Chronic inflammatory bowel disease (IBD) and infectious enterocolitis are exacerbated by dysregulation of the intestinal barrier integrity. An intact epithelial barrier is the keystone of innate host defense and as such, is tightly controlled by epithelial cell migration, cell adhesion, and cell-cell contacts regulated by the actin cytoskeleton. cAMP is a central second messenger which regulates diverse cellular processes including cytoskeletal remodeling, migration and adhesion. This regulation occurs through the cAMP effectors PKA and Epac, and in part, via monomeric G protein signaling to the actin cytoskeleton. Although cAMP signaling is a robust target for therapeutic intervention, the mechanisms whereby cAMP regulates wound repair and restitution in the gastrointestinal mucosal remain entirely unexplored. The objective of the present application is to elucidate the molecular signaling mechanisms by which cAMP abrogates intestinal epithelial migration. The following specific aims will be addressed:
Aim 1. Resolve the mechanism by which increased Protein Kinase A activity influences intestinal epithelial migration machinery.
Aim 2. Determine the mechanism by which increased Epac activity influences intestinal epithelial migration.
Aim 3. Quantify the expression of PKA and Epac in an in vivo murine colitis model of epithelial repair. These studies will use established in vitro epithelial cell culture models of intestinal wound repair as well as an in vivo murine model of colitis to elucidate the mechanistic role for cAMP in the repair and recovery phase of disease, while providing mechanistic insight into how cAMP effectors are involved in the initial steps of barrier dysregulation and repair. Relevance: These data, while contributing to our understanding of wound repair in the intestine, will set a foundation by establishing a critical link between cyclic nucleotide regulation and diseases such as the IBD. The utility of therapies targeting cyclic nucleotide signaling in inflammatory diseases underscores the importance of these studies and may shed light on novel avenues of treatment.
| Zimmerman, Noah P; Kumar, Suresh N; Turner, Jerrold R et al. (2012) Cyclic AMP dysregulates intestinal epithelial cell restitution through PKA and RhoA. Inflamm Bowel Dis 18:1081-91 |
| Zimmerman, Noah P; Vongsa, Rebecca A; Faherty, Sheena L et al. (2011) Targeted intestinal epithelial deletion of the chemokine receptor CXCR4 reveals important roles for extracellular-regulated kinase-1/2 in restitution. Lab Invest 91:1040-55 |
