Determinants of apicoplast maintenance in malaria parasites

疟疾寄生虫含有一种名为顶体的叶绿体细胞器，它是寄生虫在 用于人类和传播给蚊子。顶生质体一直被认为是一种重要的来源 新的药物靶点来对抗不可避免的抗药性问题，然而，事实证明很难 鉴定和验证对寄生虫生存至关重要的质外体蛋白。这个目标现在是可以实现的。 使用新的遗传工具结合新陈代谢旁路的顶生质体。治疗血液期寄生虫 与异戊二烯化合物IPP(异戊烯基焦磷酸盐)一起，质外体抑制物-即使是那些 导致细胞器的破坏和细胞器基因组的丢失。最近，我们使用了IPP代谢 绕过证明铁-硫簇生物合成对于细胞器的维持是必不可少的。我们 建议使用反向和正向遗传方法与代谢旁路相结合来识别其他 核编码的蛋白质，对于质外体功能和寄生虫的生存是必不可少的。我们还将使用 一种新的条件定位工具，可进一步表征特定蛋白质和表型的作用 与他们的损失有关。我们的实验将有助于建立一个更完整的新陈代谢图景 原生质体功能和寄生虫生存所需的途径和非代谢过程。最终，我们 打算确定新的目标，并验证未来治疗疟疾药物开发的已知目标 并停止它的传播。

Malaria parasites contain a plastid organelle called the apicoplast that is required for parasite survival in humans and for transmission to mosquitoes. The apicoplast has long been recognized as an important source of new drug targets to combat the inevitable problem of drug resistance, however, it has proven difficult to identify and validate apicoplast proteins that are essential for parasite survival. This goal is now achievable using new genetic tools in combination with metabolic bypass of the apicoplast. Blood stage parasites treated with the isoprene compound IPP (isopentenyl pyrophosphate) survive apicoplast inhibitors - even those which result in disruption of the organelle and loss of the organellar genome. Recently, we used the IPP metabolic bypass to demonstrate that iron-sulfur cluster biosynthesis is essential for maintenance of the organelle. We propose to use reverse and forward genetic approaches in conjunction with metabolic bypass to identify other nuclear-encoded proteins which are essential for apicoplast function and parasite survival. We will also use a new conditional localization tool to further characterize the roles of specific proteins and the phenotypes associated with their loss. Our experiments will help to build a more complete picture of the metabolic pathways and non-metabolic processes required for apicoplast function and parasite survival. Ultimately, we intend to identify novel targets and to validate known targets for future development of drugs to cure malaria and stop its transmission.