Functional Characterization of the Schistosome Tegument

血吸虫体皮的功能表征

• 批准号: 8964247
• 负责人: Patrick J Skelly
• 金额: $ 41.25万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8964247
• 关键词: Activities of Daily Living; Applications Grants; Back; Binding; Binding Proteins; Biological Assay; Blood; Blood Platelets; Blood coagulation; Calpain; Cause of Death; Chronic; Cleaved cell; Coagulants; Coagulation Process; Country; Cytolysis; Disease; Environment; Enzymes; Fibronectins; Funding; Gene Expression; Genes; Hemostatic Agents; Hemostatic function; High-Molecular-Weight Kininogen; In Vitro; Intervention; Knowledge; Life; Measures; Mediating; Molecular; Monitor; Mus; Parasite Control; Parasites; Peptide Hydrolases; Pharmaceutical Preparations; Plasma; Plasmin; Plasminogen; Platelet Activating Factor; Platelet Activation; Platelet aggregation; Platyhelminths; Polyps; Process; Property; Protein Binding; Proteins; Proteome; RNA Interference; Reaction; Recombinants; Research; Role; Schistosoma; Schistosome Parasite; Schistosomiasis; Sphingomyelinase; Sphingomyelins; Staging; Stream; Surface; System; Testing; Thrombelastography; Vaccines; Vertebrates; Work; comparative; design; disability; enolase; functional restoration; human disease; improved; interest; killings; novel; pathogen; public health relevance; research study; response; thrombolysis

 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.

 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。这种寄生虫在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，但它们似乎对宿主的止血系统几乎没有任何明显的反应。我们假设，在上一个资金周期中确定的宿主相互作用表面的蛋白质是寄生虫阻碍宿主止血能力的核心。在这一竞争更新中，我们建议检验几个关键假说：1)被膜外酶在阻断血小板激活和聚集中的作用，2)被膜蛋白酶(S)裂解关键凝血蛋白的能力，以及3)被膜纤溶酶原结合蛋白在激活纤溶酶和促进溶栓中的作用。这些研究将为血吸虫用来钝化宿主血栓反应的分子机制提供重要的新信息。此外，这项工作可能会识别对寄生虫生存至关重要的被膜蛋白，从而进行后续筛选，以发现抑制这些分子的潜在血吸虫杀伤性药物和/或测试其疫苗潜力的试验。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。此外，鉴于人们对了解凝血控制机制的广泛兴趣，了解血吸虫如何调节这一过程将是真核病原体研究领域之外的浓厚兴趣。