Functional Characterization of the Schistosome Tegument

描述(申请人提供)：血吸虫是一种寄生扁虫，引起一种慢性、衰弱的疾病，困扰着70多个国家的2亿多人。这些寄生虫在一个本应是非常恶劣的环境--脊椎动物的血液--中存活数年，有时甚至数十年，然而，它们似乎几乎没有引起宿主的两个主要防御系统--止血系统和免疫系统--的保护性反应。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中心，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，如在我们之前的资助RO1 AI056273下首次开发用于血吸虫的RNA干扰，以测试几个关键假设，涉及：1)被膜外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通透性的能力，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，结合使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，旨在提供关于血吸虫宿主相互作用表面的重要新信息。此外，这项工作旨在识别对寄生虫在宿主中的生存至关重要的被膜蛋白，随后将进行筛选，以发现抑制这些分子的药物。通过这种方式，我们计划中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。 与公共卫生相关：血吸虫是一种寄生虫，生活在70多个国家2亿多人的血液中。这些寄生虫是世界范围内死亡和残疾的主要原因。这种蠕虫具有非凡的特性，使它们能够在人体内生活多年。这些特性包括阻止我们的免疫反应针对它们的能力，从我们的血液中吸收营养的能力，以及检测环境压力并做出适当反应的能力。通过更准确地了解寄生虫是如何实现这些目的的，我们的目标是阻止这些能力并杀死蠕虫。

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. PUBLIC HEALTH RELEVANCE: Schistosomes are parasite worms that live in the blood streams of over 200 million people in more than 70 countries. These parasites are a major cause of death and disability worldwide. The worms have remarkable properties that allow them live inside people for many years. These properties include an ability to block our immune responses from targeting them, an ability to take in nutrients from our blood and an ability to detect environmental stresses and respond appropriately. By understanding more precisely how the parasites achieve these ends, we aim to block these capabilities and kill the worms.