Determinants of apicoplast maintenance in malaria parasites

疟疾寄生虫含有一种称为顶质体的质体细胞器， 人类和传播给蚊子。顶质体长期以来被认为是一个重要的来源 新的药物靶点来对抗不可避免的耐药性问题，然而，事实证明， 鉴定和验证寄生虫生存所必需的顶质体蛋白。这个目标现在是可以实现的 使用新的遗传工具结合顶质体的代谢旁路。治疗的血液期寄生虫 与异戊二烯化合物IPP（异戊烯焦磷酸）一起存活的顶质体抑制剂-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IPP代谢 旁路，以证明铁硫簇生物合成是必不可少的细胞器的维护。我们 建议使用反向和正向遗传方法结合代谢旁路来识别其他 核编码的蛋白质是顶质体功能和寄生虫生存所必需的。我们还将使用 新的条件定位工具，以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图片的代谢 顶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 目是鉴定新的靶点并验证已知的靶点，以便将来开发治疗疟疾的药物 并阻止其传播

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.