权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting epigenetics for antimalarial development

针对抗疟疾开发的表观遗传学

基本信息

批准号：
2876747
负责人：
金额：
--
依托单位：
University of Dundee
依托单位国家：
英国
项目类别：
Studentship
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=studentship-2876747
关键词：
Targeting epigenetics antimalarial development

项目摘要

Epigenetic regulation is an important means of controlling gene expression in eukaryotes. In the malaria parasite, Plasmodium, chromatin remodelling factors are implicated in diverse aspects of pathogenicity, including the activation of invasion-related genes, the suppression of cytoadherence receptors to preserve immune evasion, and the developmental commitment to transmissible sexual forms. However, our understanding of the roles of specific chromatin modifying factors in the dynamic regulation of gene expression across the different life-cycle stages of this apicomplexan parasite is incomplete. Furthermore, chemical inhibitors developed against essential epigenetic targets provide important tools for probing parasite biology, and could act as starting points for new drug discovery. This project will combine CRISPR-based genome editing and chemical biology approaches to probe the roles of the "readers, writers and erasers" of the epigenetic code. Taking two parallel approaches, this project will generate conditional knock-out lines of several epigenetic regulators using CRISPR genome editing, and will use epigenetic probe compounds ('epi-probes') with antimalarial activity to evolve resistance in vitro in order to establish their targets. These genetic and chemical resources will then be used to evaluate the impact of epigenetic regulation on lifecycle transitions of the parasite and the expression of multigene families involved in immune evasion.

表观遗传调控是控制真核生物基因表达的重要手段。在疟疾寄生虫中，染色质重塑因子涉及致病性的不同方面，包括激活入侵相关基因，抑制细胞黏附受体以保持免疫逃避，以及对可传播性形式的发育承诺。然而，我们对特定染色质修饰因子在这种顶端复合体寄生虫不同生命周期阶段基因表达动态调节中的作用的了解还不完全。此外，针对必要的表观遗传靶点开发的化学抑制剂为探测寄生虫生物学提供了重要工具，并可作为新药发现的起点。该项目将结合基于CRISPR的基因组编辑和化学生物学方法来探索表观遗传密码的“读取者、写入者和擦除者”的角色。采用两种平行的方法，该项目将使用CRISPR基因组编辑生成几个表观遗传调节因子的条件敲除系，并将使用具有抗疟疾活性的表观遗传探针化合物(‘epi-探针’)在体外进化耐药性，以建立它们的靶点。这些遗传和化学资源将被用来评估表观遗传调控对寄生虫生命周期转变的影响，以及参与免疫逃避的多基因家族的表达。