Pediatrics and Biochemistry & Molecular Biology
Keck School of Medicine
Childrens Hospital Los Angeles
- Receptor tyrosine kinase signaling
- Crohn's disease
- ulcerative colitis
- intestinal growth and repair colitis-associated cancer
Research OverviewMy lab’s research program is focused on the involvement of ErbB receptor tyrosine kinases and their cognate ligands in the intestinal response to injury, intestinal inflammation, and colitis-associated carcinogenesis.
Crohn’s disease and ulcerative colitis, collectively known as the inflammatory bowel diseases (IBD), are chronic disorders characterized by high levels of inflammatory cytokines which can damage or kill colon epithelial cells. Colon epithelial apoptosis contributes to a breakdown of the barrier separating the organism from the contents of the intestine, leading to exacerbated injury and inflammation. Identifying signaling pathways which can be used to protect the colon epithelium could dramatically improve treatment of IBD.
ErbB family members may be useful targets for treatment of IBD, based on their ability to promote mucosal healing in cell culture, animal models, and clinical trials. However, ErbBs are thought to play a double role in the GI tract, promoting wound healing and resolution of inflammation but also supporting inappropriate cell survival and proliferation during tumorigenesis. Thus, a clear understanding of the short- and long-term consequences of ErbB activation and signaling will be necessary to develop safe and effective therapies targeting this receptor family. We are investigating these processes using novel in vitro and in vivo models of inflammation and colitis-associated cancer.
In particular, we are interested in the physiological function of ErbB4, the least-well understood member of the ErbB family. Cultured colon epithelial cells expressing ErbB4 are resistant to cytokine-induced apoptosis via a PI3K and COX-2 dependent mechanism. However, ErbB4 is paradoxically present at high levels in the colon mucosa of both mice with experimental colitis and human inflammatory bowel disease patients, indicating that expression of this receptor alone is insufficient to protect the gut in vivo. This may reflect a lack of appropriate ErbB4-activating ligands in the inflammatory milieu. Ongoing projects in the laboratory include:
1. Determine the regulatory mechanisms controlling NRG4 expression and ErbB4 activation in healthy and diseased intestines.
2. Test whether ErbB4-induced COX-2 accumulation predisposes the colon epithelium to cellular transformation/tumorigenesis.
3. Determine whether ErbB4 activation with exogenous ligand is therapeutic in experimental IBD models.
4. Identify novel downstream targets of ErbB receptor signaling and determine their role(s) in intestinal homeostasis and disease.