Meiosis in Plasmodium: How does it work?

这项研究的主要目标是了解可逆蛋白质磷酸化-一个开关蛋白质的关键过程-如何调节属于疟原虫属的单细胞寄生虫的性发育，这种寄生虫是疟疾的病原体。这些寄生虫在哺乳动物宿主和蚊子媒介中有一个复杂的生命周期，蚊子的有性阶段负责传播给宿主。对这一应用特别重要的是，我们之前已经证明，疟疾寄生虫依赖两种酶--一种名为NEK4的蛋白激酶和一种名为PPM2的蛋白磷酸酶--来驱动有性繁殖中一个称为减数分裂的必要过程。减数分裂是有性生殖的重要组成部分，它产生准备受精的性细胞(如精子和卵细胞)。与人类等模型系统相比，疟疾寄生虫的减数分裂非常不同，因为它在发育中的受精卵中进行受精后受精，这是蚊子传播所需的关键阶段。NEK4和PPM2推动了这一过程；然而，它们开启和关闭的蛋白质以及它们所针对的蛋白质的功能在很大程度上是未知的。因此，对NEK4和PPM2调控蛋白的鉴定可能会揭示推动疟原虫减数分裂的关键因素，最重要的是，这些蛋白是否可能成为防止疟疾传播的药物的靶点。感染人类的疟疾寄生虫的有性阶段(即减数分裂阶段)很难进行实验研究，因此我们将使用一种名为伯氏疟原虫的啮齿动物疟疾寄生虫作为模拟人类寄生虫的模型。至关重要的是，通过伯氏疟原虫，我们可以了解和研究寄生虫的整个生命周期，特别是蚊子的有性阶段。我们还将利用几种最先进的方法，包括蛋白质组学、磷酸蛋白质组学和细胞生物学技术，以了解NEK4和PPM2如何控制疟疾寄生虫细胞的减数分裂，以及我们是否可以识别驱动其功能的新蛋白质。要解决的主要问题是这些分子在哪里以及如何工作，它们在减数分裂过程中以什么蛋白质为靶标，以及我们能否为其靶标确定新的功能？总体而言，我们的目标是提供管理蚊子疟疾发展的减数分裂过程的基本知识，并可能发现新的治疗药物，并期望所提供的发现和新的见解将直接适用于人类疟疾寄生虫。

The main goal of this research is to understand how reversible protein phosphorylation - a key process that switches proteins on and off - regulates sexual development of single-cell parasites belonging to the genus Plasmodium, which are the causative agent of malaria. These parasites have a complex life-cycle in mammalian hosts and the mosquito vector, and the sexual stages in the mosquito are responsible for transmission to the host. Of particular importance for this application, we have shown previously that the malaria parasite relies on two enzymes - a protein kinase called NEK4 and protein phosphatase called PPM2 - to drive an essential process in sexual reproduction called meiosis. Meiosis is an essential part of sexual reproduction that produces sex cells (e.g. sperm and egg cells) ready for fertilisation. Compared to model systems, such as humans, meiosis is highly different in the malaria parasite since it proceeds post-fertilisation in the developing zygote, a crucial stage required for transmission from the mosquito. NEK4 and PPM2 drive this process; however, the proteins they switch on and off are largely unknown, as are the functions of the proteins they target. Hence, identification of the proteins NEK4 and PPM2 regulate may uncover the key players that drive Plasmodium meiosis, and most importantly whether these could be targeted by drugs that will prevent malaria transmission. The sexual stages of the malaria parasite (i.e. meiosis stages) that infects humans are difficult to study experimentally, and therefore we will be using a rodent malaria parasite called Plasmodium berghei as a model that mimics the human parasite. Crucially, with P. berghei we can access and study the whole parasite life cycle, particularly the sexual stages in the mosquito. We also will utilise several state-of-the-art methods including proteomics, phosphoproteomics and cell biology techniques towards understanding how NEK4 and PPM2 control meiosis in the malaria parasite cell, and whether we can identify new proteins that drive its function. The main questions to be addressed are where and how these molecules work, what proteins do they target during meiosis and can we identify new functions for their targets? Overall, we aim to deliver fundamental knowledge of the meiotic processes that govern malaria development in the mosquito and potentially uncover novel therapeutic agents, and expect that the discoveries and new insights provided will be directly applicable to human malaria parasites.