? Inflammatory disorders of the gastrointestinal tract, including infectious colitis and inflammatory bowel disease (IBD), result in breakdown of the intestinal epithelial barrier in the form of erosion and ulceration. In order to reestablish epithelial barrier function, the epithelium must close wounds and reform intestinal crypts. Intestinal epithelial cell migration is a critical event in mucosal wound healing and regeneration. Cell migration requires the coordination of actin cytoskeletal reorganization with dynamic matrix adhesion and matrix remodeling. Annexin 2 is a calcium-dependent phospholipid and actin binding protein that has been shown to play crucial roles in the cellular events underlying migration. The mechanisms by which annexin 2 regulates intestinal epithelial motility during wound healing and crypt regeneration are not fully understood.
The specific aims of this proposal are 1) to define the mechanisms by which annexin 2 regulates the actin cytoskeleton during intestinal epithelial cell migration; 2) to investigate the role of annexin 2 in intestinal epithelial cell-matrix remodeling during migration and crypt regeneration; 3) to identify and examine the role of novel annexin 2 protein interactions in intestinal epithelial cell migration. These studies will model restitution using IEC lines grown in two dimensional culture. Crypt regeneration will be modeled using Caco-2 cells grown in three dimensional culture systems. A transfection based approach will be used to study the role of annexin 2 in regulating Rho dependent actin polymerization during IEC migration. The role of surface annexin 2 in regulating plasmin generation to achieve IEC invasion and cyst formation will be explored using reagents specifically inhibiting surface annexin 2. Using a bait peptide approach, we have identified a novel annexin 2 interaction with HSP 70. Interestingly, HSP 70 has been shown to interact with annexin 2 binding partners implicated in cell migration. Additionally, we have identified an association of HSP 70 with tissue-type plasminogen activator (t-PA). The significance of the HSP 70 association with annexin 2 and t-PA during cell migration will be explored. These studies will provide insight into the molecular mechanisms underlying intestinal epithelial cell migration important in mucosal wound healing and regneration. The candidates long term goal is to develop an academic career as a physician/scientist. ? ?
| Babbin, Brian A; Koch, Stefan; Bachar, Moshe et al. (2009) Non-muscle myosin IIA differentially regulates intestinal epithelial cell restitution and matrix invasion. Am J Pathol 174:436-48 |
| Babbin, Brian A; Sasaki, Maiko; Gerner-Schmidt, Kirsten W et al. (2009) The bacterial virulence factor lymphostatin compromises intestinal epithelial barrier function by modulating rho GTPases. Am J Pathol 174:1347-57 |
| Babbin, Brian A; Laukoetter, Mike G; Nava, Porfirio et al. (2008) Annexin A1 regulates intestinal mucosal injury, inflammation, and repair. J Immunol 181:5035-44 |
| Babbin, Brian A; Jesaitis, Algirdas J; Ivanov, Andrei I et al. (2007) Formyl peptide receptor-1 activation enhances intestinal epithelial cell restitution through phosphatidylinositol 3-kinase-dependent activation of Rac1 and Cdc42. J Immunol 179:8112-21 |
