Analysing the roles of peptidases in Leishmania infectivity and pathogenicity

分析肽酶在利什曼原虫感染性和致病性中的作用

• 批准号: G0700127/1
• 负责人: Jeremy Mottram
• 金额: $ 190.21万
• 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: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0700127%2F1
• 关键词: Analysing; roles; peptidases; Leishmania; infectivity

Leishmaniasis is a severe disease of humans and animals in the tropics and sub-tropics (including Southern Europe) and has severe costs in both health and economic terms and drains resources that could be used to promote growth of developing nations. There is no effective vaccine against the disease and chemotherapy is the prime means for reducing the leishmaniasis burden. Unfortunately the drugs available have many limitations and new drugs are desperately needed. Our aim in this programme of work is to characterise key biological processes of Leishmania, the parasite that causes leishmaniasis, and so identify and validate potential drug targets. We have shown that peptidases, enzymes that digest proteins, play central roles in the development of Leishmania and are important in the infectivity and pathogenicity of the parasite. Our work will concentrate on 3 key areas of the biology of the parasite. Firstly, on the changes in cell shape mediated by a process called autophagy (self-cannibalism), which leads to the development of infectious parasites and allows the parasite to live within a mammalian host. We now aim to elucidate the key roles and molecular mechanism of autophagy in Leishmania under different stimuli, such as starvation and stress. We will determine the importance of autophagy for the multiplication of amastigotes of Leishmania (the parasite form that lives in humans) and so whether it can be effectively targeted by drug intervention. We will also investigate whether Leishmania modulates autophagy in its host cell as a survival strategy. Secondly, on the crucial role of the parasite?s internal membranous structures for interactions with the mammalian host, and how factors that make the parasite virulent are released from the cell. Thirdly, we will investigate the function of a parasite-specific peptidase, metacaspase, which is essential for growth of the parasite but the function of which is unclear. A key approach will be to genetically manipulate important Leishmania genes to find out what role the encoded proteins play in the parasite?s infectivity and virulence. One outcome from this study will be greatly improved understanding on the roles of these biological processes in Leishmania, and the molecular mechanisms of the processes themselves ? which will be relevant to many areas of biology. Another expected outcome will be knowledge on which peptidases are valid drug targets and this information will be exploited by collaborating to discover inhibitors of peptidases, which should be leads in the development of new drugs.

利什曼病是热带和亚热带（包括南欧）人类和动物的一种严重疾病，在健康和经济方面造成严重损失，并耗尽可用于促进发展中国家增长的资源。目前尚无针对该疾病的有效疫苗，化疗是减轻利什曼病负担的主要手段。不幸的是，可用的药物有很多局限性，并且迫切需要新的药物。我们该工作计划的目标是描述利什曼原虫（引起利什曼病的寄生虫）的关键生物过程，从而识别和验证潜在的药物靶点。我们已经证明，肽酶（消化蛋白质的酶）在利什曼原虫的发展中发挥着核心作用，并且对于寄生虫的感染性和致病性也很重要。我们的工作将集中在寄生虫生物学的三个关键领域。首先，关于由称为自噬（自食同类）的过程介导的细胞形状的变化，该变化导致传染性寄生虫的发展并允许寄生虫在哺乳动物宿主体内生存。我们现在的目标是阐明利什曼原虫在不同刺激（如饥饿和应激）下自噬的关键作用和分子机制。我们将确定自噬对于利什曼原虫（人类体内的寄生虫）增殖的重要性，以及是否可以通过药物干预有效地靶向自噬。我们还将研究利什曼原虫是否调节宿主细胞中的自噬作为生存策略。其次，关于寄生虫的内部膜结构对于与哺乳动物宿主相互作用的关键作用，以及如何从细胞中释放使寄生虫有毒的因子。第三，我们将研究寄生虫特异性肽酶（metacaspase）的功能，它对于寄生虫的生长至关重要，但其功能尚不清楚。一个关键方法是对重要的利什曼原虫基因进行基因操作，以找出编码的蛋白质在寄生虫的感染性和毒力中发挥的作用。这项研究的一个成果将大大提高对利什曼原虫中这些生物过程的作用以及这些过程本身的分子机制的理解？这将与生物学的许多领域相关。另一个预期成果将是了解哪些肽酶是有效的药物靶点，并且将通过合作发现肽酶抑制剂来利用这些信息，这将成为新药开发的主导。