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Malaria is currently considered the most devastating parasitic disease in the world, with more than 500 million people infected worldwide, 1-3 millions death annually, and 40% of the world population at risk of infection. The emergence and rapid spread of multidrug resistant Plasmodia parasites coupled to the lack of an effective vaccine has resulted in the re-emergence of the disease. Efficient and cost effective drug alternatives are not yet available Contributing to the magnitud of the problem is the lack of a full understanding of the mechanisms responsible for the development of parasite drug resistance. Great efforts have been made to understand the mechanisms of Plasmodia drug resistance and several genes have been implicated. It is now well recognized that drug resistance in malaria is multifactorial and that multiple genes/factors play a critical role. The long term goal of our research is to elucidate molecular mechanisms underlying Plasmodia drug resistance. We are focusing our efforts on genes from the glutathione biosynthesis pathway (gamma glutamylcysteine synthase and others) and on genes encoding ABC transporter proteins, which have been previously shown by our laboratory and others to contribute to malaria drug resistance. In addition, regulation of gene expression and identification of regulatory elements in genes associated with Plasmodia drug resistance are under investigation. The approach we are using to study this phenomenon in the rodent malaria model Plamodium berghei is a combination of the latest molecular biology techniques to assess gene function, including genetic manipulation (transfection), and bioinformatics. Our studies should contribute to a better understanding of the mechanisms underlying drug resistance in Plasmodia, which is fundamental to the surfacing of new approaches to malaria chemotherapy. The high morbidity and mortality associated to this disease, as well as its resulting economic impact, makes such understanding not only needed, but warranted.
Recentl, we have expanded our research to include the identification of drug targets in Plasmodia. The long-term goal of this collaborative effort is to identify novel antimalarial targets that could lead to the development of alternative drugs or to the overcoming of drug resistance. The focus of this research is on unique Plasmodia proteins, which will be identified using comparative genomics in combination with functional assays. The proposed work should significantly contribute to a better understanding of the biology of Plasmodia and further help in the development of new approaches to malaria drug therapy.
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