Locomotion in Parasitic Nematodes

描述（由申请人提供）：寄生线虫是人类发病的主要原因，并且会严重导致残疾调整生命年的损失。更重要的是，有效的化疗仍然无法控制某些感染，例如淋巴丝虫病或河盲症。线虫寄生虫对牲畜和植物造成的破坏性经济影响可能不太被人们所认识，但对于人类适当的营养和健康同样重要，并且在所有环境中都迫切需要新的抗蠕虫和药物靶点。血清素 (5-HT) 显着抑制多种自由生活和寄生线虫的运动和体壁肌肉的收缩，这表明血清素信号传导可能是药物发现的绝佳靶点。我们建议使用双系统方法，旨在利用线虫和猪线虫模型系统的实验优势，来表征 5-HT 抑制运动途径中的受体和下游信号成分。首先，将通过生物信息学、克隆受体的异源表达和推定的 5-HT 受体无效突变体的使用来表征线虫中 5-HT 信号传导在运动抑制中的作用，特别关注受体及其下游信号传导途径的鉴定。其次，将从 A. suum 中克隆和表征相关秀丽隐杆线虫 5-HT 受体的潜在直系同源物，并通过检查 A. suum 中的相关生理终点（即运动和肌肉收缩）来测试由秀丽隐杆线虫产生的运动的 5-HT 抑制的拟议途径。由于线虫之间存在巨大的多样性，线虫中的过程可能无法在寄生虫中完全重复，因此这项研究的结果不仅应该确定血清素信号通路中的关键靶标，而且还应该强调这两个重要模型系统之间的潜在差异。寄生线虫在世界范围内造成严重的医学、兽医和农业问题。本研究旨在表征参与 5-HT 运动抑制的受体和下游信号成分。运动是抗线虫药物发现的关键目标，这些研究应该为调节神经递质释放和体壁肌肉活动状态的途径提供基本见解，并为药物发现确定大量潜在的新型分子目标。 项目叙述 寄生线虫在世界范围内造成严重的医学、兽医和农业问题。这些研究旨在表征参与血清素抑制运动的受体和下游信号成分。运动是抗线虫药物发现的关键目标，这些研究应该可以深入了解调节神经递质释放的途径和体壁肌肉的活动状态，并确定大量潜在的新型药物靶点。

DESCRIPTION (provided by applicant): Parasitic nematodes are a major cause of human morbidity and contribute significantly to a loss of Disability Adjusted Life Years. More importantly, effective chemotherapy is still not available to control some infections, such as lymphatic filariasis or river blindness. Perhaps less well appreciated, but equally important for proper human nutrition and health, is the devastating economic impact of nematode parasites on livestock and plants and new anti-helminthic and drug targets are both desperately needed in all settings. Serotonin (5-HT) dramatically inhibits locomotion and the contraction of body wall muscle in a variety of free-living and parasitic nematodes, suggesting that serotonergic signaling may be an excellent target for drug discovery. We propose to use a dual systems approach, designed to exploit the experimental advantages of both the C. elegans and A. suum model systems, to characterize the receptors and downstream signaling components in the pathway of 5-HT inhibition of locomotion. First, the role of 5-HT signaling in the inhibition of locomotion will be characterized in C. elegans by bioinformatics, the heterologous expression of cloned receptors and the use of putative 5-HT receptor null mutants, with special focus on the identification of the receptors and their downstream signaling pathways. Second, potential orthologues of the relevant C. elegans 5-HT receptors will be cloned and characterized from A. suum and the proposed pathway of 5-HT inhibition of locomotion generated from C. elegans tested by examination of relevant physiological end points in A. suum (i.e. locomotion and muscle contraction). Because of the enormous diversity among nematodes, processes in C. elegans may not be duplicated exactly in the parasites, so the results of this study should not only identify key targets in serotonergic signaling pathways, but also highlight potential differences between these two important model systems. Parasitic nematodes cause significant medical, veterinary and agricultural problems worldwide. The present studies are designed to characterize the receptors and downstream signaling components involved in the 5-HT inhibition of locomotion. Locomotion is a key target for anti-nematodal drug discovery and these studies should provide basic insights into pathways regulating neurotransmitter release and the activity state of body wall muscle, as well as identifying a wealth of potential novel molecular targets for drug discovery. PROJECT NARRATIVE Parasitic nematodes cause significant medical, veterinary and agricultural problems worldwide. These studies are designed to characterize the receptors and downstream signaling components involved in serotonin inhibition of locomotion. Locomotion is a key target for anti-nematodal drug discovery and these studies should provide insight into pathways regulating neurotransmitter release and the activity state of body wall muscle, as well as identifying a wealth of potential novel drug targets.