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，并对残疾调整寿命年的损失有很大贡献。更重要的是，仍然没有有效的化疗来控制一些感染，如淋巴丝虫病或河盲症。线虫寄生虫对牲畜和植物的破坏性经济影响，以及新的抗寄生虫和药物靶标在所有环境中都迫切需要，这一点或许不太受欢迎，但对适当的人类营养和健康同样重要。5-羟色胺(5-羟色胺)显著抑制多种自由生活和寄生线虫的运动和体壁肌肉收缩，提示5-羟色胺能信号可能是药物开发的一个很好的靶点。我们建议使用双系统方法，旨在利用线虫和猪链霉菌模型系统的实验优势，来表征5-羟色胺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5-羟色胺受体缺失突变体的使用来表征5-羟色胺信号在线虫运动抑制中的作用，特别是对受体及其下游信号通路的鉴定。其次，将从猪链霉菌中克隆和鉴定相关线虫5-羟色胺受体的潜在同源基因，并通过检测猪链霉菌相关的生理终点(即运动和肌肉收缩)来验证所提出的抑制线虫运动的5-羟色胺途径。由于线虫之间的巨大多样性，线虫中的过程可能不会在寄生虫中完全复制，因此本研究的结果不仅应该识别5-羟色胺能信号通路中的关键靶点，而且还应该突出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重大的医疗、兽医和农业问题。本研究旨在研究参与5-羟色胺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靶点，这些研究将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的见解，并为药物发现提供大量潜在的新分子靶点。 项目叙述寄生线虫在世界范围内造成重大的医疗、兽医和农业问题。这些研究旨在表征参与5-羟色胺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靶点，这些研究将有助于深入了解调节神经递质释放和体壁肌肉活动状态的途径，以及识别大量潜在的新药物靶点。

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.