Exploring an Essential and Dangerous Pathway in Leishmania Parasites

描述（由申请人提供）：利什曼原虫属寄生虫是一组严重疾病（称为利什曼病）的病原体，全世界有1000万至1200万人感染。目前治疗利什曼病的药物存在着低疗效和高毒性的问题。由于耐药性上升，而且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稳定供应。PI的长期目标是破译利什曼原虫在白蛉和哺乳动物中茁壮成长的分子策略。在基本发病机制的进展可以导致新的和改进的治疗方法。在哺乳动物细胞中，鞘碱（SBs）及其磷酸化衍生物是调节多种重要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，具有重要但不明确的功能。本应用程序的目的是阐明至关重要的

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.