Identification and characterization of telomere proteins in Plasmodium falciparum.

恶性疟原虫端粒蛋白的鉴定和表征。

• 批准号: BB/K009206/1
• 负责人: Catherine Merrick
• 金额: $ 45.52万
• 依托单位: Keele University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK009206%2F1
• 关键词: Identification; characterization; telomere; proteins; Plasmodium

The proposed research concerns the human malaria parasite Plasmodium. Malaria is one of the world's most debilitating infectious diseases and Plasmodium is related to several other major parasites of humans and livestock, so a better understanding of it may help us to understand and control other human and animal diseases as well. The lack of effective vaccines against most of these parasites and the emergence of drug-resistant parasites mean that there is an urgent need for research leading to new treatment strategies for malaria and related diseases. Single-celled parasites can replicate very rapidly inside infected people or animals. One basic function that all rapidly-replicating cells must perform is the maintenance of their telomeres: the ends of the chromosomes that make up the cell's genome. Telomeres become slightly shorter every time a cell divides and will eventually become too short for survival if they are not regularly extended. Cancer cells, for example, usually develop a method for replenishing their telomeres that allows them to replicate endlessly and grow out of control, whereas most normal cells in an adult body cannot do this.The malaria parasite, like any other single-celled organism, replenishes its telomeres every time it divides, giving it an infinite capacity for replication. However, Plasmodium is a rather unusual microbe and we know very little about the machinery that controls its telomeres. Our understanding of telomeres in human cells is quite good, but the machinery that maintains telomeres in malaria parasites does not resemble the machinery in human cells. This project therefore focuses on the maintenance of telomeres in the malaria parasite. A better understanding of this could point us in the direction of new drug targets, since disrupting the structure and maintenance of telomeres is often lethal.To find this machinery will require a biological fishing expedition. The whole genome of the malaria parasite will be broken up into pieces and the telomeric DNA will be fished out along with the proteins bound to it. These will then be identified and the experiment will be followed up by knocking out some of these proteins in parasites grown in the lab, to test whether they actually do control telomeres. Overall, the study will give us a better understanding of the mechanisms that maintain the telomeres of these unusual parasites. It may inform new drug strategies to combat malaria and related parasitic diseases affecting both humans and animals. The outcomes of the research will be published in open-access scientific journals and presented at international conferences. They will be communicated to the general public via lay summaries on appropriate websites and via science-writing in magazines and/or online.

这项拟议中的研究涉及人类疟疾寄生虫疟原虫。疟疾是世界上最致命的传染病之一，疟原虫与人类和牲畜的其他几种主要寄生虫有关，因此更好地了解它可能有助于我们了解和控制其他人类和动物疾病。缺乏针对大多数这些寄生虫的有效疫苗以及抗药性寄生虫的出现意味着迫切需要进行研究，以制定疟疾和相关疾病的新治疗策略。 单细胞寄生虫可以在受感染的人或动物体内非常迅速地复制。所有快速复制的细胞都必须执行的一个基本功能是维持它们的端粒：构成细胞基因组的染色体末端。端粒在细胞每次分裂时都会变短，如果不定期延长，最终会变得太短而无法生存。例如，癌细胞通常会发展出一种补充端粒的方法，使它们能够无休止地复制并失控地生长，而成年人体内的大多数正常细胞则无法做到这一点。疟疾寄生虫就像其他单细胞生物一样，每次分裂时都会补充端粒，使其具有无限的复制能力。然而，疟原虫是一种相当不寻常的微生物，我们对控制其端粒的机制知之甚少。我们对人类细胞中的端粒的理解相当好，但疟疾寄生虫中维持端粒的机制与人类细胞中的机制并不相似。因此，该项目的重点是维持疟疾寄生虫的端粒。更好地理解这一点可以为我们指出新的药物靶点的方向，因为破坏端粒的结构和维护通常是致命的。疟疾寄生虫的整个基因组将被分解成片段，端粒DNA将被沿着与之结合的蛋白质一起打捞出来，然后这些蛋白质将被鉴定出来，实验将通过敲除实验室中培养的寄生虫中的一些蛋白质来进行，以测试它们是否真的控制端粒。总的来说，这项研究将使我们更好地了解维持这些不寻常的寄生虫端粒的机制。它可以为防治疟疾和影响人类和动物的相关寄生虫病的新药物战略提供信息。研究成果将发表在开放获取的科学期刊上，并在国际会议上发表。将通过适当网站上的非专业摘要以及杂志和/或在线上的科学写作向公众传达这些信息。

项目成果

Plasmodium falciparum GBP2 Is a Telomere-Associated Protein That Binds to G-Quadruplex DNA and RNA.

恶性疟原虫 GBP2 是一种端粒相关蛋白，可与 G-四链体 DNA 和 RNA 结合。

• DOI: 10.17863/cam.80362
• 发表时间: 2022
• 作者: Edwards-Smallbone J

Plasmodium falciparum GBP2 is a telomere-associated protein that binds to G-quadruplex DNA and RNA

• DOI: 10.1101/2021.07.02.450898
• 发表时间: 2022-02-22
• 期刊: FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
• 影响因子: 5.7
• 作者: Edwards-Smallbone，James;Jensen，Anders L.;Merrick，Catherine J.
• 通讯作者: Merrick，Catherine J.

BrdU labelling of DNA replication in Plasmodium falciparum (poster presentation, BioMalPar conference 2015)

恶性疟原虫中 DNA 复制的 BrdU 标记（海报展示，BioMalPar 会议 2015）

• 发表时间: 2015
• 作者: Merrick, C. J.

Transfection with thymidine kinase permits bromodeoxyuridine labelling of DNA replication in the human malaria parasite Plasmodium falciparum.

• DOI: 10.1186/s12936-015-1014-7
• 发表时间: 2015-12-02
• 期刊: Malaria journal
• 影响因子: 3
• 作者: Merrick CJ

Single-molecule analysis reveals that DNA replication dynamics vary across the course of schizogony in the malaria parasite Plasmodium falciparum.

• DOI: 10.1038/s41598-017-04407-z
• 发表时间: 2017-06-21
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Stanojcic S;Kuk N;Ullah I;Sterkers Y;Merrick CJ
• 通讯作者: Merrick CJ