFDB signaling, and that CD results when this downregulation is lost.
Aim 1 will study this ITCH-induced ubiquitination event to determine the biochemistry and physiologic function of ITCH-induced RIP2 ubiquitination.
In Aim 2, we will determine the role of tyrosine phosphorylation of R1P2 and the role that pharmacological inhibition of this phosphorylation plays in ITCH-induced R1P2 ubiquitination and N0D2- induced cytokine responses.
In Aim 3, we will characterize the Gl inflammation of the Itchy mouse and will determine whether tarceva or iressa can alleviate chronic intestinal inflammation in these mice. Our preliminary data shows that Itchy mice have increased gastrointestinal permeability. This increased permeability allows MDP leakage into the lamina propria and causes prolonged NFkappaB activation to occur. We hypothesize that tarceva and iressa will inhibit exaggerated lamina propria N0D2 activation in the itchy mice and alleviate the chronic inflammation. The overall objective of this project is to determine the biochemistry of the ITCH:RIP2 interaction, the physiologic significance of this interaction, and most importantly, whether this interaction can be inhibited pharmacologically to ameliorate chronic intestinal inflammation.

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 #
8716738
Study Section
Special Emphasis Panel (ZDK1-GRB-6)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
$188,679
Indirect Cost
$78,511
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Ryan, Sean O; Leal Jr, Sixto M; Abbott, Derek W et al. (2014) Mgat2 ablation in the myeloid lineage leads to defective glycoantigen T cell responses. Glycobiology 24:262-71
Goodman, W A; Garg, R R; Reuter, B K et al. (2014) Loss of estrogen-mediated immunoprotection underlies female gender bias in experimental Crohn's-like ileitis. Mucosal Immunol 7:1255-65
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Tigno-Aranjuez, Justine T; Benderitter, Pascal; Rombouts, Frederik et al. (2014) In vivo inhibition of RIPK2 kinase alleviates inflammatory disease. J Biol Chem 289:29651-64
Corridoni, Daniele; Arseneau, Kristen O; Cominelli, Fabio (2014) Functional defects in NOD2 signaling in experimental and human Crohn disease. Gut Microbes 5:340-4
Corridoni, Daniele; Arseneau, Kristen O; Cominelli, Fabio (2014) Inflammatory bowel disease. Immunol Lett 161:231-5
Cavalcanti, Elisabetta; Vadrucci, Elisa; Delvecchio, Francesca Romana et al. (2014) Administration of reconstituted polyphenol oil bodies efficiently suppresses dendritic cell inflammatory pathways and acute intestinal inflammation. PLoS One 9:e88898
Goodman, Wendy A; Pizarro, Theresa T (2013) Regulatory cell populations in the intestinal mucosa. Curr Opin Gastroenterol 29:614-20
Pastorelli, Luca; De Salvo, Carlo; Vecchi, Maurizio et al. (2013) The role of IL-33 in gut mucosal inflammation. Mediators Inflamm 2013:608187

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