Digestive vacuole biogenesis in the malaria parasite

描述（由申请人提供）：本申请旨在了解疟疾寄生虫恶性疟原虫的消化液泡（DV）的生物发生。这种酸性溶酶体样细胞器负责从宿主红细胞摄取的大量血红蛋白的降解。DV也是4-氨基喹啉类抗疟药物的最大和历史上最有临床用途的作用位点。尽管这种细胞器在寄生虫发育和抗疟疾化疗中很重要，但目前对生物合成的寄生虫蛋白和宿主细胞质成分如何在红细胞生命周期中传递到DV知之甚少。我建议通过细胞内运输的特定阶段的遗传和化学破坏来确定哪些运输步骤是寄生虫和宿主细胞蛋白质运输到DV所必需的。这些研究将使我们能够解决寄生虫蛋白质运输到DV的一个途径依赖于蛋白质分泌和分选的Sec和Vps成分的假设。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.