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。

基本信息

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

项目摘要

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.

已知该群体的小寄生虫引起许多人类和动物疾病，包括热带疟疾中最致命的感染之一。它们通常是由昆虫向量传播的，在发育过程中，它们经历了许多不同外观和功能的生命形式。为了通过这些复杂的生命周期进行，寄生虫需要能够及时和协调的方式打开和关闭其每个基因。大多数经常研究的生物都通过使用称为转录因子的蛋白质来实现这一目标，该蛋白可以用作整个基因组的分子开关。然而，在Apicomplexa中只有很少的数量已经鉴定出来，这表明它们控制基因表达的机制显着差异。对这些机制的理解可以为新的抗寄生虫治疗开辟道路，同时还可以更好地控制寄生虫在实验室条件下生命周期，从而使药物筛查的大量期望的生命阶段产生。我们最近确定了一组寄生虫特异性蛋白质，具有特定的能力，可以特异性地结合其在核酸（RNA）之间 - 核糖核酸（RNA） - 核糖核酸（RNA） - 核糖核酸（RNA） - 核糖核酸的界限或核糖核酸的界限 - 降解可用于微调基因表达。这些蛋白质都存在于所有Apicomplexa及其最近的亲戚中，但在包括寄生虫宿主在内的任何其他生物中都不存在。重要的是，在疟疾感染的实验室模型中，其中许多似乎是寄生虫的生长和感染性所必需的。尽管这些蛋白质可能构成一组主要的apicomplexa特异性基因调节剂，但其作用的细节仍然未知。拟议的项目计划研究了这些蛋白质，了解其功能的细节并确定与他们相互作用的分子/基因。为了实现这一目标，我们计划：1）研究这些蛋白质的演变，查看它们在apicomplexa扩展过程中所经历的变化，绘制它们之间的相似性和在不同物种之间的相似性和差异，并将它们与寄生虫中存在的其他蛋白质家族进行比较，并在模型寄生虫（寄生虫）中（葡萄球菌berghei）中缺乏这些蛋白质的蛋白质和研究的蛋白质，这些蛋白质缺乏这些蛋白质，这些蛋白质缺乏这些蛋白质，这些蛋白质却缺乏这些蛋白质，这些蛋白质的作用是这些蛋白质的作用。 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目标。上述研究中的组合数据将为这些新鉴定的蛋白质在疟疾（及相关寄生虫）中的基因表达调节中发挥作用的作用提供全面的描述，并为在多种寄生虫物种中进一步研究生成工具和途径，这可能有助于寄生虫感染控制的新策略。