Functional Characterization of the Schistosome Tegument

血吸虫体皮的功能表征

• 批准号: 10384389
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384389
• 关键词: Adenosine; Applications Grants; Biochemical; Biological Assay; Blood; Blood Circulation; Blood coagulation; Blood flow; Calpain; Chronic; Cleaved cell; Coagulation Process; Country; Cytolysis; Disease; Electrodes; Environment; Enzymes; Fibronectins; Funding; Genes; Growth; Helminths; Hemostatic Agents; Hemostatic function; Histopathology; Immune response; Impairment; In Vitro; Infection; Intervention; Kininogens; Knowledge; Measures; Molecular; Monitor; Niacinamide; Nicotinamide Mononucleotide; Nutrient; Parasite Control; Parasites; Pharmaceutical Preparations; Physiological; Platelet Activating Factor; Platelet aggregation; Platyhelminths; Process; Proteins; RNA Interference; Radiolabeled; Reaction; Recombinants; Research; Role; Schistosoma; Schistosomiasis; Signaling Molecule; Supplementation; Surface; System; Testing; Thrombelastography; Thrombosis; Thrombus; Vaccines; Vertebrates; Weight; Work; design; diadenosine triphosphate; experimental study; human disease; improved; in vivo; infected vector rodent; interest; novel; pathogen; platelet function; protein function; response; thrombolysis; thrombotic; uptake

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.

血吸虫是一种寄生性扁形虫， 超过70个国家的超过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-但他们似乎很少引起，如果有的话 宿主止血系统的破坏性反应我们假设蛋白质在 在上一个资助周期中确定的主机交互界面是这方面的核心 能力在这一竞争性更新中，我们建议测试以下几个关键假设： 1)体外研究了体表胞外酶SmNPP 5和SmATPDase的止血作用， 在体内，2）表皮胞外酶SmAP和NACE产生关键营养素的能力 - 腺苷和烟酰胺-它们对果蝇的存活至关重要， 生长和3）皮层钙蛋白酶阻止凝血、促进 血栓溶解和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， 微囊体用于减弱宿主血栓反应的分子机制， 维持对重要营养物质的获取。此外，这项工作可能会识别皮层蛋白质， 这对寄生虫的生存至关重要，导致随后的筛选，以发现潜在的 抑制这些分子的药物和/或测试其疫苗的试验 潜力通过这种方式，我们计划的实验有可能揭示新颖有效的 目标，以及新的治疗方法，用于干预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 控制凝血的机制，了解线粒体如何调节这种机制， 这一过程将在真核病原体研究领域之外引起人们的浓厚兴趣。