This program project addresses the problem of childhood tumors at both a clinical and basic science level. Seven projects are included: Project 1 investigates the cellular basis of graft versus host disease and post-trensplantation immunoincompetence as well as the clinical use of monoclonal antibody to prevent graft versus host disease and reduce the incidence of leukemic relapse. Project 2 studies the regulation of the cytolytic T lymphocyte response to alloantigens, tumor antigens, and viral-induced antigens. Project 3 defines the cell-cell interactions which regulate erythropoiesis, with particular reference to the T cell regulatory system. The effect of inducers of differentiaton upon the cell cycle kinetics, globin chain program and erythropoietin response of human peripheral blood erythroid progenitor cells will be examined. Techniques to enrich these erythroid progenitor cells will be developed. Project 4 studies the pharmacology of chemotherapeutic agents which interfere with DNA synthesis. The role of the de novo and salvage pathways for nucleic acid synthesis will be examined in relationship to methotrexate action. The incorporation of Ara-C and Ara-A into DNA will be examined as the molecular basis for the action of these agents. Project 5 studies the selective synthesis of cellular proteins as a rapid response of BALB/c-3T3 cells to the addition of growth factors; variants of BALB/c-3T3 cells which don't require these growth factors, will be isolated and shown to constitutively synthesize these proteins. Project 6 studies the replicative cycle of hr-t mutants of polyoma virus, which display coordinate defects in virus growth and cell transformation; the block in hr-t replication, which appears to be a defect in the assembly or maturation of infectious particles, will be defined. Project 7 studies transmembrane signalling using a model system, the galactose-terminal glycoprotein receptor of rat hepatocytes; the receptor protein will be identified and the receptor-mediated translocation of the ligand will be characterized.
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