CHEMICAL GENETIC APPROACHES TO BASIC CELL BIOLOGY

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The aim of our program is to develop a novel approach to discovering molecular mechanism in biology, chemical genetics, and to change shape; and vesicle trafficking, the study of how cells selectively import and export proteins in different compartments. For both of these biological areas, chemical tools are particularly important because the events we wish to study happen in seconds or minutes, and most other methods of study are slow. The chemical genetics approach aims to emulate classical genetics as a discovery tool, by using chemicals that alter the functions of specific proteins as a way to understand the functions of these proteins. In particular, we want to use chemicals to identify new proteins, not previously known to be important in the function of the cytoskeleton or in vesicle trafficking. We therefore plan to accumulate large collections of chemicals (chemical libraries) and use high-throughput screening to identify chemicals that interfere with these processes, and only then identify the proteins that the chemicals bind to. In parallel, we will screen for inhibitors of active chemicals to share with the whole scientific community. In Projects 1 and 2, we will discover chemicals that inhibit cell migration and several key proteins involved in formation and function of the cytoskeleton. In Project 3, we will identify novel inhibitors of in-bound and out-bound vesicle traffic. In Project 4, we will develop new methods for identifying the targets of those chemicals, and new ways to assess the usefulness of a chemical library for biological screening. In Project 5, we will construct a chemical library patterned after alkaloids, which we expect to be a rich source of biologically active chemicals. Three Cores will support this work: Core A will provide administrative support, Core B will make the screening and database functions of the Program possible, and Core C will support all projects with synthetic chemistry expertise.