The role of the vascular endothelium in schistosomiasis

血管内皮在血吸虫病中的作用

• 批准号: 6421422
• 负责人: MELISSA J BEALL
• 金额: $ 8.22万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6421422
• 关键词: Schistosoma mansoni; antigen antibody reaction; biological signal transduction; confocal scanning microscopy; enzyme activity; enzyme induction /repression; growth factor receptors; helminthic antigen; host organism interaction; immune tolerance /unresponsiveness; immunocytochemistry; immunoprecipitation; laboratory mouse; mesentery; molecular cloning; nitric oxide synthase; northern blottings; parasitism; protein kinase; schistosomiasis; tissue /cell culture; transforming growth factors; vascular endothelium; vasodilation

DESCRIPTION (provided by applicant): Schistosomiasis, which results from infection by a parasitic trematode, affects approximately 200 million people worldwide. Despite the availability of effective treatments, high rates of re- infection, the sequelae of chronic infection, and the threat of drug resistance remain major health concerns. Previous studies suggest that Schistosoma mansoni requires host-derived factors for normal development and sexual maturation. Understanding the intricate interactions between host and parasite may suggest methods to prevent the development of patent infections. Adult parasites survive for years within the mesenteric veins of their host, with intimate contact occurring between the dorsal surface of the male parasite and the vascular endothelium of the host. This training proposal will focus on host-parasite interactions at the level of the vascular endothelium, investigating how the parasite may respond to endothelial-derived growth factors and may modulate the intravascular environment through the release of vasoactive factors and parasite antigens. The S. mansoni receptor kinase (SmRK1), a transforming growth factor-beta (TGF-beta) receptor-like molecule on the dorsal surface of the male parasite, is a likely candidate for mediating both parasite development and host-parasite interactions, since members of the TGF-beta superfamily are known to be involved in a variety of regulatory processes in a wide range of species. Our preliminary studies suggest that SmRKl can be activated by recombinant human TGF-beta and signal through the schistosome Smad2 (smSmad2) when both schistosome proteins are expressed in a heterologous system Specific aim one of this proposal will investigate the ability of endogenous SmRKl to become activated and signal in response to exogenous TGF-beta. The role of host accessory proteins present on the vascular endothelium and known to bind TGF-Beta will also be studied for their ability to facilitate TGF-beta interactions with SmRK1. Specific aim two will investigate parasite-derived factors which may influence vascular homeostasis and immune evasion. Preliminary studies have identified a nitric oxide synthase-like protein from the parasite and experiments will be performed to sequence, clone and characterize this enzyme and its role in parasite survival. Other experiments will address the ability of certain antigens derived from adult male parasites to induce specific immunological tolerance through their interactions with liver sinusoidal endothelial cells, thereby facilitating the parasite's ability to evade the host immune response.

描述（由申请人提供）：血吸虫病是由寄生虫感染引起的，影响了大约2亿人 全世界。尽管有有效的治疗可用性，但重新率高 感染，慢性感染的后遗症和药物的威胁 抵抗仍然是主要的健康问题。先前的研究表明 曼氏血吸虫需要宿主衍生的因素，以进行正常发展和 性成熟。了解主机和 寄生虫可能提出防止专利感染发展的方法。 成年寄生虫在宿主的肠系膜静脉内生存了多年 雄性背面之间发生亲密接触 寄生虫和宿主的血管内皮。该培训建议将 专注于血管内皮水平上的宿主 - 寄生虫相互作用， 调查寄生虫如何对内皮衍生的增长做出反应 因素，可能通过释放来调节血管内环境 血管活性因子和寄生虫抗原。 S. Mansoni受体激酶 （SMRK1），一种转化的生长因子β（TGF-β）受体样分子 在男性寄生虫的背侧表面，可能是 介导寄生虫的发展和宿主寄生虫相互作用，因为 众所周知，TGF-Beta超家族的成员参与了各种 在广泛的物种中的监管过程。我们的初步研究 建议可以通过重组人TGF-beta和信号激活SMRKL 通过黑螺旋体SMAD2（SMSMAD2），两种螺旋体蛋白是 在异源系统中表达的特定目的是该提案之一 研究内源性SMRKL被激活并发出信号的能力 对外源TGF-β的反应。宿主配件蛋白的作用 还将研究血管内皮和结合TGF-β的血管内皮 它们促进TGF-β与SMRK1相互作用的能力。具体目标两个 将研究可能影响血管的寄生虫衍生因素 稳态和免疫逃避。初步研究已经确定了一氮 来自寄生虫的氧化物合酶样蛋白，实验将是 进行顺序，克隆和表征这种酶及其在 寄生虫生存。其他实验将解决确定的能力 源自成年男性寄生虫以诱导特定免疫学的抗原 通过与肝脏正弦内皮细胞相互作用的耐受性， 从而促进了寄生虫逃避宿主免疫反应的能力。