The objective of this K01 application is to provide a 5 yr training program in vascular biology that allows the PI to acquire essential skills and knowledge to explore the mechanism(s) of endothelial dependent vascular permeability. This represents a new area of research for the PI. The Pi's scientific development will be mentored by Dr. Tanya Mayadas, a recognized leader in the field of vascular inflammation The work will be conducted in the Vascular Research Division which is led by Dr. Michael Gymboree, Chairman of Pathology, who has done pioneering work in elucidating the role of the endothelium in health and disease. The overall goal of this training is to provide the PI the necessary expertise to lead an independent academic research group in the area of vascular biology that is proposed in this application. The regulation of vascular permeability is important to elicit an efficient immune response while maintaining vascular integrity. Its dysregulation is associated with morbidity and mortality in diseases in many organs systems. In the skin, thermal injury, atopic and contact dermatitis are associated with edema which exacerbates these conditions. The goal of this project is to define mechanisms of endothelial barrier function regulated by the very recently identified exchange factor for the Rho and Rap family of GTPases, DOCK4 which directs adherens junction formation in osteosarcoma cells through activation of Rap1. Preliminary data shows robust DOCK4 expression in human umbilical vein endothelial cells and in the endothelium of normal human heart and kidney tissue. In addition, DOCK4 was regulated by endothelial barrier inducing agonists, and its deficiency resulted in changes in the actin cytoskeleton and an increase in endothelial permeability. This proposal is based on the hypothesis that DOCK4 regulation of Rap and Rac GTPases regulates junction remodeling in endothelial cells.
The aims will characterize molecular pathways that regulate DOCK4 function and elucidate its downstream targets in endothelial cells and identify the endothelial phenotypes dependent on this protein using in vitro approaches and in vivo models. Results from this work should aid in understanding how endothelial cell barrier function is regulated. We anticipate that this will provide insights into the mechanisms of endothelial dysfunction and tissue injury in skin disorders and rheumatic diseases and identify possible therapeutic targets for treatment of these conditions.
