Investigating the role of SCF ubiquitin ligases during sexual development of Plasmodium falciparum

研究 SCF 泛素连接酶在恶性疟原虫性发育过程中的作用

基本信息

批准号：
MR/W025566/1
负责人：
Katerina Artavanis-Tsakonas
金额：
$ 69.53万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FW025566%2F1
关键词：
Investigating role SCF ubiquitin ligases

项目摘要

Ubiquitin and Nedd8 are involved in fundamental cellular processes and are essential to all eukaryotes. As such, enzymes mediating their dynamic attachment and removal from substrates present attractive targets for therapeutic intervention for both chronic and communicable diseases. Despite being evolutionarily conserved, differences in how these pathways are controlled in higher and lower eukaryotes do exist and could potentially be exploited to generate pathogen-specific inhibitors. It is, therefore, necessary to understand the cell biological mechanisms behind how these pathways are regulated. The SCF complex comprises a group of multi-subunit enzymes that catalyse ligation of ubiquitin onto substrate proteins. The role of these ligases in controlling cell-cycle progression in eukaryotes is well-established, however neither their composition nor function have been studied in the malaria parasite, Plasmodium. We aim to characterize the SCF complex during critical transitions of Plasmodium falciparum parasite development and assess whether their activity can be selectively inhibited to block transmission. Through this work, we hope to define novel targets for the development of control strategies aimed at reducing both the clinical pathology of infected individuals and the number of malaria cases at the population level.

泛素和 Nedd8 参与基本的细胞过程，对所有真核生物至关重要。因此，介导其动态附着和从底物上去除的酶为慢性病和传染病的治疗干预提供了有吸引力的靶标。尽管在进化上是保守的，但高等真核生物和低等真核生物中这些途径的控制方式确实存在差异，并且有可能被用来产生病原体特异性抑制剂。因此，有必要了解这些途径如何调节背后的细胞生物学机制。 SCF 复合物包含一组多亚基酶，可催化泛素与底物蛋白的连接。这些连接酶在控制真核生物细胞周期进程中的作用已得到充分证实，但它们的组成和功能尚未在疟疾寄生虫疟原虫中进行研究。我们的目标是表征恶性疟原虫寄生虫发育的关键转变过程中的 SCF 复合体，并评估是否可以选择性抑制其活性以阻止传播。通过这项工作，我们希望为制定控制策略确定新的目标，旨在减少感染个体的临床病理和人口层面的疟疾病例数量。