Lay Summary

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, 2010

Recognition proteins called Toll-like and Nod-like receptors (TLRs and NLRs) are used to rapidly detect infection and activate the body’s defense response.  A major defense response is the inflammatory response, which occurs when specific TLRs/NLRs have been activated, triggering the turning-on of a key inflammatory activator, called caspase-1.

This results in the rapid recruitment of defense cells to the infected area and efficient eradication of infection.  Sometimes however, inflammatory diseases such as Crohn’s disease (CD) and ulcerative colitis arise due to faulty activation of receptors or caspase-1.  An alteration in a specific type of NLR, called Nod2, has been linked to the development of CD, however the mechanism through which it activates inflammation is still unknown. Understanding how our body controls the turning-on and off these specific molecules is critical to developing solutions to alleviate the symptoms of inflammatory bowel disease.

This proposal aims to understand the mechanisms involved in caspase-1 activation, which require both TLR and NLR receptors.

The specific research objectives are to:

(i) Determine the level of co-operation between TLRs and NLRs (especially Nod2) during the activation of caspase-1.

(ii) Characterize caspase-1 activating complexes that are thought to facilitate its turn-on and determine whether normal or altered Nod2 protein is involved in these complexes.