Roles of Sphingolipid Metabolites in Leishmania Differentiation

描述（由申请人提供）：利什曼原虫寄生虫引起一系列破坏性疾病，称为利什曼病。利什曼原虫感染的关键步骤是从复制性、非毒性的前循环体分化为非复制性、高毒性的后循环体。我们的长期目标是确定调节这种转变的细胞内分子（称为后循环发生），并了解它们的作用模式。在哺乳动物和真菌中，鞘脂（SL）代谢产物是细胞凋亡、内吞、生长和分化的重要介质。我们最近的研究表明，SL在利什曼原虫感染中也起着重要作用：1）SL的降解是产生乙醇胺的主要途径，乙醇胺是代谢循环所必需的; 2）除了乙醇胺的产生，某些SL代谢产物也可能作为毒力的负调节剂。该提议将检验细胞内SL代谢物水平控制利什曼原虫分化的假设。具体目标包括：1）评价外源性SL代谢产物对利什曼原虫代谢和毒力的影响; 2）测定利什曼原虫生长和分化过程中SL代谢产物的细胞内水平。这些目标的成功完成将揭示一个以前未认识到的SL代谢在利什曼原虫感染中的作用。未来的工作包括SL结合蛋白的鉴定和SL介导的信号通路在利什曼原虫的表征。了解SL在后循环发生中的作用将为利什曼原虫分化的调节提供基本的见解，这一过程是这种寄生原生动物的感染性和毒性的核心。利什曼原虫寄生虫在人类中引起一系列毁灭性疾病，称为利什曼病，全球感染1000 - 1200万人。本研究旨在探讨利什曼原虫感染过程中脂质分子亚群的作用。该提案的成功完成将有助于揭示这些医学上重要的（但经常被忽视的）病原体的发病机制。

DESCRIPTION (provided by applicant): Leishmania parasites cause a spectrum of devastating diseases known as leishmaniasis. A critical step in Leishmania infection is the differentiation from replicative, non-virulent procyclics to non-replicative, highly virulent metacyclics. Our long term goal is to identify intracellular molecules that regulate this transition (termed metacyclogenesis) and understand their mode of action. In mammals and fungi, sphingolipid (SL) metabolites are vital mediators of apoptosis, endocytosis, growth, and differentiation. Our recent studies indicate SLs also play important roles in Leishmania infection: 1) degradation of SLs is the major route to produce ethanolamine, which is essential for metacyclogenesis; 2) besides ethanolamine production, certain SL metabolites may also serve as negative regulators of virulence. This proposal will test the hypothesis that intracellular levels of SL metabolites control Leishmania differentiation. Specific aims include: 1) to evaluate the effects of exogenous SL metabolites on metacyclogenesis and virulence; 2) to determine the intracellular levels of SL metabolites during Leishmania growth and differentiation. Successful completion of these aims will reveal a previously unrecognized role of SL metabolism in Leishmania infection. Future work includes the identification of SL- binding proteins and the characterization of a SL-mediated signaling pathway in Leishmania parasites. Understanding the role of SLs in metacyclogenesis will provide fundamental insights into the regulation of Leishmania differentiation, a process that is central to the infectivity and virulence of this parasitic protozoan .Leishmania parasites cause a spectrum of devastating diseases in humans known as leishmaniasis, which infect 10-12 million people worldwide. This proposal aims to investigate the roles of a subset of lipid molecules in Leishmania infection. Successful completion of the proposal will help reveal the mechanism of pathogenesis in these medically important (yet often neglected) pathogens.