The long term objectives of the proposed research are related to understanding the role of protein-protein interactions in the regulation of certain metabolic processes and to understanding structure-function relationships in enzymes. Specific projects and 1) the polymerization of actin and the role of actin binding proteins in the polymerization process as well as in the structure and nature of actin gels in both in vitro and in vivo systems; 2) the characterization of tubulin from erytrocytes; 3) the mechanism of action of adenosine deaminase and dihydrofolate reductase; and 4) the kinetics and mechanism of protein folding using wild type and site directed mutants of dihydrofolate reductase. Work with actin, actin binding proteins and tubulin is directly related to various cellular functions in non-muscle cells including cell motility, cytoskeletal structure, endocytosis, cell division and so on. Of particular interest are proposed experiemnts to measure the consequences of known shear stresses on cellular dynamics using digital imaging techniques. Both adenosine deaminase and dihydrofolate reductase are targets for inhibitory therapeutic drugs. Inhibitors of adenosine deaminase have been used in patients with T-cell acute lymphoblastic leukemia while inhibitors of dihydrofolate reductase have been used both as antibacterial agents and anticancer agents presumably because the tetrahydrofolate produced is ultimately related to DNA synthesis. The folding experiments proposed with wild type and site directed mutants of dihydrofolate reductase may lead to a better undrstanding of structure-function relationships in proteins and subsequently to the ability to create new enzymes with specific functions.
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