Molecular basis of environmental sensing in fungi and protozoan parasites

真菌和原生动物寄生虫环境传感的分子基础

• 批准号: 2672557
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2672557
• 关键词: Molecular; basis; environmental; sensing; fungi

Many of the unicellular eukaryotic parasites that cause disease in humans are exquisitely adapted to navigate the complex and dynamic environments that they encounter in their hosts in order to sustain their life cycles and spread infection. For example, the human malaria parasite, Plasmodium falciparum, switches between human and mosquito hosts where it targets specific tissue niches in order to replicate and reproduce, and the pathogenic fungus, Cryptococcus neoformans invades the brain to causes fungal meningitis and encephalitis. These adaptations require the parasite to be able to sense and respond to the various chemical stimuli present in its' surroundings by, as yet, mostly unknown mechanisms. How do they achieve this and which proteins and mechanisms allow parasites to fulfil such complex infectious cycles?This project addresses this question by investigating candidate genes in parasitic protozoa and fungi that are predicted bioinformatically to encode cell-surface channels and receptors, but are currently uncharacterised. These proteins have no homologues in humans, so hold particular promise for drug development for a range of infectious diseases, including malaria, which alone kills hundreds of thousands of people yearly and for which the development of drug-resistance is an increasing concern. The recent explosion in genomic data means we can use protein sequence information to bridge studies in different organisms and ask whether the function and mechanism of action of proteins is conserved across the tree of life. The project will, therefore, have an interdisciplinary approach, using biochemical methods to investigate the structure and activity of candidate channels and receptors in vitro, and malaria and fungal model systems together with genetic and molecular technologies to explore and compare their roles throughout the parasitic lifecycles.

许多导致人类疾病的单细胞真核寄生虫都非常适应它们在宿主体内遇到的复杂和动态的环境，以维持它们的生命周期和传播感染。例如，人类疟疾寄生虫恶性疟原虫（Plasmodium falciparum）在人类和蚊子宿主之间切换，在宿主中它针对特定的组织壁龛进行复制和繁殖，而致病性真菌新隐球菌（Cryptococcus neoformmans）侵入大脑，引起真菌脑膜炎和脑炎。这些适应需要寄生虫能够感知周围环境中存在的各种化学刺激并做出反应，而这些化学刺激的机制大多是未知的。它们是如何做到这一点的？哪些蛋白质和机制允许寄生虫完成如此复杂的感染周期？该项目通过研究寄生原生动物和真菌中的候选基因来解决这个问题，这些候选基因被生物信息学预测为细胞表面通道和受体编码，但目前尚未表征。这些蛋白质在人体中没有同源物，因此对包括疟疾在内的一系列传染病的药物开发具有特别的希望。疟疾每年导致数十万人死亡，耐药性的发展日益引起人们的关注。最近基因组数据的爆炸式增长意味着我们可以使用蛋白质序列信息来连接不同生物体的研究，并询问蛋白质的功能和作用机制是否在整个生命树中都是保守的。因此，该项目将采用跨学科的方法，使用生化方法研究体外候选通道和受体的结构和活性，以及疟疾和真菌模型系统，结合遗传和分子技术探索和比较它们在寄生虫生命周期中的作用。