Inhibition of angiogenesis has recognized potential for treating major diseases for which there are no satisfactory therapies ("angiogenic" diseases, including cancer, chronic inflammations, ophthalmic diseases). The long-term objective is to develop novel angiogenesis inhibitors using a unique and not previously investigated molecular target-the endothelium-specific adhesion molecule VE--cadherin (VEC). VEC is a transmembrane protein involved in the formation of adherens junctions between endothelial cells through cadherin--cadherin homophilic binding and may be involved in the assembly of these cells into capillaries during blood vessel generation. The hypothesis will be tested that inhibition of VEC interactions will block neovascularization. Specific aims of initial research are (1) to clone and express the extracellular domain of VEC (soluble VEC), (2) to develop an assay that will allow the identification of inhibitors of VEC interaction, (3) to test whether soluble VET and monoclonal antibodies will inhibit VEC interactions and angiogenesis. This research will establish proof of principle with respect to VEC involvement in angiogenesis and provide molecular tools for high throughput screening assay development and the discovery of new types of macromolecular and small molecule angiogenesis inhibitors. It may thus be of considerable interest to the pharmaceutical industry. PROPOSED COMMERCIAL APPLICATION: A novel high throughput screening assay is a commercially valuable asset in drug discovery. This work has the potential to lead to novel therapeutic drugs in the areas of cancer, chronic inflammatory and major ophthalmic diseases, each having large and currently unsatisfied markets.
Project Terms:
angiogenesis inhibitors; antineoplastics; athymic mouse; biotechnology; cadherins; drug design /synthesis /production; laboratory mouse; membrane proteins; molecular cloning; monoclonal antibody; pharmacology; polymerase chain reaction; protein engineering; protein structure; transfection /expression vector
