Functional Characterization of the Schistosome Tegument

血吸虫是一种寄生的扁虫，会引起一种慢性的、令人衰弱的疾病。 分布在70个国家的2亿人。这些寄生虫在一个应该是非常 恶劣的环境-脊椎动物的血液-然而它们似乎几乎没有引起什么 宿主止血系统的破坏性反应。我们假设蛋白质在 在上一个资金周期中确定的东道主互动界面对此至关重要 才能。在这场相互竞争的更新中，我们建议测试以下几个关键假设： 1)外膜外酶SmNPP5和SmATPDase的体外和体外止血作用 在体内，2)被膜外酶SMAP和NACE产生关键营养物质的能力 分别是腺苷和烟酰胺，它们对血吸虫的生存和 生长和3)被膜钙蛋白抑制凝血、促进 溶解血栓，阻断体内局部血栓形成。这些研究旨在揭示 这些蛋白质的生理功能，并将产生重要的新信息 血吸虫用来钝化宿主血栓反应的分子机制 维持获取重要营养素的途径。此外，这项工作可能会识别被膜蛋白 对寄生虫的生存至关重要，导致后续筛查发现潜在的 抑制这些分子的血吸虫杀灭药物和/或测试其疫苗的试验 潜力。通过这种方式，我们计划中的实验有可能揭示出新奇和有效的 目标以及新的治疗方法，以干预这种仍然广泛存在的寄生虫 也是人类疾病的主要原因。此外，鉴于人们对了解 凝血控制的机制，了解血吸虫是如何调节的 这一过程将在真核病原体研究领域之外引起人们的极大兴趣。

Schistosomes are parasitic flatworms that cause a chronic, debilitating disease afflicting >200 million people in >70 countries. The parasites live for years in what should be a very hostile environment – the blood of vertebrates – yet they appear to elicit little if any damaging responses from the host’s hemostatic systems. We hypothesize that proteins at the host-interactive surface, identified in the previous funding cycle, are central to this ability. In this competing renewal, we propose to test several key hypotheses concerning: 1) the hemostatic roles of tegumental ectoenzymes SmNPP5 & SmATPDase in vitro and in vivo, 2) the ability of tegumental ectoenzymes SmAP & NACE to generate key nutrients - adenosine and nicotinamide respectively - that are vital for schistosome survival and growth and 3) the ability of tegumental calpain to impede coagulation, promote thrombolysis and to block local thrombus formation in vivo. These studies aim to reveal the physiological functions of these proteins and will yield significant new information on the molecular mechanisms used by schistosomes to blunt the host thrombotic response while maintaining access to vital nutrients. In addition, the work may identify tegumental proteins critical for parasite survival leading to subsequent screens to discover potential schistosome-killing drugs that inhibit these molecules and/or to trials testing their vaccine potential. In this way, our planned experiments have the potential to reveal novel and valid targets, as well as new treatments, for intervention in a parasite that remains a widespread and major cause of human disease. Additionally, given wide interest in understanding the mechanisms governing coagulation control, knowing how schistosomes regulate this process will be of keen interest beyond the field of eukaryotic pathogen research.