Plasmodium Falciparum Metal Metabolism

描述(申请人提供)：喹啉类和青蒿素类药物对疟原虫金属代谢的干扰是一种已被证实的化疗靶标。尽管取得了很大的进展，但喹啉类药物的靶标--血红素晶体形成的确切分子过程尚不清楚。靶向干预对金属疟原虫生物学的全球代谢影响尚未确定。长期目标是进一步确定喹啉类药物靶标的血红素晶体形成生物学的分子过程，并将疟原虫代谢图谱发展为一种药物靶标验证方法，首先集中在金属相关的代谢上。血红素晶体形成的具体目标是比较亚细胞寄生虫分级、体外脂肪或蛋白质配方启动的血红素晶体形成和抑制。代谢图谱的特殊目的是识别未感染的红细胞与感染的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疾药物产生反应，并分析耐药株中改变的疟原虫代谢谱。将使用扫描电子显微镜、疟原虫培养和亚细胞分离以及质谱分析技术来实现这些目标。 详细描述血红素晶体形成的意义与喹啉药物作用和耐药性的基础知识有关。作为美国国立卫生研究院研究细胞代谢过程成分和网络的“路线图”的一部分，疟原虫代谢图谱将补充目前药物靶标验证的转录组和蛋白质组分析。疟原虫寄生提供了一种简单的红细胞与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.