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

• 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

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，是所有真核生物所必需的。因此，介导其动态附着和从底物去除的酶为慢性和传染性疾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，但这些途径在高等和低等真核生物中的控制方式确实存在差异，并且可能被利用来产生病原体特异性抑制剂。因此，有必要了解这些途径是如何调节的细胞生物学机制。SCF复合物包含一组多亚基酶，其催化泛素连接到底物蛋白上。这些连接酶在真核生物中控制细胞周期进程的作用是公认的，但是它们的组成和功能在疟疾寄生虫疟原虫中都没有研究过。我们的目的是描述SCF复合物在恶性疟原虫寄生虫发育的关键转变过程中的特征，并评估它们的活性是否可以被选择性地抑制以阻断传播。通过这项工作，我们希望确定新的目标，以制定控制战略，旨在减少感染者的临床病理学和人口一级的疟疾病例数。