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，每年有200-3亿人受到这种疾病的困扰，超过100万儿童死于这种感染。抗药性疟疾的威胁越来越大，这对新药产生了迫切的需求。针对宿主细胞中没有发现的寄生虫的独特特征，为新药开发提供了一种方法。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将寄生虫蛋白靶向红细胞。我们已经证明，靶向事件是由蛋白质上独特的宿主靶向信号介导的。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红细胞膜是如何被细胞内寄生虫进入的，并确定与关键寄生虫因子相互作用的红细胞伴侣和其他红细胞靶标。这些研究将有助于我们了解红细胞修饰的基本机制、寄生虫的生物学以及为抗疟疾治疗开辟新的靶点，从而为人类健康做出贡献。分子、遗传工具结合生物信息学、高分辨率成像技术和生化亚细胞分级分析将被用来将分泌型结构表达为反式基因，并评估感染红细胞中的基因敲除。将评估反式基因表达和敲除对红细胞表面变异抗原表达的影响。这些研究对于了解红细胞重塑和疟疾毒力的现有机制很重要。

DESCRIPTION (provided by applicant): Malaria is a major infectious disease. Conservative estimates predict 2-300 million people are afflicted and over a million children die from the infection each year. The growing threat of drug resistant forms of malaria has created an urgent requirement for new drugs. Targeting unique features of the parasite not found in host cells 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 targeting parasite proteins to the red cell. We have shown that targeting events are mediated by unique host-targeting signals on the proteins. 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 membrane is accessed by the intracellular parasite and the identification of erythrocyte chaperones and other erythrocyte targets that interact with critical parasite factors. The studies will contribute to our understanding of basic mechanisms of erythrocyte modification, biology of the parasite as well as open up new targets for anti-malarial therapy, and thereby contribute to human health. Molecular, genetic tools using transfection combined with bioinformatics, high resolution imaging techniques and biochemical subcellular fractionation assays will be used to express secretory constructs as trans genes and evaluate knockouts in infected erythrocytes. The consequence of trans gene expression and knock outs on variant antigen expression on the erythrocyte surface will be evaluated. These studies are important for understanding existing mechanisms of erythrocyte remodeling and malarial virulence.