Approaches to detect and block transition stages in Trypanosoma brucei

学生战略优先领域：定量系统医学关键词：单细胞；布鲁氏锥虫；轨迹推断；细胞进展锥虫是一组单细胞寄生虫，属于动叶虫目。其中一种寄生虫布鲁氏锥虫是采采蝇传播的昏睡病的罪魁祸首，影响非洲的人和牲畜。目前只有为数不多的几种药物可用，其中许多都不有效，而且有严重的副作用。不断涌现的数据探索了寄生虫从哺乳动物到媒介再回来时，不同寄生虫之间传播所需的一些因素，但绝不是全部。值得注意的是，人们对采采集载体中的发育程序知之甚少，而且，至关重要的是，很少有工作研究生命周期转变期间基因表达变化的时间顺序。在这篇博士论文中，我们的目标是检测布氏毛滴虫从媒介阶段向哺乳动物阶段转变所必需的基因，以确定可能成为新化合物靶标的途径。我们将从这些阶段获得并分析单细胞RNA-seq。通过伪时间和分支分析，我们将检测到对转换至关重要的基因。最后，学生将去除这些基因，并试图阻止这些因素，询问它们在生命周期中的作用，并测试它们是否可能成为药物靶标。这是一个跨学科的项目，旨在培训学生的量化方法，并汇集了一个具有不同背景的导师团队。到博士学位结束时，学生将学习到在精确医学领域至关重要的新基因组学和实验室技术。

Studentship strategic priority area:Quantitative Systems Medicine Keywords:Single cell; Trypanosoma brucei; Trajectory inference; cell progression Trypanosomatids are a grouping of single-celled parasites belonging to the order Kinetoplastea. One of these parasites, Trypanosoma brucei, is responsible for the sleeping sickness diseases transmitted by the tsetse fly, affecting humans and livestock in Africa. Only a handful of drugs are available, many of which are not efficient and have severe side effects.Emerging data has explored the factors needed for some, but by no means all, aspects of transmission between the distinct parasites forms found as the parasite moves from mammals to vector and back. Notably, the developmental programme in the tsetse vector is poorly understood and, crucially, little work has examined the temporal order of gene expression changes during life cycle transitions. In this PhD we aim to detect genes essential in the transition from the vector stages to the mammalian stages in T. brucei in order to identify pathways that could be targeted by novel compounds. We will obtain and analyse single cell RNA-seq from these stages. Through pseudo time and branching analysis we will detect genes crucial for transition. Finally, the student will ablate these genes and attempt to block the factors, to ask how they act in the life cycle and test if they might be drug targets. This is an interdisciplinary project to train students in quantitative methods and brings together a supervisor team with a diverse background. By the end of the PhD, the student will have learned novel genomics and laboratory techniques that are crucial in the field of precision medicine.