9710143 Lauffenburger This project will combine approaches of biochemical engineering, cell biology, and molecular biology to increase the quantitative understanding and manipulation of growth factor/receptor dynamics at both the cell and tissue level. Work will focus on the dynamics of autocrine growth factor signaling, particularly with respect to the spatial regulation of ligand release and receptor occupancy. A major goal in this direction will be to determine whether autocrine ligands provided information to cells regarding their tissue "community" as opposed to their local microenvironment, and how physico-chemical parameters influence this information. Work will also continue to build on current models of receptor trafficking to include new experimental information about the sorting compartment, and to extend these models to incorporate key components of related signal transduction pathways. This will allow a quantitative evaluation of the effects of altered receptor trafficking on signaling pathways underlying previous studies of cell proliferation responses. Understanding these sorts of integrated dynamical influences on growth factor signaling will continue to generate a rational basis for the design of improved pharmacological growth factor mimics or antagonists. By using the human epidermal growth factor/receptor system transfected into defined cell lines, tools for molecular biology such as monoclonal antibodies, site-directed receptor mutants, and recombinant site- directed ligand variants can be used for biochemical engineering purposes. The work for the new grant period has been organized into three specific aims which are designed to facilitate the understanding of receptor and ligand dynamics in growth factor regulation of cell function. ***
