Plasmodium Falciparum Metal Metabolism

描述（由申请方提供）：喹啉类和青蒿素类对疟原虫金属代谢的干扰是一种经证实的化疗靶点。尽管取得了很大的进展，血红素晶体形成的精确分子过程，喹啉的目标，是不了解。针对疟原虫金属生物学的有针对性的干预措施的全球代谢后果尚未确定。广泛的长期目标是进一步定义喹啉靶向的血红素晶体形成生物学的分子过程，并开发疟原虫代谢谱作为首先关注金属相关代谢的药物靶标验证方法。血红素晶体形成的具体目的是比较血红素晶体形成和抑制启动亚细胞寄生虫分级，在体外脂质或蛋白质制剂。代谢谱分析的具体目的是确定未感染红细胞与感染红细胞相比的共同和独特的代谢物，这些代谢物也对针对金属的抗疟药物有反应，并分析抗药性菌株中改变的疟原虫代谢谱。扫描电子显微镜、疟原虫培养和亚细胞分级分离以及质谱分析技术将用于实现这些目标。 详细描述血红素晶体形成的意义涉及喹啉类药物作用和耐药性的基础知识。疟原虫代谢谱将补充目前的药物靶点验证的转录组和蛋白质组学分析，作为NIH“路线图”的一部分，以研究细胞中的代谢过程组分和网络。疟原虫寄生提供了“简单的”红细胞与更复杂的感染细胞的比较。

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.