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NEDD8参与了基本的细胞过程，对所有真核生物都是必不可少的。因此，介导其动态附着和从底物中去除的酶为慢性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，但确实存在这些途径如何控制这些途径的差异，并且确实存在，并且有可能被利用以产生病原体特异性抑制剂。因此，有必要理解这些途径如何调节的细胞生物学机制。 SCF复合物包括一组多生糖酶，该酶催化泛素连接到底物蛋白上。这些连接酶在控制真核生物中的细胞周期进展中的作用是良好的，但是在疟原虫寄生虫质质子疟原虫中均未研究它们的组成和功能。我们的目的是在恶性疟原虫发育的临界过渡期间表征SCF复合物，并评估是否可以选择性地抑制其活性以阻止传播。通过这项工作，我们希望为制定旨在减少感染个体的临床病理和人群疟疾病例的临床病理的控制策略定义新的目标。