Plasmodium Falciparum Metal Metabolism

恶性疟原虫金属代谢

• 批准号: 7036055
• 负责人: DAVID Joseph SULLIVAN
• 金额: $ 33.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7036055
• 关键词: HeLa cells; Plasmodium falciparum; SDS polyacrylamide gel electrophoresis; antimalarial agents; cell line; chloroquine; divalent cations; drug resistance; drug screening /evaluation; erythrocyte membrane; erythrocytes; heme; immunoelectron microscopy; immunoprecipitation; intracellular transport; ion transport; iron metabolism; malaria; membrane transport proteins; microorganism culture; northern blottings; pharmacokinetics; polymerase chain reaction; quinoline; site directed mutagenesis; western blottings

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.

描述（由申请人提供）：喹啉和青蒿素对疟原虫金属代谢的干扰是经过验证的化疗靶标。尽管取得了很大进展，但血红素晶体形成的精确分子过程（喹啉的目标）尚不清楚。对疟原虫金属生物学进行针对性干预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药物靶点验证的方法，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形成和用亚细胞寄生虫分级、体外脂质或蛋白质制剂引发的抑制。代谢分析的具体目的是识别未感染红细胞与感染红细胞相比的常见和独特代谢物，这些代谢物也对针对金属的抗疟药物有反应，并分析耐药菌株中改变的疟原虫代谢特征。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。 详细介绍血红素晶体形成的意义涉及喹啉药物作用和耐药性的基础知识。疟原虫代谢分析将补充当前药物靶标验证的转录组和蛋白质组分析，作为 NIH 研究细胞代谢过程组件和网络的“路线图”的一部分。疟原虫寄生提供了“简单”红细胞与更复杂的感染细胞的比较。