Scientific Abstract

Proposal No. IBD-0197
Principal Investigator:  Emma M. Creagh, Ph.D.
Applicant Organization:  University of Dublin, Trinity College (Ireland)
Project Title:  Understanding the role and regulation of caspase-1 activation in inflammatory bowel disease
Period of Award:  May 1, 2008 – October 31, 2011

Microorganisms are recognized rapidly by immune cells expressing molecules such as Toll- and NOD-like receptors (TLRs and NLRs). Certain TLRs and NLRs impact on the pro-inflammatory protease, caspase-1, which acts to process pro-IL1beta and pro-IL-18 to active forms for secretion.  The ability to inhibit the damaging effects of excessive IL-1β has significant therapeutic potential for IBD, thus understanding how caspase-1 activation is achieved during IBD is an important issue.

The emerging importance of NLRs in immunity, combined with their similarity to TLRs, suggests that a certain amount of synergy exists between them.  Mutations in the NLR, NOD2, are associated with Crohn’s disease (CD). The first goal of this project is to examine whether NOD2 has a synergistic role during TLR signalling, leading to enhanced caspase-1 activation, as a mutant form of NOD2 has been linked to enhanced production of mature IL-1beta.  This will be carried out experimentally by comparing caspase-1 activation status in primary monocytes obtained from CD patients (with and without the NOD2 mutation), ulcerative colitis patients and normal healthy controls.

The ‘inflammasome’-based mechanisms proposed to activate caspase-1 following TLR stimulation have yet to be clearly defined, and the second goal of the project is to characterize and compare native inflammasomes in control and IBD primary monocytes using proteomics. Particular focus will be on the recruitment of NOD2 into assembling inflammasomes.  These two key aims should yield significant insights into the involvement of caspase-1 activation in IBD.