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，并显著导致残疾调整寿命年的损失。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也许不太受重视，但对适当的人类营养和健康同样重要，在所有情况下都迫切需要新的抗蠕虫和药物靶标。5-羟色胺（5-HT）显著抑制多种自由生活和寄生线虫的运动和体壁肌肉的收缩，表明5-羟色胺能信号传导可能是药物发现的极好靶点。我们建议使用双系统的方法，旨在利用实验的优势，这两个C。elegans和A. suum模型系统，以表征5-HT抑制运动途径中的受体和下游信号组分。首先，5-HT信号传导在运动抑制中的作用将在C.通过生物信息学、克隆受体的异源表达和假定的5-HT受体无效突变体的使用，特别关注受体及其下游信号通路的鉴定。第二，相关C.线虫5-HT受体将从A. suum产生的5-HT抑制运动的可能途径。elegans通过检查A. suum（即运动和肌肉收缩）。由于线虫的巨大多样性，C。因此，这项研究的结果不仅应该确定了能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引起严重的医学、兽医和农业问题。本研究旨在表征参与5-HT抑制运动的受体和下游信号组分。运动是抗帕金森病药物发现的关键靶点，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分子靶点。 寄生线虫在世界范围内引起了严重的医学、兽医和农业问题。这些研究旨在表征参与5-羟色胺运动抑制的受体和下游信号传导组分。运动是抗结节药物发现的关键靶点，这些研究应该提供对调节神经递质释放和体壁肌肉活动状态的途径的深入了解，以及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.