Inflammatory bowel disease (IBD) is a debilitating disease that is characterized by constant, uncontrolled irritation of the intestine. Over 1 million people in the United States suffer from this disease, which can persist for decades. IBD is a complex autoimmune disease that results from faulty communication between the immune system and the intestinal epithelium. There is a wealth a knowledge pertaining to the inflammatory component of IBD, but little is known about the epithelial aspects of the disease. In this context, our goal is to understand, at the molecular level, how the intestinal epithelium responds to acute and chronic inflammatory stimuli. It is increasingly clear from large-scale studies of signaling that one cannot fully understand how a cell responds to a given stimulus by examining a single molecular pathway in isolation. Moreover, in vitro experimental systems fail to capture the biological complexity, for example cellular differentiation state or cell- cell interaction, that is of central importance to disease onset and progression. Because of this, we aim to develop computational models of cellular signaling in response to inflammatory stimuli in vivo in the intestinal epithelium. These models will provide novel insights into the pathways that regulate how the intestinal epithelium responds to inflammatory stimuli. A central aspect of our study is the hypothesis that signaling pathways activated by mutant K-Ras and N-Ras modulate the response of the intestinal epithelium to inflammatory stimuli. By genetically manipulating Ras function in our experimental system, we will be able to refine our computational models to place these on coproteins within the context of the entire cellular network of inflammatory response. In the end, our computational analysis will identify potential therapeutic targets to modulate the inflammatory response within the intestinal epithelium. All of the treatments currently used to treat IBD target the immune component of the disease and are largely ineffective over the long term. Our goal it to make a unique contribution to the study of this complex disease by focusing on ways to protect the intestine from the inflammation. We expect that combining therapies to treat both the inflammatory and epithelial components of IBD will result in more robust and sustained clinical responses in patients suffering from the disease. In the end, these studies will broaden our knowledge of the molecular pathways that contribute to IBD and may have a direct impact on the health and well being of many patients suffering from this terrible disease.

Public Health Relevance

Inflammatory bowel disease affects over 1 million Americans. Our study aims to utilize emerging technologies and computational modeling to characterize the molecular and cellular responses of the intestinal epithelium to inflammatory stimuli in vivo. Our ultimate goal is to identify new therapeutic targets that protect the intestinal epithelium from the ravaging effects of chronic inflammation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZGM1-GDB-2 (CP))
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Krasnewich, Donna M
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Massachusetts General Hospital
United States
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Lau, Ken S; Schrier, Sarah B; Gierut, Jessica et al. (2013) Network analysis of differential Ras isoform mutation effects on intestinal epithelial responses to TNF-*. Integr Biol (Camb) 5:1355-65
Lau, Ken S; Juchheim, Alwin M; Cavaliere, Kimberly R et al. (2011) In vivo systems analysis identifies spatial and temporal aspects of the modulation of TNF-*-induced apoptosis and proliferation by MAPKs. Sci Signal 4:ra16
Lau, Ken S; Haigis, Kevin M (2009) Non-redundancy within the RAS oncogene family: insights into mutational disparities in cancer. Mol Cells 28:315-20