Our laboratory studies diseases of the gastrointestinal tract, with emphasis on colorectal cancer (CRC) and inflammatory bowel disease (IBD). We use both conventional and systems biology approaches to integrate studies of genetically engineered mouse models, human cell lines, and primary patient samples in the search for novel therapies.

Activating Ras mutations are found in 40% of CRCs and cancers expressing mutant Ras are largely resistant to conventional chemotherapies, ionizing radiation, and most targeted therapies. As a result, our research is strongly motivated by the great need for new therapies targeting Ras or Ras-related signaling pathways. We have developed mouse models of CRCs expressing mutationally activated forms of K-Ras and N-Ras, the two Ras family members that are commonly mutated in the human disease. We are using these genetically engineered mouse strains (1) to understand how mutant forms of Ras influence tissue homeostasis and (2) as a preclinical platform for therapeutic studies. We are also studying how Ras function is controlled by post-translational modification. In this domain, we recently identified acetylation of lysine 104 as a modification that controls the ability of Ras to cycle from the GDP-bound inactive state to the GTP-bound active state. Going forward, we hope to understand whether modulation of Ras acetylation, as well as other post-translational modifications, could represent a novel strategy for therapeutic intervention.

Our lab also applies systems biology approaches in an effort to better understand intestinal inflammatory diseases. Crohn's disease and ulcerative colitis, the two predominant forms of IBD, are genetically complex, with more than 160 risk alleles identified via genome-wide association studies. But the identification of risk alleles has not translated into new therapeutic opportunities. We are taking a protein-based approach to identifying new therapeutic target for IBD. By applying computational modeling methods to protein signaling data from humans and mice with IBD, we can identify signaling pathways that are activated during onset and progression of disease. Experimental perturbation in mouse models then allows us to determine whether any given pathway is critical for chronic inflammation.