RESISTANT (MDR) GENE IN RODENT MALARIA

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The long term goal of our project is to elucidate the mechanism(s) of drug resistance in Plasmodium spp, particularly, to determine the role played by the multidrug resistance genes (mdr). This subject is of immense biomedical relevance considering the alarming increase in malaria treatment failures resulting from drug resistance. Despite the magnitude of the problem the mechanism(s) of parasite resistance to the majority of antimalarial drugs are not clearly understood. A better understanding of these mechanism(s) would lead to new strategies for the control of the disease. Two mdr-like genes have been identified in P. falciparum, and one of them, the pfmdf1 gene, has been associated with the drug resistance phenotype. However, there is still significant controversy with regard to athe involvement of the pfmdr genes in chloroquine resistance. The P. falciparum model has important limitations for studying the role of these genes, for example only erythrocytic stages could be maintained in vitro and the appropriate animal model, the chimpanzee, is expensive and impractical. The use of rodent malaria clones in vivo (P. berghei and P. yoeli), expressing different patterns of drug sensitivity, provides an excellent model to study the molecular mechanisms of this phenotype. In the present proposal, we will focus our efforts to ascertain the role of the murine multidrug resistance genes in malaria drug resistance. We have shown that mdr-like genes are present in P. berghei and probably, P. yoelii. To determine whether the P. berghei and p. yoelii mdr-homolgues play a role in parasite drug resistance, we will analyze the behavior of these genes at the DNA, RNA, protein and chromosomal level in five P. berghei derived lines and four P. yoelii 17X derived lines expressing different patterns of drug resistance.