We are pursuing studies in three related areas: A major interest of the laboratory is to understand the regulation of the barrier properties of endothelial and epithelial cells. Dr. Malik's laboratory studies the events that occur at the level of receptors and the signalling pathways that regulate the barrier function of these monolayers. As thrombin has been shown to increase endothelial permeability, we are studying, using this agonist, how the activation of its proteolytically cleaved receptor leads to the observed increase in permeability. Studies have localized the domains of the receptor involved in both activation and inactivation of endothelial cell signalling. Researchers are exploring ways to inhibit the thrombin-induced barrier dysfunction by such as by introducing dominant negative forms of the receptor to inhibit thrombin receptor activation. Studies are also characterizing cellular effector pathways that increase vascular permeability to understand how the activation of the signalling pathways mobilizes these effectors (i.e., actin-myosin motor, cadherin-catenin complex and the intermediate cytoskeletal filaments).

An additional objective of the laboratory is to develop and test novel strategies for drug and gene delivery. We are specifically interested in targeting cells of the vessel wall which are critical in the pathogenesis of a variety of inflammatory diseases, atherosclerosis, and cancer metastasis. The intent is to prevent, in a specific manner, the expression of endothelial adhesion molecules. Among the approaches being studied include the selective expression, using inducible promoters in order to target the expression of "anti-adhesive" proteins in endothelial cells. This laboratory is also developing non-viral means of gene delivery to transduce endothelial proteins of interest. The approaches taken involve molecular biology as well as physiological monitoring in experimental models.

NIF is present in cells of alveolar-capillary membrane and in intraluminal leukocytes 48 h after injection of the pCR3-NIF liposome construct; red blood cells in vessels did not show staining (bottom).

Finally, this laboratory is studying the expression of the adhesion molecule ICAM-1 at the level of gene transcription. In particular, we are interested in identifying how certain cytokines and oxidants induce the expression of the ICAM-1 gene at the level of its promoter, the nature of the intra-cellular signalling pathways that regulate ICAM-1 expression, and how gene activation is regulated by the redox state of the cell. This group identified an element in the promoter that is activated by hydrogen peroxide. Activated transcription factors bind in a complex manner to this element and initiate ICAM-1 transcription. The objective of these studies is to understand the genetic basis of ICAM-1 expression, so that strategies can be developed to control the expression of this adhesion molecule and reduce pathological leukocyte trafficking across the vascular endothelium.

Lab Members