Leukocyte activation by chemoattractants is instrumental for host defense against microbial and viral agents as well as for surveillance against the development and spread of neoplasms. A better understanding of the regulation of normal leukocyte activation and differentiation will allow the development of more specific antineoplastic agents for the treatment of leukemias and lymphomas and may result in new therapies for augmentation of the immune response in the Acquired Immunodeficiency Syndrome (AIDS). Oligopeptide chemoattractant receptors present on the surface of human leukocytes mediate a wide variety of inflammatory functions including superoxide production, chemotaxis and lysosomal enzyme release. Transmembrane signaling induced by occupancy of these receptors requires the generation of second messenger molecules including inositol phosphates, diacylglycerol, arachidonic acid metabolites and calcium with subsequent activation of protein kinases. Very little is understood about the synthesis and metabolism of the reservoir for second messenger molecules in human leukocytes, the phosphoinositides. In the proposed studies, we will characterize the enzymatic pathways for synthesis of the phosphoinositides in leukocytes. The enzyme system which synthesizes the phosphoinositides, phosphatidylinositol and phosphatidylinositol-4-phosphate kinases, will be characterized in human neutrophils. The regulation of these enzymes by transmethylation reactions and S-adenosylmethionine metabolism will be studied. In addition, we will determine the role of the cytoskeleton in membrane protein-lipid interactions in human PMN activation. These studies will include elucidating the effects of cytoskeletal disruption on the metabolism of polar and nonpolar lipids, including the phosphoinositides, as well as determining its effects in chemoattractant-mediated protein kinase translocation and activation. Certain anti-neoplastic agents such as vinblastine and vincristine are thought to exert their effects through disruption of the cytoskeleton. In addition, the antitumor activity of deoxycorformycin, an inhibitor of adenosine deaminase, is thought to exert part of its effects through inhibition of transmethylation reactions. A better understanding of the biochemistry of normal leukocyte activation should enhance the development of new immunosuppressive therapies for treatment of hematologic malignancies as well as of immunostimulatory agents to enhance the immune response in AIDS.
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