Bridging epigenetics, metabolism and cell cycle in pathogenic trypanosomatids

连接致病性锥虫的表观遗传学、代谢和细胞周期

• 批准号: MR/S019650/1
• 负责人: Mike Barrett
• 金额: $ 109.1万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS019650%2F1
• 关键词: Bridging; epigenetics; metabolism; cell; cycle

We propose to bring together a group of researchers across the UK and in Sao Paulo to share expertise that will allow us to understand the biology of parasites that cause neglected tropical diseases and improve our ability to intervene against them. Disease-causing microbes remain a major problem for health the world over. This is seen disproportionately in tropical countries, were a combination of environmental factors (e.g. climatic conditions supporting the propagation of insects that can transmit disease) and relatively scarce economic resource ensure the maintenance of infectious disease. Parts of rural Brazil, like other areas in Latin America, suffer from diseases caused by parasitic protozoa, which are single-celled organisms. One parasite, Trypanosoma cruzi, causes Chagas disease, affecting several million people across Latin America. Closely-related parasites, belonging to the genus Leishmania, cause a range of diseases called the leishmaniases in many parts of the world. Chagas disease is transmitted by triatomine bugs that suck the blood of mammals including humans and in the process defecate upon their victims. Parasites in the faeces then enter the body and over a long period of time, sometimes twenty years or more, the insidious Chagas disease develops. Quite often patients do not know they have the disease. In around 30% of cases though, a chronic inflammatory response to the heart or digestive system can lead to death. The leishmaniases are transmitted by sandflies through the saliva whilst they feed on their victims. Depending on which species of the Leishmania parasite is transmitted, the disease can either occur in the skin (cutaneous leishmaniasis) or else migrate to the liver and spleen (visceral leishmaniasis). Some species, including Leishmania braziliensis, causes the horrible disease known in Brazil as Espundia, where human cells called macrophages (in which the parasite resides) migrate to the mucosal membranes of our lips and nostrils and cause them to disintegrate. Sometimes, following treatment, after a lapse that can last a few years, the visceral form of the disease relapses into a form we call post Kalar-Azar dermal leishmaniasis (PKDL).Although drugs exist to treat both Chagas disease and the leishmaniases, they are far from ideal. Some are toxic, others have to be given over a protracted period, and several are available only by needle injections. Resistance has emerged to existing drugs, and it has been known for a long time that some parasites do not respond to treatment even if resistance has not been selected. This collaborative project aims to bring together a team of researchers across the UK and Sao Paulo to look specifically at the processes that enable parasites to thrive in the insect vectors that carry them and then within the very different environment of their mammalian host. Since the parasites keep exactly the same genome (which is the blueprint that encodes every aspect of their ultimate makeup) they need to choose which parts of the genome to express in different environments. This involves subtle changes to the structure of the protein architecture that holds their genes together, in a structure we call chromatin. In other organisms it has, in recent years, become clear that the addition of small molecules to those chromatin-associated proteins can change their function. Removing those adaptations causes them to change back again. These alterations, which do not involve modifying the sequence of the DNA blueprint itself, and yet do influence how that DNA is expressed, are described as "epigenetic" alterations. We will investigate how epigenetic alterations impact on gene expression in T. cruzi and leishmanias, and work out how we can manipulate this epigenetic process by altering the availability of the small molecule metabolites responsible for those changes. We hope to find new therapeutic drugs treatment interventions to act on these epigenetic targets.

