Dysregulated Signaling in Crohn s Disease
Abstract
Our overarching goal is to understand how dysregulated protein signaling pathways contribute to Crohn s disease (CD). Because signaling pathways are readily targetable with small molecule or antibody-based therapies, understanding CD-related protein signaling will undoubtedly lead to the identification of new treatment strategies. CD is a chronic and debilitating inflammatory disorder of the small and large intestine. Few effective therapies are available to the 700,000 CD patients living in the United States. The genetics of CD are extremely complex, and environment plays a significant role in promoting the disease, making it difficult to identify the underlying molecular drivers of CD. In particular, the role that protein signal transduction cascades play in CD is not well understood. Our working hypothesis is that genetically and environmentally diverse individuals can present with common symptoms of CD because they share a common dysregulated protein signaling state in their gastrointestinal tracts. By extension, we postulate that new therapeutic strategies will emerge from a better understanding of CD-related protein signaling. Therefore, the objectives of our study are to (1) identify the signaling pathways that are dysregulated in CD and (2) determine which of these dysregulated pathways are pathogenic. Our approach integrates mouse modeling, proteomics, and computational analysis to identify signaling pathways that drive the onset and progression of intestinal inflammation in mouse models. To begin, we expand upon exciting preliminary data that implicate MIP-1alpha and MIP-1beta, two related chemokines involved in neutrophilic inflammation, as drivers of CD. Next, we will identify signaling pathways that are dysregulated in several different mouse models of CD, with the goal of identifying pathogenic signaling pathways relevant to humans with genetically diverse forms of CD. The cross-species comparison will allow us to broadly identify conserved drivers of GI inflammation and, in the process, reveal the animal models that will be the most effective for preclinical therapeutic studies for CD. Finally, we will apply emerging methods in quantitative mass spectroscopy to analyze protein signaling in inflamed intestine at an unprecedented level. In the end, we hope that insights into the dysregulated signaling network will reveal therapeutic targets that are not easily gleaned from genetic analysis of CD patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610042
Entities
People
- Kevin M Haigis
Organizations
- Beth Israel Deaconess Medical Center
- United States Army