FILARIAL EICOSANOIDS--BIOSYNTHESIS AND CELLULAR ACTIONS

丝虫类二十烷酸——生物合成和细胞作用

基本信息

批准号：
2056992
负责人：
LEO X LIU
金额：
$ 8.78万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-08-01 至 1995-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2056992
关键词：
Filarioidae Wuchereria arachidonate eicosanoids fatty acid biosynthesis filariasis gerbil /jird high performance liquid chromatography human subject immunomodulators leukocytes physical chemical interaction platelets radioimmunoassay vascular endothelium

项目摘要

Lymphatic filariasis remains a major global health problem. Little is known about parasite pathogenicity and modulation of host immune responses in human filarial infections. In particular, interactions between bloodborne microfilariae and host blood cells, including platelets, leukocytes, and endothelial cells, are largely unexplored. In mammalian cells, arachidonic acid is metabolized to eicosanoids, biologically active lipid derivatives that mediate a wide range of inflammatory and immune responses. Brugia malayi, a filarial parasite of humans, avidly incorporates arachidonic acid and cal also metabolize arachidonic acid to eicosanoids in vitro. Such parasite-derived eicosanoids could present newly recognized mediators of the in vivo interactions between microfilariae and host cells. The major training goal of this Physician Scientist Award is to provide the physician-applicant with training in concepts and methods of the basic sciences relevant to the study of metazoan parasites, in order to provide him with a solid foundation for developing an independent research career. The major research goals of this proposal are to elucidate the biosynthesis of eicosanoids in B. malayi microfilariae and their roles in mediating interactions between these parasites and host blood cells. Phase I of the Award will emphasize training in research methods as well as coursework and seminars in biochemistry, cell biology, and immunology. Studies of microfilarial eicosanoid production will be continued using sensitive techniques of HPLC, TLC, and RIA to detect parasite products of arachidonic acid metabolism. This phase will also provide intensive training in analytical biochemistry techniques, including gas chromatography - mass spectroscopy, to structurally characterize unknown and novel parasite-derived eicosanoids. In Phase II, these techniques will be applied and expanded to study the effects of microfilarial eicosanoids on human blood cells, including leukocytes, platelets, and endothelial cells. The effects of diethylcarbamazine, the major antifilarial drug, and other pharmacologic inhibitors of mammalian eicosanoid biosynthesis on the biosynthesis and actions of microfilarial eicosanoids will also be assessed. These investigations will help to define the role of parasite-derived eicosanoids in the pathogenesis and immunology of human filariasis. While these studies are focused on filarial parasites, other metazoan parasites are likely to possess similar capabilities to form bioactive lipids. Rigorous studies of parasite-derived eicosanoids may provide new insights in the molecular means by which metazoan parasites elude natural or vaccine-induced immunity. Such understanding may influence the development of useful drugs and synthetic vaccines to control important metazoan parasites. The educational and training components of this Award will provide the applicant with the scientific expertise that will enable his to successfully pursue basic studies of host-parasite interactions as an independent investigator.

淋巴丝虫病仍然是全球主要的健康问题。几乎没有关于寄生虫致病性和宿主免疫反应的调节已知在人类丝状感染中。特别是，之间的相互作用血源性的微丝菌和宿主血细胞，包括血小板，白细胞和内皮细胞在很大程度上没有探索。在哺乳动物细胞，蛛网膜酸代谢为类花生酸，生物活性介导广泛的炎症和免疫的脂质衍生物回答。 Brugia Malayi，一种人类的丝状寄生虫，狂热掺入花生四烯酸和CAL还将蛛网膜酸代谢为体外类花生酸。这种寄生虫衍生的类花生酸可以存在新认识的体内相互作用的介体微丝菌和宿主细胞。该医师科学家奖的主要培训目标是提供医师对基本概念和方法培训的培训与后生寄生虫研究有关的科学，以提供他为发展独立的研究职业提供了坚实的基础。该建议的主要研究目标是阐明生物合成马来芽孢杆菌中的类花生酸酯及其在介导中的作用这些寄生虫与宿主血细胞之间的相互作用。该奖项的第一阶段将强调研究方法的培训以及生物化学，细胞生物学和免疫学的课程和研讨会。将继续使用微虫类花生酸的研究 HPLC，TLC和RIA的敏感技术检测寄生虫产物花生四烯酸代谢。此阶段还将提供密集分析生物化学技术的培训，包括气体色谱 - 质谱，结构表征未知和新颖的寄生虫衍生的类花生酸。在第二阶段，这些技术将应用和扩展以研究微脊髓类固醇的影响在人类血细胞上，包括白细胞，血小板和内皮细胞。二乙基加仑的影响，主要的抗抗性药物和哺乳动物类类生物合成的其他药理学抑制剂微椰子类花生酸的生物合成和作用也将是评估。这些调查将有助于定义寄生虫衍生的作用人类丝虫病的发病机理和免疫学中的类花生酸酯。尽管这些研究的重点是丝状寄生虫，其他后生寄生虫可能具有形成生物活性脂质的类似能力。对寄生虫衍生的类花生酸的严格研究可能会提供新的见解在分子手段中，后生寄生虫避免自然或疫苗诱导的免疫力。这种理解可能会影响发展有用的药物和合成疫苗控制重要的后生动物寄生虫。该奖项的教育和培训组成部分将向申请人提供科学专业知识，使他的专业知识能够成功地追求宿主 - 寄生虫相互作用的基础研究独立研究者。