Meiosis in Plasmodium: How does it work?

疟原虫减数分裂：它是如何运作的？

• 批准号: BB/X014681/1
• 负责人: David Guttery
• 金额: $ 52.22万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX014681%2F1
• 关键词: Meiosis; Plasmodium; How; does; work

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.

这项研究的主要目标是了解可逆的蛋白质磷酸化-一个关键的过程，开关蛋白质打开和关闭-调节属于疟原虫属的单细胞寄生虫的性发育，这是疟疾的病原体。这些寄生虫在哺乳动物宿主和蚊子媒介中具有复杂的生命周期，并且蚊子的性阶段负责传播给宿主。对于这一应用特别重要的是，我们以前已经证明疟疾寄生虫依赖于两种酶-一种称为NEK 4的蛋白激酶和一种称为PPM 2的蛋白磷酸酶-来驱动有性生殖中一个称为减数分裂的重要过程。减数分裂是有性生殖的重要组成部分，产生准备受精的性细胞（例如精子和卵细胞）。与模型系统（如人类）相比，疟原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，这是蚊子传播所需的关键阶段。NEK 4和PPM 2驱动这一过程;然而，它们打开和关闭的蛋白质在很大程度上是未知的，它们靶向的蛋白质的功能也是未知的。因此，对NEK 4和PPM 2调节蛋白的鉴定可能会揭示驱动疟原虫减数分裂的关键因素，最重要的是，这些因素是否可以被预防疟疾传播的药物靶向。感染人类的疟原虫的性阶段（即减数分裂阶段）很难通过实验研究，因此我们将使用一种名为伯氏疟原虫的啮齿类疟原虫作为模拟人类疟原虫的模型。至关重要的是，通过伯氏疟原虫，我们可以访问和研究整个寄生虫生命周期，特别是蚊子的性阶段。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NEK 4和PPM 2如何控制疟原虫细胞的减数分裂，以及我们是否可以识别驱动其功能的新蛋白质。需要解决的主要问题是这些分子在哪里以及如何工作，它们在减数分裂期间靶向哪些蛋白质，以及我们能否为它们的靶点确定新的功能？总的来说，我们的目标是提供减数分裂过程的基本知识，这些减数分裂过程控制着蚊子中的疟疾发展，并可能发现新的治疗药物，并期望所提供的发现和新见解将直接适用于人类疟疾寄生虫。