The ErbB4 receptor tyrosine kinase is induced by inflammation in the colon epithelium, and ErbB4 overexpression promotes colonocyte survival in vitro without affecting proliferation or migration. Thus, ErbB4 induction may be a compensatory response meant to protect the epithelium. However, preliminary data developed for this application show that expression of the specific ErbB4 ligand neuregulin-4 (NRG4) is deficient in both human IBD and murine colitis. Furthermore, in murine colitis models, although ErbB4 expression is elevated, it is not phosphorylated/activated. These results suggest that, in the context of inflammation, NRG4 downregulation leads to deficient signaling despite ErbB4 upregulation. Additional preliminary studies show that exogenous NRG4 protects colonocytes from cytokine-induced apoptosis both in vitro and in vivo, and reduces the severity of acute murine DSS colitis. We propose therefore that NRG4 could be used to stimulate ErbB4 during colitis, and thus to inhibit colonocyte apoptosis and improve pathology. As ErbB4 (a) has ligand binding properties and downstream targets that are unique among tyrosine kinases, and (b) can directly associate with both anti-apoptotic signaling molecules (e.g., PI3K, Src) and inflammatory mediators (e.g., STAT1), it has significant potential as a novel and selective IBD therapeutic target. However, neither the role of ErbB4 in colon biology in vivo nor the colonic response to its selective activation has been defined. Therefore, this project is designed to test the hypothesis that downregulation of NRG4 worsens colitis, and thus exogenous NRG4 treatment may improve colitis by activating anti-apoptotic signaling in colon epithelial cells. Planned experiments will use coordinated cell culture, crypt culture, and in vivo models to (1) determine the effects of loss of NRG4-ErbB4 function on colitis and define the mechanisms of NRG4 loss, (2) test the effectiveness of exogenous NRG4 in colitis, and (3) define signaling pathways which are required for NRG4-induced colon epithelial cell survival. Together, these studies will investigate the exciting possibility that NRG4-ErbB4 signaling is a novel therapeutic avenue for IBD.
These studies are designed to advance our understanding of key molecular mechanisms which protect the lining of the intestinal tract and promote repair in the colon after injury or inflammation. They will define cellular targets which could be used for future therapies, and thus are important and directly relevant for gastrointestinal disorders including inflammatory bowel diseases.
|Frey, Mark R; Brent Polk, D (2014) ErbB receptors and their growth factor ligands in pediatric intestinal inflammation. Pediatr Res 75:127-32|
|Brown, Kathryn S; Gong, Huiyu; Frey, Mark R et al. (2014) Tumor necrosis factor induces developmental stage-dependent structural changes in the immature small intestine. Mediators Inflamm 2014:852378|
|McElroy, Steven J; Castle, Shannon L; Bernard, Jessica K et al. (2014) The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis. Am J Pathol 184:2768-78|