Polyamine Transport in Schistosomes

总结： 血吸虫是一种血管内寄生蠕虫，可引起使人衰弱的血吸虫病， 影响超过70个国家的2亿人。在这个建议中，我们专注于多胺代谢， 讨厌鬼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。 physiology.对基因组数据库的详尽搜索显示，染色体缺乏所有从头开始的功能。 多胺生物合成酶这使得双质体成为唯一已知的营养缺陷型后生动物 对于聚胺。这些蠕虫如何获得这些必需的代谢产物尚不清楚。P5型ATP酶， CATP 5，在线虫C.已显示秀丽线虫作为多胺转运蛋白发挥作用。这里 我们在S. mansoni -SmCATP 5-这是发现在染色体 我们假设，它的功能是从宿主血液中输入多胺。敲低 使用RNAi的SmCATP 5表达使培养物中的蠕虫衰弱，而多胺补充增强了SmCATP 5的表达。 蠕虫生存能力在这个建议中，我们的目标是表征多胺的功能性，特异性和动力学 运输在高速公路上。我们将使用异源表达系统在一个细胞中检测SmCATP 5的功能。 多胺摄取缺陷细胞系（CHO-MG）以及直接在寄生虫体内。这项工作是 旨在揭示SmCATP 5的生理功能，并应产生重要的新信息， 多胺体用于获得重要营养物质（多胺）的分子机制。因为， 完全依赖于宿主作为多胺的来源，阻断SmCATP 5的功能应该会削弱 这种蠕虫可以形成一种新的抗寄生虫疗法的基础-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.