Functional Characterization of the Schistosome Tegument

描述（由申请人提供）：血吸虫是一种寄生的扁形虫，它会导致一种慢性、使人衰弱的疾病，影响着70多个国家的2亿多人。这些寄生虫可以在脊椎动物的血液中生存数年，有时甚至数十年，这应该是一个非常恶劣的环境。然而，它们似乎很少从宿主的两个主要防御系统——止血系统和免疫系统——那里得到任何保护反应。我们假设宿主相互作用表面的蛋白质是寄生虫抑制宿主免疫和止血能力的核心，同时允许代谢物交换。在这一竞争更新中，我们建议使用新的分子方法，如RNA干扰，这是在我们之前的资助（RO1 AI056273）下首次开发用于血吸虫，来测试几个关键假设：1)被膜外泌酶在止血和免疫调节中的作用，2)被膜鞘磷脂酶改变寄生虫表面渗透性的能力，以及3)跨被膜代谢物交换的分子机制。我们在这里采用的功能基因组学方法，再加上采用更传统的细胞生物学和生物化学技术的独立和直接的后续实验，旨在提供有关血吸虫宿主相互作用表面的重要新信息。此外，这项工作旨在鉴定对寄生虫在宿主中生存至关重要的被膜蛋白，随后的筛选将发现抑制这些分子的药物。通过这种方式，我们计划的实验有可能揭示新的和有效的目标，以及新的治疗方法，以干预寄生虫，这种寄生虫仍然是人类疾病的广泛和主要原因。

DESCRIPTION (provided by applicant): Schistosomes are parasitic flatworms that cause a chronic, debilitating disease afflicting over 200 million people in over 70 countries. The parasites live for years, sometimes decades, in what should be a very hostile environment - the blood of vertebrates - yet they appear to solicit little if any protective reaction from two of the host's major defensive systems: the hemostatic system and the immune system. We hypothesize that proteins at the host-interactive surface are central to the parasites ability to dampen host immunity and hemostasis while, at the same time, permitting metabolite exchange. In this competing renewal, we propose to use new molecular methods such as RNA interference that were first developed for use with schistosomes under our previous grant, RO1 AI056273, to test several key hypotheses concerning: 1) the role of tegumental ecto-enzymes in hemostasis and immunomodulation, 2) the ability of tegumental sphingomyelinase to alter permeability properties at the parasite surface, and 3) the molecular mechanisms of trans- tegumental metabolite exchange. The functional genomics approach we adopt here coupled with independent and direct, follow-up experiments employing more traditional cell biology and biochemistry techniques are designed to provide significant new information concerning the schistosome host interactive surface. In addition the work is designed to identify tegumental proteins critical for parasite survival in the host and subsequent screens will be undertaken to discover drugs that inhibit these molecules. 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.