Exploring an Essential and Dangerous Pathway in Leishmania Parasites

描述（由申请人提供）：利什曼原虫属的原生动物寄生虫是一组严重疾病（称为利什曼病）的病原体，在全球范围内感染了1000万至1200万人。目前治疗利什曼病的药物存在疗效低、毒性大的问题。由于耐药性不断上升，又没有安全的疫苗可用，因此迫切需要保持新药和潜在药物靶点的源源不断。PI的长期目标是破译利什曼原虫寄生虫在白蛉和哺乳动物中茁壮成长的分子策略。发病机制的基本机制的进步可以导致新的和改进的治疗。在哺乳动物细胞中，类鞘氨醇碱基（SB）及其磷酸化衍生物是调节多种必需途径的强大信号分子。最近的研究表明，利什曼原虫具有非常活跃的SB代谢，具有重要但定义不清的功能。本申请的目的是阐明 SB代谢在利什曼原虫增殖和毒力中的作用。在强有力的初步研究的基础上制定的核心假设是，SB代谢是利什曼原虫适应哺乳动物恶劣环境所必需的，清除有毒代谢物，合成必需的磷脂。拟议研究的理由是，更好地了解这一至关重要且有点危险的途径将为寄生虫-宿主相互作用提供新的见解，并发现控制利什曼病的新线索。两个具体的目标将进行测试的中心假设：目的1是阐明鞘氨醇激酶（SB代谢的关键酶）在利什曼原虫的关键作用;和目的2是确定为什么利什曼原虫需要乙醇胺磷酸盐（SB代谢的中间体）生存。每个目标将探索利什曼原虫SB代谢途径的一个分支。将使用分子、细胞和生物化学方法产生和表征基因敲除突变体及其互补对照。这些研究的成功完成将显著提高我们对利什曼原虫SB代谢和脂质代谢物功能的理解。这个项目是非常重要的，因为除了令人兴奋的新知识，一些新的药物靶点可能会出现在这些研究的结论。

DESCRIPTION (provided by applicant): Protozoan parasites of the genus Leishmania are the causative agents for a group of serious diseases (known as Leishmaniasis) infecting 10-12 million people worldwide. Current drugs for leishmaniasis are plagued with low efficacy and high toxicity. With resistance on the rise and no safe vaccine available, there is an urgent need to maintain a steady stream of new drugs and potential drug targets. The PI's long term goal is to decipher the molecular strategy utilized by Leishmania parasites to thrive in sandflies and mammals. Advancement in the fundamental mechanism of pathogenesis can lead to new and improved treatments. In mammalian cells, sphingoid bases (SBs) and their phosphorylated derivatives are powerful signaling molecules regulating a plethora of essential pathways. Recent studies demonstrate that Leishmania parasites possess a very active SB metabolism with important yet poorly defined functions. The objective of this application is to elucidate the vital roles of SB metabolism in Leishmania proliferation and virulence. Formulated on the basis of strong preliminary studies, the central hypothesis is that SB metabolism is required for the adaptation of Leishmania parasites to the harsh environment in mammals, the removal of toxic metabolites, and the synthesis of essential phospholipids. Rationale for the proposed research is that a better understanding of this critically important and somewhat dangerous pathway will provide novel insight into parasite-host interaction and uncover new clues to control leishmaniasis. Two specific aims will be undertaken to test the central hypothesis: aim 1 is to elucidate the crucial roles of sphingosine kinase (a key enzyme in SB metabolism) in Leishmania; and aim 2 is to determine why Leishmania needs ethanolamine phosphate (an intermediate in SB metabolism) to survive. Each aim will explore one branch of the SB metabolic pathway in Leishmania. Genetic knockout mutants and their complemented controls will be generated and characterized using molecular, cellular, and biochemical approaches. Successful completion of these studies will significantly improve our understanding of SB metabolism in Leishmania and the function of lipid metabolites in general. This project is highly significant because in addition to the exciting new knowledge, a number of novel drug targets may emerge at the conclusion of these studies.