Trafficking Signals in P. Falciparum

疟疾是一种主要的传染病。据保守估计，有2- 3亿人受到影响， 每年有100多万儿童死于这种感染。抗药性疟疾的威胁日益严重 对新药产生了迫切的需求针对宿主中未发现的寄生虫的独特特征 细胞为新药开发提供了一种途径。恶性疟原虫引起最致命的 人类疟疾的一种。恶性疟原虫红细胞感染的一个显著特征是靶向寄生虫蛋白 到红细胞。我们已经证明，靶向事件是由细胞膜上独特的宿主靶向信号介导的。 proteins.与酵母和哺乳动物细胞的细胞器不同，红细胞的目的地在血浆之外 寄生虫的膜。此外，红细胞没有内源性运输结构或机制。的 本建议的长期目标是了解和表征红细胞膜是如何进入的 通过细胞内寄生虫和红细胞伴侣蛋白和其他红细胞靶标的鉴定 与关键的寄生虫因子相互作用。这些研究将有助于我们了解基本的 红细胞修饰的机制，寄生虫的生物学，以及开辟新的目标， 疟疾治疗，从而有助于人类健康。使用转染的分子遗传工具 结合生物信息学、高分辨率成像技术和生化亚细胞分离 将使用测定来表达作为转基因的分泌构建体， 红细胞转基因表达和敲除对变异抗原表达的影响 这些研究对于理解现有的机制具有重要意义 红细胞重塑和疟疾毒力。

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 evaulated.These studies are important for understanding existing mechanisms of erythrocyte remodeling and malarial virulence.