Plasmodium Falciparum Metal Metabolism

描述（由申请人提供）：喹啉类药物和青蒿素干扰金属疟原虫代谢是一个已被证实的化疗靶点。尽管取得了很大的进展，但对血红素晶体形成的精确分子过程，即喹啉类药物的目标，仍不清楚。有针对性的干预措施对金属疟原虫生物学的全球代谢后果尚未确定。广泛的长期目标是进一步确定喹啉类药物靶向的血红素晶体形成生物学的分子过程，并将疟原虫代谢谱作为一种药物靶标验证方法，首先关注金属相关代谢。血红素晶体形成的具体目的是比较血红素晶体的形成和抑制与亚细胞寄生虫的分离，体外脂质或蛋白质配方。代谢谱的具体目标是确定未感染红细胞与感染红细胞的共同和独特代谢物，这些红细胞也对针对金属的抗疟药物有反应，并分析耐药菌株中疟原虫代谢谱的改变。扫描电子显微镜、疟原虫培养和亚细胞分离以及质谱分析技术将被用于实现这些目标。

DESCRIPTION (provided by applicant): 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.