Computer Modeling of Perlecan as a Vascular Regulator

Blood circulation is a complex system. At every moment a multitude of molecules are transported imultaneously and continuously to specific targets in the vasculature. The ability to regulate whole panels If molecules by controlling the circulating concentration of a single moiety, if discrete, could provide a lowerful tool to understand the causes, prevention and treatment of cardiovascular disease and other lisorders relating to blood vessels. Perlecan, an important molecule in blood vessel and tumor growth could Ie such a molecule. Our hypothesis is that, based on its high affinity for a number of growth factors that are rucial to normal and pathological vascular growth and development, circulating perlecan has the potential to ,equester these growth factors in blood, preventing their interactions with vascular surfaces. Because of the :omplexity of this system, however, it is difficult to characterize at a macro level using in vitro or in vivo Ipproaches alone. Computer modeling provides us with a powerful tool to test parameters and conditions, uch as multiple ligand interactions in solution and on vascular surfaces under flow, which are crucial ,omponents in developing an accurate understanding. A simulated vessel model under flow will be used to test the predictive value of the model using a variety of testable conditions. Our specific aims are to: 1. Develop a model of endothelial cell binding based on the binding characteristics of three growth factors [and the proteoglycan perlecan 2. Test the model using competitive binding assays with growth factors alone or in combination with other factors as a function of perlecan concentration 3. Refine the model to mimic the interactions of the growth factors and perlecan under flow and adjust the model to accommodate changes between what is observed in experimental assays and what is predicted based on flow conditions Our model will be the first step in attaining our long range goal of designing and testing pharmaceuticals that exploit similar regulatory characteristics. By using a systems biology approach the interrelatedness of the blood vessels and the components being transported through them will be characterized at the level of the organism as a whole.