Control of gene expression in trypanosomes: Defining the nuclear lamina

寄生原生动物是疾病的重要病原体，困扰着世界上很大一部分人口。在进化方面，寄生虫与它们的宿主非常不同，这经常反映在许多独特或不寻常的机制的存在上，这些机制支撑着它们的生物学。这一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。在锥虫中，免疫逃避是生存和传播的关键，锥虫是导致睡眠病、恰加斯病和黑热病(内脏利什曼病)和许多其他疾病的一个群体。非洲锥虫的长期生存高度依赖于抗原变异--这一过程非常成功，以至于锥虫可以感染宿主数月，有时甚至数年。免疫逃避的主要机制是抗原变异，即通过免疫上不同形式的变异表面糖蛋白(VSG)的顺序表达来周期性地切换寄生虫表面。了解VSG的表达是解开锥虫毒力机制的核心，也是该领域的长期目标。在细胞核的边缘，DNA被压缩成异染色质，异染色质在转录上是沉默的，是放置在那里的基因失活的机制。为了确保一次只表达一个VSG，锥体使用异染色质作为除一个以外所有可能表达的VSG基因的储存库。最近，我们发现了一个定位于锥体核边缘的蛋白质系统，这些蛋白质调节异染色质、核结构和其他功能。最值得注意的是，这些蛋白质与宿主中组成同等系统的蛋白质不同。这项申请建议详细询问组成这一系统的蛋白质的组织方式，它们如何发挥功能，以及最终它们如何调节VSG基因的表达。

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.