Person:

Bennett, Paul

Restoration of epithelial and endothelial barrier function is critical for tissue homeostasis. Yet, the molecular pathways response for modulating barrier properties remains largely unknown. This study investigates the role of DOCK4, a guanine nucleotide exchange factor (GEF) for RAC and RAP GTPases, in the regulation of barrier function in vivo. Through the generation of a novel knockout animal model and bone marrow chimeras, we assessed the role of this GEF in gut permeability and restoration of barrier function in response to chemical injury to the intestinal epithelium. In response to Dextran Sodium Sulfate (DSS) induced Colitis, which directly induces injury to the lumen of the intestine DOCK4 deficient animals exhibited significantly greater weight loss compared to wild-type mice. Bone marrow chimeras suggested the important of DOCK4 in intrinsic rather than hematopoietic cells in this phenotype. Direct analysis of epithelial permeability following intragastric FITC-Dextran administration showed an increase in leakage of this reporter into the blood of DOCK4 deficient compared to wild-type mice. These studies suggest that DOCK4 plays a significant role in restoring proper epithelial barrier function following chemical mediated injury to the epithelial intestinal lining.