Tissue and Cellular Pharmacodynamics of Vascular Growths

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DESCRIPTION (provided by applicant): Growth factors(GF) control a range of physiological processes in multiple cell types. They should be ideal therapeutic compounds, and yet striking tissue culture and animal model effects become marginal in the clinic. Effective use of vascular GF is challenging principally because their complex structures make them unstable, and the biological parameters they affect are ubiquitous and tightly regulated. Some have explained the difficulty with achieving clinical effect on physicochemical properties. Indeed, it is almost exclusively controlled release that produces positive effects in animal and clinical trials. Initial thoughts were that controlled release circumvented rapid clearance, sustaining release and prolonging receptor-ligand interaction. However, GF with identical physicochemical parameters behave differentially when controlled release, with these differences being accentuated in disease states. Thus, pharmacokinetic clearance alone cannot explain why mode of delivery is so critical to GF biology. Three convergent, interrelated events control the biology of a GF once released to a target tissue and we will progressively examine these events in the normal and diseased tissue states. They include, tissue binding, transport, deposition and distribution of the GF, metabolism, clearance and degradation of the GF, and intercellular communication and signaling. In this revised grant we establish an iterative program which integrates all of these elements by making use of unique tools developed in our laboratory combining aspects of cellular and molecular biology, growth factor biochemistry, materials science, polymer chemistry and controlled-release technology in vitro and in vivo with mathematical modeling. We will specifically: 1 examine the impact of growth factor binding to target tissue under different disease states and after different modes of delivery; 2 define how cellular pharmacokinetics constrains cell-growth factor interactions, 3 characterize the impact on growth factor action of intercellular gap junction signaling; and 4 codify the biological regulatory response to growth factors using mathematical models. The results of these studies will add to our understanding of GF biology and possibly the means by which we develop therapies around these compounds.