Scientific Abstract

Proposal No. IBD-0221R
Principal Investigator:  Liam O'Mahony, Ph.D.
Applicant Organization:  University College Cork (Ireland)
Project Title:  Building a computation modeling foundation for emerging information for inflammatory bowel disease
Period of Award:  January 7, 2008 – March 6, 2009

Biological researchers have been cataloguing the elements, pathways, and networks of human physiology, providing a foundational understanding of human health and disease. In the process, they have found that pathophysiology usually results from multiple perturbations of complex biochemical and cellular pathways rather than disruption of single gene products. An understanding of how these pathways and networks interact and their feedback mechanisms and latencies is imperative to advance and improve drug and diagnostic target discovery and validation. The molecular pathways that regulate cellular response to intestinal bacteria are central to the disease process that causes inflammatory bowel disease (IBD). The molecular nexus of the pathophysiology of IBD appears to include defects in the innate immune response to microbial challenge from the lumen of the gut. Research evidence suggests that intestinal dendritic cells are critical for regulation of immunity in the gut and are pivotal in the balance between tolerance and active immunity to commensal microorganisms that is fundamental to inflammatory conditions, including Crohn’s disease and ulcerative colitis. Thus, development in IBD will benefit from comprehensive and integrated understanding of the signaling pathways that regulate dendritic cell response to bacteria.

Dendritic cells are the principle antigen-presenting cell in the gut and their maturation state and cytokine production regulates the T cell response, ultimately modulating mucosal homeostasis vs. inflammation. We propose a computational model of toll-like receptor 4 (TLR4) signaling, TLR4 pathway modulation through DC-SIGN and other inhibitors, and NOD2 signaling in dendritic cells. This computer simulation contains a number of the principal molecular pathways that regulate the response of dendritic cells to bacterial pathogens, including MyD88-dependent and independent signaling, pathway inhibitors such as DC-SIGN, NOD2 signaling, and NF-κB activation.