Functional Characterization of the Schistosome Tegument

 描述（由申请人提供）：血吸虫是一种寄生性扁形虫，可引起一种慢性、使人衰弱的疾病，困扰着70多个国家的2亿多人。这种寄生虫可以在一个非常恶劣的环境中生活数年，有时甚至数十年--脊椎动物的血液--但它们似乎很少引起宿主止血系统的明显反应。我们假设，在主机相互作用的表面，在以前的资金周期中确定的蛋白质，是中央寄生虫的能力，阻碍主机止血。在这一竞争性更新中，我们提出测试几个关键假设：1）皮层胞外酶在阻断血小板活化和聚集中的作用，2）皮层蛋白酶切割关键凝血蛋白的能力，3）皮层纤溶酶原结合蛋白在活化纤溶酶和促进血栓溶解中的作用。这些研究将产生重要的新信息的分子机制，使用的crossome钝宿主血栓反应。此外，这项工作可能会确定对寄生虫生存至关重要的表皮蛋白，从而导致随后的筛选，以发现抑制这些分子的潜在的寄生虫杀伤药物和/或测试其疫苗潜力的试验。通过这种方式，我们计划的实验有可能揭示新的有效靶点，以及新的治疗方法，用于干预仍然是人类疾病的广泛和主要原因的寄生虫。此外，鉴于对了解凝血控制机制的广泛兴趣，了解核糖体如何调节这一过程将超出真核病原体研究领域。

 DESCRIPTION (provided by applicant): Schistosomes are parasitic flatworms that cause a chronic, debilitating disease afflicting over 200 million people in over 70 countries. The parasite live for years, sometimes decades, in what should be a very hostile environment - the blood of vertebrates - yet they appear to elicit little if any overt reaction from the host's hemostatic system. We hypothesize that proteins at the host-interactive surface, identified in the previous funding cycle, are central to the parasites ability to impede host hemostasis. In this competing renewal, we propose to test several key hypotheses concerning: 1) the role of tegumental ecto-enzymes in blocking platelet activation and aggregation, 2) the ability of tegumental protease(s) to cleave key coagulation proteins, and 3) the role of tegumental plasminogen-binding proteins in activating plasmin and promoting thrombolysis. These studies will yield significant new information on the molecular mechanisms used by schistosomes to blunt the host thrombotic response. 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.