我们建议将英国各地和圣保罗的一组研究人员聚集在一起，分享专业知识，使我们能够了解导致被忽视的热带病的寄生虫的生物学，并提高我们干预它们的能力。致病微生物仍然是全世界健康的主要问题。这在热带国家尤为常见，是环境因素(例如，气候条件支持可传播疾病的昆虫的繁殖)和相对稀缺的经济资源的综合作用，以确保传染病的维持。像拉丁美洲的其他地区一样，巴西农村的部分地区也受到寄生原虫引起的疾病的困扰，原虫是单细胞有机体。一种名为克氏锥虫的寄生虫会引起恰加斯病，影响整个拉丁美洲的数百万人。与利什曼原虫关系密切的寄生虫属于利什曼原虫属，在世界许多地区引起一系列称为利什曼原虫的疾病。恰加斯病是通过三聚氰胺细菌传播的，这种细菌吸食包括人类在内的哺乳动物的血液，并在此过程中将粪便排在受害者身上。然后，粪便中的寄生虫进入人体，经过很长一段时间，有时是20年或更长时间，潜伏的恰加斯病就会发展起来。很多时候，病人并不知道自己得了这种病。然而，在大约30%的病例中，心脏或消化系统的慢性炎症反应可能会导致死亡。利什曼病是由沙蝇通过唾液传播的，它们以受害者为食。根据传播利什曼原虫的种类，这种疾病可能发生在皮肤上(皮肤利什曼病)，也可能转移到肝脏和脾(内脏利什曼病)。包括巴西利什曼原虫在内的一些物种会导致一种可怕的疾病，在巴西被称为埃斯普迪亚，在这种疾病中，被称为巨噬细胞的人类细胞(寄生虫居住在巨噬细胞中)迁移到我们嘴唇和鼻孔的粘膜，导致它们分解。有时，在经过几年的治疗后，这种疾病的内脏形式会复发，我们称之为后卡拉尔-阿扎尔皮肤利什曼病(PKDL)。尽管有治疗恰加斯病和利什曼病的药物，但它们远不是理想的。有些是有毒的，另一些必须长期服用，还有一些只能通过针头注射获得。对现有药物出现了抗药性，人们很早就知道，即使没有选择抗药性，一些寄生虫对治疗也没有反应。这个合作项目旨在将英国和圣保罗的一个研究团队聚集在一起，专门研究使寄生虫在携带它们的昆虫媒介中繁衍生息的过程，然后在它们的哺乳动物宿主非常不同的环境中繁殖。由于寄生虫保持完全相同的基因组(这是编码它们最终构成的各个方面的蓝图)，它们需要选择基因组的哪些部分在不同的环境中表达。这涉及到蛋白质结构的微妙变化，这种结构将它们的基因结合在一起，我们称之为染色质。在其他生物中，近年来已经清楚地表明，在这些与染色质相关的蛋白质中加入小分子可以改变它们的功能。移除这些适应会导致它们再次改变。这些改变并不涉及修改DNA蓝图本身的序列，但确实影响了DNA的表达方式，被描述为“表观遗传”改变。我们将研究表观遗传变化如何影响克鲁兹毛滴虫和利什曼原虫的基因表达，并找出我们如何通过改变导致这些变化的小分子代谢物的可用性来操纵这一表观遗传过程。我们希望找到新的治疗药物和治疗干预措施来作用于这些表观遗传靶点。

项目成果

Halogenated tryptophan derivatives disrupt essential transamination mechanisms in bloodstream form Trypanosoma brucei.

卤素色氨酸衍生物破坏了血液中的基本跨跨机制，形成了锥虫瘤。

• DOI: 10.1371/journal.pntd.0008928
• 发表时间: 2020-12
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Cockram PE;Dickie EA;Barrett MP;Smith TK
• 通讯作者: Smith TK

Genome deletions to overcome the directed loss of gene function in Leishmania.

• DOI: 10.3389/fcimb.2022.988688
• 发表时间: 2022
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7

Truncated S-MGBs: towards a parasite-specific and low aggregation chemotype.

• DOI: 10.1039/d1md00110h
• 发表时间: 2021-08-18
• 期刊: RSC medicinal chemistry
• 影响因子: 4.1
• 作者: Brooke DP;McGee LMC;Giordani F;Cross JM;Khalaf AI;Irving C;Gillingwater K;Shaw CD;Carter KC;Barrett MP;Suckling CJ;Scott FJ
• 通讯作者: Scott FJ

An aromatic imidazoline derived from chloroquinoline triggers cell cycle arrest and inhibits with high selectivity the Trypanosoma cruzi mammalian host-cells infection.

• DOI: 10.1371/journal.pntd.0009994
• 发表时间: 2021-11
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Cuevas-Hernández RI;Girard RMBM;Krstulović L;Bajić M;Silber AM
• 通讯作者: Silber AM

Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response.

• DOI: 10.1371/journal.pntd.0010779
• 发表时间: 2022-09
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8