Interference with Plasmodium metal metabolism by the quinolines and artemisinins is a proven chemotherapeutic target. Despite great progress, the precise molecular process of heme crystal formation, the target of the quinolines, is not understood. Global metabolic consequences of targeted interventions to Plasmodium metal biology have not been defined. The broad long term objective is to further define the molecular process of heme crystal formation biology that the quinolines target and to develop Plasmodium metabolic profiling as a method of drug target validation focused at first on metal related metabolism.
The specific aims for heme crystal formation are to compare heme crystal formation and inhibition initiated with subcellular parasite fractionations, in vitro lipid or protein formulations. The metabolic profiling specific aims are to identify common and unique metabolites of the uninfected erythrocyte compared to the infected erythrocyte that also respond to antimalarial drugs directed at metals and to analyze the altered Plasmodium metabolic profile in drug-resistant strains. The techniques of Scanning Electron Microscopy, Plasmodium culture and subcellular fractionation, and mass spectroscopic analysis will be used to achieve these aims. ? The significance of detailing heme crystal formation relates to fundamental knowledge of quinoline drug action and resistance. Plasmodium metabolic profiling will complement current transcriptome and proteomic analysis of drug target validation as part of the NIH """"""""roadmap"""""""" to study metabolic process components and networks in cells. Plasmodium parasitism provides a comparison of """"""""simple"""""""" erythrocyte cell to more complex infected cell. ? ?
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