Characterisation of a new family of zinc finger proteins and their role in apicomplexan parasites' development and transmission.

锌指蛋白新家族的表征及其在顶复门寄生虫发育和传播中的作用。

• 批准号: BB/T016736/1
• 负责人: Katarzyna Modrzynska
• 金额: $ 62.23万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT016736%2F1
• 关键词: Characterisation; new; family; zinc; finger

The small parasites from the group called Apicomplexa are known to cause a number of human and animal diseases, including one of the most deadly infections in tropics - malaria. They are often being transmitted by the insect vectors and during their development go through a number of life forms of different appearance and function. To progress through these complex life cycles, the parasites need to be able to switch on and off each of their genes in a timely and coordinated manner. Most of the commonly studied organisms are achieving this by using the proteins called transcription factors, which can act as molecular switches of the whole groups of genes. However only a very small number of them have been identified in the Apicomplexa, suggesting that their mechanisms of controlling the gene expression are significantly different. The understanding of these mechanisms could open the way to new antiparasitic treatments but also allow better control of the parasites life cycles in laboratory conditions allowing the generation of a large number of desired life stages for the drug screening.We have recently identified a group of parasite-specific proteins with the capacity to specifically bind the ribonucleic acids (RNA) - the key intermediates between the activated gene and its final product, whose stabilisation or degradation can be used to fine-tune the gene expression. These proteins are present in all Apicomplexa and their nearest relatives but not in any of the other organisms including the parasite hosts. Importantly in the laboratory model of malaria infection, a number of them appear to be necessary for parasite's growth and infectivity. While these proteins may constitute a major group of Apicomplexa-specific gene regulators, the details of their role remain unknown.The proposed project plans to investigate these proteins, understand the details of their function and identify the molecules/gene they are interacting with. In order to achieve this we plan to: 1) Study the evolution of these proteins, looking at the changes they underwent during the expansion of the Apicomplexa, mapping their similarities and differences between different species and comparing them to other protein families present in the parasites2) In the model parasite (Plasmodium berghei) generate the mutants lacking each of the 11 proteins from the investigated family present in this species, and study the effects of these mutations on the parasite's ability to progress through its life cycle and control its RNA content3) Choose 3-4 proteins, identified in the previous point as important for Plasmodium development, and study their function by a) identifying the RNA molecules they interact with (using three different complementary methods), b) studying the effects they have on the gene expression and c) discovering the proteins they interact with and mechanism by which the may degrade and/or stabilised their targets.The combined data from the above investigations will provide a comprehensive picture of the role these newly identified proteins play in the gene expression regulation in malaria (and related parasites) and generate tools and avenues for their further investigation in multiple parasite species, potentially contributing to the new strategies of parasitic infections control.

这种名为Apicomplexa的小型寄生虫已知会导致许多人类和动物疾病，包括热带地区最致命的感染之一-疟疾。它们通常是由昆虫媒介传播的，在它们的发育过程中经历了许多不同外观和功能的生命形式。为了在这些复杂的生命周期中取得进展，寄生虫需要能够及时和协调地打开和关闭它们的每个基因。大多数被普遍研究的生物体是通过使用被称为转录因子的蛋白质来实现这一点的，转录因子可以充当整个基因组的分子开关。然而，在Apicomplexa中只发现了非常少数的这些基因，这表明它们控制基因表达的机制有很大的不同。对这些机制的了解可以为新的抗寄生虫治疗开辟道路，也可以在实验室条件下更好地控制寄生虫的生命周期，从而产生大量所需的生命阶段用于药物筛选。我们最近发现了一组寄生虫特异的蛋白质，能够特异性地结合核糖核酸(RNA)--激活的基因及其最终产物之间的关键中间产物，其稳定或降解可用于微调基因的表达。这些蛋白存在于所有Apicomplexa及其近亲中，但不存在于包括寄生虫宿主在内的任何其他生物中。重要的是，在疟疾感染的实验室模型中，它们中的一些似乎对寄生虫的生长和传染性是必要的。虽然这些蛋白质可能构成Apicomplexa特异性基因调控的主要群体，但它们的作用细节仍不清楚。拟议的项目计划调查这些蛋白质，了解它们的功能细节，并确定它们相互作用的分子/基因。为了实现这一点，我们计划：1)研究这些蛋白质的进化，观察它们在顶体复合体扩张过程中所经历的变化，绘制它们在不同物种之间的异同，并将它们与寄生虫中存在的其他蛋白质家族进行比较。2)在模式寄生虫(伯氏疟原虫)中，产生缺乏该物种中所研究的家族中的11种蛋白质中的每一种的突变体，并研究这些突变对寄生虫在其生命周期中进展和控制其RNA含量的能力的影响。3)选择3-4种蛋白质，在前一点被确定为对疟原虫发育重要，并通过a)确定它们与之相互作用的RNA分子(使用三种不同的互补方法)，b)研究它们对基因表达的影响，以及c)发现它们与之相互作用的蛋白质和可能降解和/或稳定其靶标的机制来研究它们的功能。上述研究的综合数据将提供这些新发现的蛋白质在疟疾(和相关寄生虫)的基因表达调控中所起的作用的全面图景，并为它们在多种寄生虫物种中的进一步研究提供工具和途径，潜在地有助于寄生虫感染控制的新策略。