Control of gene expression in trypanosomes: Defining the nuclear lamina

锥虫基因表达的控制：定义核层

• 批准号: MR/N010558/1
• 负责人: Mark Field
• 金额: $ 74.5万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN010558%2F1
• 关键词: Control; gene; expression; trypanosomes; Defining

Parasitic protozoa are important agents of disease, and afflict a major proportion of the world's population. In evolutionary terms parasites are very different to their hosts, and this is frequently reflected in the presence of a great many unique or unusual mechanisms that underpin their biology. This aspect presents multiple opportunities for the understanding of pathogenesis and also the possibility of identifying therapeutic targets. In trypanosomes, which as a group cause Sleeping sickness, Chagas' disease and Kala Azar (visceral leishmaniasis) and a great many other diseases, immune evasion is vital for survival and transmission. African trypanosomes are highly reliant on antigenic variation for their longterm survival - the process is so successful that trypanosomes can infect their host for many months and in some cases years. The primary mechanism of immune evasion is antigenic variation, the periodic switching of the parasite surface through sequential expression of immunologically distinct forms of the variant surface glycoprotein (VSG). Understanding VSG expression is central to unravelling the mechanisms of trypanosome virulence and is a longstanding goal in the field. At the rim of the nucleus DNA is compacted into heterochromatin, which is transcriptionally silent and acts as a mechanism for the inactivation of genes placed there. To ensure that only one VSG is expressed at a time trypanosomes use heterochromatin as a store for all potentially expressed VSG genes except one. Recently we have uncovered a system of proteins that are localised to the rim of the trypanosome nucleus, and which regulate heterochromatin, nuclear structure and other functions. Most remarkably these proteins are distinct from those that make up the equivalent system in the host. This application proposes to interrogate in detail the manner in which the proteins comprising this system are organised, how they function and ultimately how they regulate VSG gene expression.

寄生原生动物是重要的疾病媒介，困扰着世界上大部分人口。从进化的角度来看，寄生虫与其宿主非常不同，这通常反映在支持其生物学的许多独特或不寻常的机制的存在上。这方面为理解发病机制提供了多种机会，也为确定治疗靶点提供了可能性。 锥虫作为一个群体会导致昏睡病、恰加斯病和黑热病（内脏利什曼病）以及许多其他疾病，免疫逃避对于生存和传播至关重要。非洲锥虫的长期生存高度依赖抗原变异——这一过程非常成功，锥虫可以感染宿主数月甚至数年。免疫逃避的主要机制是抗原变异，即通过免疫学上不同形式的变体表面糖蛋白（VSG）的顺序表达来周期性切换寄生虫表面。了解 VSG 表达对于揭示锥虫毒力机制至关重要，也是该领域的长期目标。 在细胞核边缘，DNA 被压缩成异染色质，异染色质在转录上是沉默的，并充当位于此处的基因失活的机制。为了确保一次仅表达一种 VSG，锥虫使用异染色质作为除一种之外的所有潜在表达 VSG 基因的储存库。最近，我们发现了一个位于锥虫核边缘的蛋白质系统，它调节异染色质、核结构和其他功能。最值得注意的是，这些蛋白质与构成宿主中等效系统的蛋白质不同。本申请旨在详细探讨组成该系统的蛋白质的组织方式、它们如何发挥作用以及最终如何调节 VSG 基因表达。

项目成果

The kinetochore and the origin of eukaryotic chromosome segregation.

动粒和真核染色体分离的起源。

• DOI: 10.1073/pnas.1908067116
• 发表时间: 2019
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Field MC

A leucine aminopeptidase is involved in kinetoplast DNA segregation in Trypanosoma brucei.

• DOI: 10.1371/journal.ppat.1006310
• 发表时间: 2017-04
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Peña-Diaz P;Vancová M;Resl C;Field MC;Lukeš J
• 通讯作者: Lukeš J

Evolution and diversification of the nuclear envelope.

• DOI: 10.1080/19491034.2021.1874135
• 发表时间: 2021-12
• 期刊: Nucleus (Austin, Tex.)
• 作者: Padilla-Mejia NE;Makarov AA;Barlow LD;Butterfield ER;Field MC
• 通讯作者: Field MC

Proteomics Uncovers Novel Components of an Interactive Protein Network Supporting RNA Export in Trypanosomes.

• DOI: 10.1016/j.mcpro.2022.100208
• 发表时间: 2022-03
• 期刊: Molecular & cellular proteomics : MCP
• 作者: Inoue AH;Domingues PF;Serpeloni M;Hiraiwa PM;Vidal NM;Butterfield ER;Del Pino RC;Ludwig A;Boehm C;Field MC;Ávila AR
• 通讯作者: Ávila AR

Comparative interactomics provides evidence for functional specialization of the nuclear pore complex.

比较相互作用组学为核孔复合体的功能特化提供了证据。

• DOI: 10.1080/19491034.2017.1313936
• 发表时间: 2017
• 期刊: Nucleus (Austin, Tex.)
• 作者: Obado SO