Dissecting fatty acid metabolism in livestock trypanosomes
剖析家畜锥虫中的脂肪酸代谢
基本信息
- 批准号:BB/X009807/1
- 负责人:
- 金额:$ 51.71万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Fellowship
- 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:
- 关键词:
项目摘要
Animal African Trypanosomiasis (AAT), also known as Nagana, is a devastating disease affecting cattle and other livestock across sub-Saharan Africa, with more than 60 million cattle at risk and in excess of 3 million deaths per year, with a great socio-economic impact on agricultural communities. AAT is principally caused by the single-celled parasite Trypanosoma congolense. There are no vaccines to treat the disease, and treatment failure is common due to resistance against the drugs used to treat AAT. New drugs are sorely needed, but a major problem hindering their development is a lack of biological understanding of T. congolense. Instead, most of our current knowledge on trypanosomes derives from the related species T. brucei, variants of which cause the human disease Sleeping Sickness. One potential avenue to drug discovery against AAT is by gaining an understanding of parasite cell metabolism, and how drugs may affect this in ways that kill the pathogen without impacting the host.African trypanosomes are unique in their metabolism, and whilst it was previously thought that T. congolense and T. brucei were very similar in their biology, recent data I have generated has highlighted several metabolic distinctions between these species. For example, whilst T. brucei is known to rely almost entirely on host-derived glucose for its energy demands, T. congolense appears to use less glucose, and metabolise it at a reduced rate. In addition, T. brucei is able to use some of the products of glucose metabolism to generate a class of metabolites called fatty acids, an important group of molecules for cellular structure. In contrast, we found no evidence of glucose-derived fatty acids in T. congolense.I recently found that whilst T. brucei is able to synthesise fatty acids, T. congolense prefers to scavenge these from the bloodstream of the host. In particular, I have identified four fatty acids that T. congolense requires to grow in the laboratory. This requirement has not previously been reported for African trypanosomes, and the ways in which these four fatty acids are used by T. congolense are therefore novel to trypanosome biology. Indeed, fatty acid metabolism is unexplored in this parasite species. Crucially, these mechanisms of fatty acid usage may also differ from host metabolism, and this could be exploited for drug development. In this study, I propose to investigate how these fatty acids are used, and metabolised by T. congolense. To do this, I will use cutting edge technologies such as mass spectrometry to map in detail how the four fatty acids are metabolised by T. congolense, and whether they are a potential source of energy for this parasite species. I will combine this approach with bioinformatic techniques and high-resolution mass spectrometry imaging to investigate the enzymes T. congolense possesses and where these are localised in the cell, in order to accurately determine the major metabolic pathways involved in fatty acid metabolism. I will then investigate how the activity in these pathways changes in response to the environment, depending on the presence and absence of exogenous fatty acids, in order to understand whether these pathways are essential to the parasite, and indeed a viable avenue for drug discovery. Finally, I will select key enzymes and use newly-available genetic tools to manipulate their presence in the cell in order to determine the overall effect on cell growth. Combined with the testing of known inhibitors, these objectives will give a very detailed picture of fatty acid metabolism in T. congolense, giving us an insight into the biology of this understudied pathogen and potentially identifying candidate drug targets.
动物非洲锥虫病(AAT),也被称为Nagana,是一种影响撒哈拉以南非洲牛和其他牲畜的毁灭性疾病,每年有超过6000万头牛处于危险之中,超过300万人死亡,对农业社区产生巨大的社会经济影响。AAT主要由单细胞寄生虫刚果锥虫引起。目前还没有治疗这种疾病的疫苗,由于对用于治疗AAT的药物的耐药性,治疗失败是常见的。新药是迫切需要的,但阻碍其发展的一个主要问题是缺乏对T的生物学理解。刚果语。相反,我们目前对锥虫的大部分知识来自相关物种T。布鲁氏菌,其变种导致人类疾病昏睡病。发现抗AAT药物的一个潜在途径是了解寄生虫细胞代谢,以及药物如何影响这种代谢,从而杀死病原体而不影响宿主。congolense和T.虽然布鲁氏菌在生物学上非常相似,但我最近生成的数据突出了这些物种之间的几个代谢差异。例如,T.已知布氏杆菌几乎完全依赖于宿主来源的葡萄糖来满足其能量需求,T.刚果人似乎使用较少的葡萄糖,并且以降低的速率代谢葡萄糖。此外,T.布鲁氏菌能够利用葡萄糖代谢的一些产物来产生一类称为脂肪酸的代谢物,脂肪酸是细胞结构的一组重要分子。相反,我们在T. congolense。我最近发现,虽然T.布氏杆菌能够合成脂肪酸,T.刚果人喜欢从宿主的血液中吸取这些病毒。特别是,我已经确定了四种脂肪酸,T。刚果需要在实验室中生长。非洲锥虫的这种需要以前没有报道过,而这四种脂肪酸被锥虫利用的方式。因此,刚果人对锥虫生物学是新的。事实上,在这种寄生虫物种中,脂肪酸代谢是未知的。至关重要的是,这些脂肪酸使用机制也可能与宿主代谢不同,这可以用于药物开发。在这项研究中,我打算研究这些脂肪酸是如何被T。刚果语。为了做到这一点,我将使用尖端技术,如质谱分析,详细绘制这四种脂肪酸是如何被T。刚果,以及它们是否是这种寄生虫物种的潜在能量来源。我将联合收割机与生物信息学技术和高分辨率质谱成像相结合,研究T。刚果人拥有这些基因,这些基因在细胞中位于何处,以便准确确定脂肪酸代谢中涉及的主要代谢途径。然后,我将研究这些途径的活性如何响应环境的变化,取决于外源性脂肪酸的存在和不存在,以了解这些途径是否对寄生虫至关重要,以及是否确实是药物发现的可行途径。最后,我将选择关键酶,并使用新的遗传工具来操纵它们在细胞中的存在,以确定对细胞生长的总体影响。结合已知抑制剂的测试,这些目标将给出一个非常详细的图片脂肪酸代谢在T。刚果,让我们深入了解这种未充分研究的病原体的生物学,并可能确定候选药物靶点。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Anti-parasitic benzoxaboroles are ineffective against Theileria parva in vitro.
- DOI:10.1016/j.ijpddr.2023.10.003
- 发表时间:2023-12
- 期刊:
- 影响因子:4
- 作者:Steketee, Pieter C.;Paxton, Edith;Barrett, Michael P.;Pearce, Michael C.;Connelley, Timothy K.;Morrison, Liam J.
- 通讯作者:Morrison, Liam J.
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