Candidate: The applicant has researched mucosal lymphocyte homing and recirculation for the past 8 years. Accomplishments include contributions at both molecular and cell biological levels to interaction of intra- epithelial lymphocytes with epithelial cells. Environment: Brigham and Women's hospital, affiliated with Harvard University, is recognized as a leader in medical research, and will provide a supportive and stimulating environment. The mentor's lab at the Vascular Research Division has access to specialized equipment and tissues necessary for this research. Research: Gastritis, ulceration, celiac sprue, Crohn disease and ulcerative colitis, glomerulonephritis, interstitial nephritis and pyelonephritis are all characterized by the activation of inflammatory cells leading to tissue injury. Leukocyte transmigration and accompanying increased vascular permeability are critical steps during the inflammatory response. Thus, integrity of the organ vasculature is necessary for normal system function, and the endothelial barrier must be breached to lead to tissue injury in these diseases. Although much is known about leukocyte-endothelial adhesion and inflammation, less information is available concerning the role played by endothelial cells in regulating permeability and leukocytes and macromolecules. Vascular endothelial cadherin is located at endothelial adherens and junctions and may regulate monolayer permeability to leukocytes and inflammatory factors. The objective of this proposal is to study the role of VE-cadherin in barrier function and cell growth in vascular endothelial cells by disruption via a dominant negative mechanism. A high efficiency if transfection will be achieved using an adenoviral expression system. This approach will allow specific disruption of one component of the adherens junction, and allow subsequent analysis of endothelial specific functions. These techniques will be used to probe the function of adherens junctions in endothelium from various vascular beds and their contribution to inflammation. The proposed studies are anticipated to allow a better understanding of the role of endothelial adherens junctions in normal and disease conditions, and may lead to novel therapeutic approaches and targets for intervention.
