Inflammatory Bowel Disease

Background

Inflammatory bowel diseases (IBD) are a set of debilitating gastrointestinal disorders manifested pathologically as diarrhea, rectal bleeding, and weight loss. They are broadly classified into two diseases: Crohn’s Disease, characterized by focal, transmural inflammation throughout the GI tract, and Ulcerative Colitis, characterized by continuous mucosal inflammation occurring in the colon. The cause of these diseases is unknown but it is generally recognized that it involves a combination of many weak risk factors that modulate complex interactions between the gut flora, intestinal epithelium, and immune system. Because these complex diseases can be viewed as shifts in the in vivo homeostatic state as opposed to dysregulation of singular pathways, we surmise that a systems level approach will be necessary for understanding the cause, progression, and treatment for these diseases.

Approach

Our goal is to identify intra- and inter-cellular inflammatory networks in the intestine. To this end, we are using acute stimulation with inflammatory cytokines to investigate early events, and genetic and non-genetic models of IBD to look at changes associated with chronic disease. Using a multi-plexed bead based assay to quantify protein, we are looking at the cytokines and phospho-proteins that may be associated with intestinal inflammation. We then build mathematical models in order to find links between these signals and quantitative and semi-quantitative phenotypes including proliferation, apoptosis, mucosal thickness and immune cell infiltration.  Based on these models, we select nodes in the networks that can be perturbed in order to alter the tissue-wide inflammatory response. Ultimately, we hope to build systems-level models that will provide valuable insight into the biology of inflammation. In doing so, we expect to identify novel pathways and networks that can be targeted for the treatment of IBD.

A major benefit of applying systems approaches to mouse models is that it allows us to characterize the complex interplay that exists between different kinds of cells in a complex tissue. Using computational modeling and experimentation, we have characterized a signaling network that allows the intestinal epithelium to communicate with the intestinal immune system in order to regulate inflammatory responses in the gut. Our current work focuses determining how perturbation of this intercellular communication network modifies the course of IBD in mouse models.