Trafficking Signals in P. Falciparum

描述(申请人提供)：疟疾是一种主要的传染病。保守估计，2012年将有2-3亿人受到感染，70万儿童死亡。抗药性疟疾的威胁越来越大，这对新药产生了迫切的需求。针对这种寄生虫的独特特征，为新药开发提供了一种途径。恶性疟原虫是人类疟疾中最致命的一种。恶性疟原虫-红细胞感染的一个显著特征是数百种寄生虫蛋白被输出到宿主细胞。这种输出机制是由寄生虫蛋白上的N端宿主靶向信号介导的，该信号与寄生虫内质网(ER)内的磷脂酰肌醇-3-磷酸[PI(3)P]结合。与酵母和哺乳动物细胞的细胞器不同，红细胞中的目的地位于寄生虫的质膜之外。此外，红细胞没有内源性运输结构或机械。这项建议的长期目标是了解和表征细胞内寄生虫是如何进入红细胞的，并确定使寄生虫能够退出ER的关键寄生虫机制。分析中将使用分子、遗传、基因组工具、生物信息学、高分辨率成像技术、生化亚细胞分离分析、脂蛋白相互作用的生物物理测量、膜弯曲和穿透，以及转基因记者、内源性寄生虫蛋白、药物和抗药性寄生虫。将评估药物对内质网中脂-蛋白相互作用、红细胞表面变异抗原表达和寄生虫杀灭的影响。这些研究是了解疟疾寄生虫生物学、红细胞重塑和疟疾毒力的基本机制所必需的。它们将为抗疟疾治疗开辟新的目标，从而为人类健康做出贡献。

DESCRIPTION (provided by applicant): Malaria is a major infectious disease. Conservative estimates predict 2-300 million people are afflicted and seven hundred thousand children die from the infection in 2012. The growing threat of drug resistant forms of malaria has created an urgent requirement for new drugs. Targeting unique features of the parasite provides one approach to new drug development. Plasmodium falciparum causes the most virulent form of human malaria. A striking feature of P. falciparum- erythrocytic infection is that hundreds of parasite proteins are exported to the host cell. The export mechanism is mediated by an N terminal host-targeting signal on parasite proteins that binds to the lipid phosphatidylinositol-3-phosphate [PI(3)P] within the parasite's endoplasmic reticulum (ER). Unlike organelles of yeast and mammalian cells, destinations in the red cell lie beyond the plasma membrane of the parasite. Moreover, the red cell has no endogenous transport structures or machinery. The long term aim of this proposal is to understand and characterize how the erythrocyte is accessed by the intracellular parasite and the identification critical parasite mechanisms that enable exit fro the parasite's ER. Molecular, genetic, genomic tools, bioinformatics, high resolution imaging techniques, biochemical subcellular fractionation assays, biophysical measurements of lipid-protein interactions, membrane bending and penetration will be used in analysis, as will transgenic reporters, endogenous parasite proteins, drugs and drug resistant parasites. The consequence of drugs on lipid-protein interactions in the ER, variant antigen expression on the erythrocyte surface and parasite killing will be evaluated. These studies are needed to understand basic mechanisms of malaria parasite biology, erythrocyte remodeling and malarial virulence. They will open up new targets for anti-malarial therapy, and thereby contribute to human health.