Proteolysis and life cycle progression in Leishmania

利什曼病是一种严重的人类疾病，也是世界上最被忽视的疾病之一，主要影响发展中国家的穷人。3.5亿人面临感染这种疾病的风险，它在健康和经济方面都造成了严重的代价，并耗尽了本可用于促进发展中国家增长的资源。目前还没有针对这种疾病的有效疫苗，化疗是减轻利什曼病负担的主要手段。不幸的是，现有的药物有许多局限性，迫切需要新药。我们在这项工作计划中的目标是描述利什曼原虫的关键生物学过程，从而识别和验证潜在的药物靶标。我们已经证明了肽酶，一种消化蛋白质的酶，在利什曼原虫的发展中发挥着核心作用，在寄生虫的传染性和致病性中起着重要的作用。我们的工作将集中在寄生虫生物学的三个关键领域。首先，我们将确定在疾病发病机制中起重要作用的多肽酶，并研究参与多肽酶功能的关键途径。特别是，我们将研究一种称为自噬(自相残杀)的过程，该过程导致传染性寄生虫的发展，并允许寄生虫生活在哺乳动物宿主内。我们还将研究寄生虫特异性多肽酶的功能，它是寄生虫生长所必需的，但其功能尚不清楚。一个关键的方法将是对重要的利什曼原虫基因进行基因操作，以找出编码蛋白在寄生虫的传染性和毒力中扮演的角色，并确定它们是否可能被用作药物靶标。为了实现这一目标，我们将开发利什曼原虫基因操作的新方法和研究工具。其次，我们将研究利什曼原虫在不同菌株和物种中发生的基因组变异。我们将对分离自苏丹患者的利什曼原虫的基因组进行测序，并确定影响疾病结局的基因。最后，我们将使用一种密切相关的寄生虫，非洲锥虫，作为研究肽酶功能调节的模型。非洲锥虫适合大规模研究，因此我们可以利用从锥虫中获得的信息来研究利什曼原虫。总体而言，我们预计这项研究的一个结果是极大地改善对这些生物过程在利什曼原虫中的作用的理解，以及这些过程本身的分子机制-这将与生物学的许多领域相关。另一个预期的结果将是了解哪些肽酶是有效的药物靶标，这些信息将通过与化学家合作制造肽酶抑制剂来利用，这可能会用于新药的开发。

Leishmaniasis is a severe disease of humans and one of the world's most neglected diseases, primarily affecting the poor in developing countries. 350 million people are at risk of contracting the disease and it 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, we will identify peptidases that are important for the pathogenesis of the disease and investigate key pathways involved in peptidase function. In particular we shall investigate 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 will also 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 and to determine whether they might be exploited as drug targets. To achieve this we will develop new methods and research tools for the genetic manipulation of Leishmania. Secondly, we shall investigate the genome variation that occurs in different strains and species of Leishmania. We will sequence the genomes of Leishmania parasites isolated from patients in the Sudan and identify genes that influence the outcome of disease. Finally, we shall use a closely related parasite, the African trypanosome, as a model for investigating the regulation of peptidase function. The African trypanosome is suitable for large scale studies, so we can utilise information obtained in trypanosomes to study Leishmania. Overall, we expect one outcome from this study to be a 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 with chemists to make inhibitors of peptidases, which might be used in the development of new drugs.