Digestive vacuole biogenesis in the malaria parasite

描述(申请人提供)：本申请旨在了解恶性疟原虫消化液泡(DV)的生物发生。这种酸性的溶酶体样细胞器负责降解从宿主红细胞摄取的大量血红蛋白。DV也是最大的、历史上最具临床用途的抗疟疾药物4-氨基喹啉类药物的作用场所。尽管这种细胞器对寄生虫的发育和抗疟疾化疗很重要，但目前对生物合成的寄生虫蛋白和宿主细胞胞浆成分在红细胞内生命周期中如何输送到DV知之甚少。我建议通过对确定的细胞内运输阶段的遗传和化学干扰来确定哪些运输步骤对于寄生虫和宿主细胞蛋白向DV的运输至关重要。这些研究将使我们能够解决这样的假设，即寄生虫蛋白向DV运输的一条途径依赖于蛋白质分泌和分类的SEC和VPS成分。我们的第二个主要假设是，血红蛋白和一些宿主红细胞胞浆成分的摄取是通过动力蛋白依赖的内吞作用进行的。

DESCRIPTION (provided by applicant): This application aims to understand the biogenesis of the digestive vacuole (DV) of the malaria parasite, Plasmodium falciparum. This acidic, lysosomal-like organelle is responsible for the degradation of large quantities of hemoglobin ingested from the host erythrocyte. The DV is also the site of action of the largest and historically the most clinically useful family of antimalarial drugs, the 4-aminoquinolines. Despite the importance of this organelle to parasite development and antimalarial chemotherapy, little is currently known about how both biosynthetic parasite proteins and components of the host cell cytosol are delivered to the DV during the intraerythrocytic lifecycle. I propose to determine which trafficking steps are essential for the transport of parasite and host cell proteins to the DV by genetic and chemical disruption of defined stages of intracellular transport. These studies will enable us to address the hypothesis that one pathway of parasite protein trafficking to the DV relies upon the Sec and Vps components of protein secretion and sorting. Our second major hypothesis is that uptake of hemoglobin and some host erythrocyte cytosol components proceeds via dynamin-dependent endocytosis.