Identifying and Characterising Developmental Regulators of Human Infectious Leishmania

人类传染性利什曼原虫发育调节因子的识别和表征

• 批准号: MR/L00092X/1
• 负责人: Pegine Walrad
• 金额: $ 56.78万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL00092X%2F1
• 关键词: Identifying; Characterising; Developmental; Regulators; Human

Species of Leishmania threaten 350 million people worldwide on four continents. The World Health Organisation estimates 12 million are currently infected and over 1 million new cases occur annually. No vaccine currently exists and available Leishmaniasis treatments are often overwhelmed by acute epidemics that are increasing in occurrence and severity. New treatments and vaccines are desperately needed and the UK government has committed to the World Health Organisation's recent call to further support Neglected Tropical Disease research. The single-cell Leishmania parasite transforms into many different forms during its lifecycle to adapt to very different hosts; moving from mammals to sandflies and back to mammals by sandfly bites. Only Leishmania parasites of certain lifecycle stage forms can infect and survive in humans. Major changes to the parasite's appearance, metabolism and virulence proteins occur during these transitions that enable them to survive. Leishmania gene expression relies almost exclusively upon mRNA regulation. In response to changes in the environment, specific parasite proteins bind mRNAs and target them for protein production to guide and promote adaptation. Proteins that control the changes these parasites go through enable them to adapt, survive in and infect humans. Such proteins are essential for the virulence and spread of the Leishmania parasite infection. By characterising such regulatory proteins and their downstream targets, we can find out what mechanisms the Leishmania parasites use to control their lifecycle changes. If we can isolate and stop control panel "Regulator" proteins, we can block the parasite from establishing an infection in humans. Significant findings would provide insight to Leishmaniasis research as well as diseases caused by related parasites, Chagas Disease and African Trypanosomiasis. Leishmania proteins are different from human proteins; therefore we can exploit these differences to target Leishmania-specific developmental regulators, block their function and block the parasites' ability to invade. Unfortunately, no Leishmania regulator proteins have yet been identified. I propose to find regulators of Leishmania spp. lifecycle changes, identify how they function, and test whether any are essential for parasite survival. Essential Regulators could serve as potential drug targets to block Leishmania parasite infection.

利什曼原虫威胁着全球四大洲3.5亿人。世界卫生组织估计，目前有1200万人感染，每年有100多万新病例。目前还没有疫苗，可用的利什曼病治疗往往被发病率和严重程度不断增加的急性流行病所淹没。迫切需要新的治疗方法和疫苗，英国政府已承诺响应世界卫生组织最近的呼吁，进一步支持被忽视的热带病研究。 单细胞利什曼原虫在其生命周期中转变为许多不同的形式，以适应不同的宿主;从哺乳动物到白蛉，再通过白蛉叮咬回到哺乳动物。只有某些生命周期阶段形式的利什曼原虫才能感染人类并在人类中存活。寄生虫的外观，代谢和毒力蛋白的主要变化发生在这些过渡期间，使它们能够生存。利什曼原虫基因表达几乎完全依赖于mRNA调控。为了应对环境的变化，特定的寄生虫蛋白质结合mRNA并靶向它们产生蛋白质，以指导和促进适应。控制这些寄生虫变化的蛋白质使它们能够适应，在人类中生存并感染人类。这些蛋白质是利什曼原虫感染的毒力和传播所必需的。通过表征这些调节蛋白及其下游靶点，我们可以发现利什曼原虫使用什么机制来控制其生命周期的变化。如果我们能分离并阻止控制面板“调节器”蛋白，我们就能阻止寄生虫在人类中建立感染。重要的发现将为利什曼病研究以及相关寄生虫、恰加斯病和非洲锥虫病引起的疾病提供深入了解。 利什曼原虫蛋白质与人类蛋白质不同;因此，我们可以利用这些差异来靶向利什曼原虫特异性发育调节因子，阻断它们的功能并阻断寄生虫的入侵能力。不幸的是，尚未鉴定出利什曼原虫调节蛋白。我建议找到利什曼原虫的调节器。生命周期的变化，确定它们是如何发挥作用的，并测试是否有任何是寄生虫生存所必需的。必需调节因子可以作为阻断利什曼原虫感染的潜在药物靶点。

项目成果

Systematic functional analysis of Leishmania protein kinases identifies regulators of differentiation or survival.

• DOI: 10.1038/s41467-021-21360-8
• 发表时间: 2021-02-23
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Baker N;Catta-Preta CMC;Neish R;Sadlova J;Powell B;Alves-Ferreira EVC;Geoghegan V;Carnielli JBT;Newling K;Hughes C;Vojtkova B;Anand J;Mihut A;Walrad PB;Wilson LG;Pitchford JW;Volf P;Mottram JC
• 通讯作者: Mottram JC

The mRNA-bound proteome of Leishmania mexicana : novel genetic insight into an ancient parasite

墨西哥利什曼原虫的 mRNA 结合蛋白质组：对一种古老寄生虫的新遗传见解

• DOI: 10.1101/592402
• 发表时间: 2019
• 作者: De Pablos L

NMD3 regulates both mRNA and rRNA nuclear export in African trypanosomes via an XPOI-linked pathway.

NMD3通过XPOI连接的途径调节非洲锥虫中的mRNA和rRNA核输出。

• DOI: 10.1093/nar/gkv330
• 发表时间: 2015-05-19
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Bühlmann M;Walrad P;Rico E;Ivens A;Capewell P;Naguleswaran A;Roditi I;Matthews KR
• 通讯作者: Matthews KR