TRANSFECTION OF MALARIA

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Malaria is a protozoan parasite which causes worldwide morbidity and mortality. Treatment and prophylaxis of this deadly human pathogen has been greatly complicated by the emergence and rapid spread of drug resistance. Studies of the phenotype of drug resistance in malaria reveal striking similarities to multiple drug resistance (mdr) in neoplastic cell lines. In both instances drugs are actively pumped out of resistant cells and this efflux is reversed by calcium channel blockers. In neoplastic cells the transfection of mdr genes into sensitive cells leads to the development of resistance and proves the crucial relationship between mdr genes and resistance. A newly developed transfection system promises to allow for the first time the direct determination and study of the role of malaria mdr genes in the molecular pathogenesis of drug resistance. Phase 1 of the PSA award will involve the didactic study of the molecular pathogenesis and biology of the malaria parasite. Intensive research training in the molecular techniques utilized in studying malaria will be provided through the refining and expansion of the recently developed malaria transfection system. Phase 2 of the project will utilize the skills and modified transfection system developed in Phase 1 to test malaria mdr genes. If these genes do mediate drug resistance interactions between the P-glycoprotein homologue which the mdr genes encode and reversal agents will be performed. The long-term goals of the project therefore are to: 1) provide an intensive didactic and research background in the molecular biology and pathogenesis of malaria and 2) provide a sound basis for independent laboratory studies of the molecular basis of drug resistance utilizing a gene transfection system.