Polyamine Transport in Schistosomes

摘要： 血吸虫是血管内的寄生蠕虫，可引起衰弱的血吸虫病 影响着70个国家的2亿人。在这项提案中，我们关注的是多胺代谢在 血吸虫。多胺是一种普遍存在的有机化合物，在细胞内起着多种重要作用 生理学。对基因组数据库的详尽搜索表明，血吸虫缺乏所有从头开始的能力 多胺生物合成酶。这使得血吸虫成为唯一已知的营养缺陷型后生动物。 对于多胺。这些蠕虫是如何获得这些重要代谢物的尚不清楚。P5型ATPase， 在线虫中发现的CATP5已被证明具有多胺转运蛋白的功能。这里 我们描述了我们在曼氏血吸虫中新发现的CATP5同源物-SmCATP5-在血吸虫中发现 被膜(皮肤)，我们假设，它的功能是从宿主血液中输入多胺。击倒 使用RNAi表达SmCATP5可削弱培养中的蠕虫，而补充多胺则可增强 蠕虫生存能力。在这项建议中，我们的目标是表征多胺的功能性、特异性和动力学。 在血吸虫体内的运输。我们将使用异源表达系统研究SmCATP5在 多胺摄取缺陷细胞系(CHO-MG)以及直接在血吸虫寄生虫体内。这项工作是 旨在揭示SmCATP5的生理功能，并应在以下方面产生重要的新信息 血吸虫用来获取重要营养物质(多胺)的分子机制。因为血吸虫是 完全依赖宿主作为多胺的来源，阻断SmCATP5功能应该会减弱 这种蠕虫可能构成一种新的抗血吸虫疗法的基础，这是这项工作的长期目标。

Summary: Schistosomes are intravascular parasitic worms that cause the debilitating disease schistosomiasis which affects > 200 million people in > 70 countries. In this proposal, we focus on polyamine metabolism in schistosomes. Polyamines are ubiquitous organic compounds that play multiple vital roles in cellular physiology. An exhaustive search of genome databases reveals that schistosomes lack all the de novo polyamine biosynthetic enzymes. This makes schistosomes the only known metazoans that are auxotrophic for polyamines. How these worms acquire these essential metabolites is not known. The P5-type ATPase, CATP5, identified in the nematode C. elegans has been shown to function as a polyamine transporter. Here we describe our newly identified CATP5 homolog in S. mansoni - SmCATP5 - that is found in the schistosome tegument (skin) where, we hypothesize, it functions to import polyamines from host blood. Knockdown of SmCATP5 expression using RNAi debilitates the worms in culture, while polyamine supplementation enhances worm viability. In this proposal, we aim to characterize the functionality, specificity and kinetics of polyamine transport in schistosomes. We will examine SmCATP5 function using a heterologous expression system in a polyamine-uptake-deficient cell line (CHO-MG) as well as directly in schistosome parasites. This work is designed to reveal the physiological function of SmCATP5 and should yield significant new information on the molecular mechanisms used by schistosomes to obtain vital nutrients (polyamines). Since schistosomes are completely dependent on their hosts as a source of polyamines, blocking SmCATP5 function should debilitate the worms and could form the basis of a new anti-schistosome therapy – the long-term aim of this work.