脂溶性分子结合蛋白FAR-1在线虫发育中的作用机制研究

寄生线虫对我国养殖业造成严重危害，但有限的几种药物普遍出现耐药性且具有副作用，亟需研发出高效低毒的寄生线虫病治疗药物。线虫特异蛋白FAR-1能结合和转运宿主来源的多种脂肪酸和视黄醇，被认为可调节虫体发育从而影响对宿主的致病性，但FAR-1对发育的作用机制未知。本项目以寄生线虫常见模型--巴西日圆线虫为研究对象，拟开展：1) 采用免疫亲和层析和脂质组学等方法，阐明FAR-1转运的脂溶性分子对虫体发育的影响；2) 采用体内外基因表达干扰方法，鉴定FAR-1在虫体发育中的作用机制；3）通过晶体结构解析、虚拟筛选和体内外验证，获得靶向FAR-1的高效拮抗剂，解析拮抗机理，评估FAR-1作为药靶的潜力。研究结果可阐明FAR-1影响寄生线虫发育的作用机制，并有助于寄生线虫病药物的研发。

Parasitic nematodes are major pathogens causing serious harm to livestock breeding, but limited drugs have drug resistance and side effects, so it is urgent to develop drugs with high-efficiency and low toxicity to parasitic nematode diseases. Far-1, a nematode specific protein, can combine with fatty acids and retinol, and is thought to regulate the development of nematode and thus affect its pathogenicity to the host. However, little is known about the mechanism of far-1 on the development of nematodes. In this study, we will employ the common model of parasitic nematode, Nippostrongylus brasiliensis, and intend to: 1) obtain the regulatory functions of lipids transferred by FAR-1 protein on the development of nematode; 2) obtain the functions of FAR-1 in the development of nematode using RNAi methods in vitro and in vivo; 3) obtain the effects of antagonist targeting FAR-1 through virtual screening and verification in vitro and in vivo, and evaluate the potential of far-1 as drug target by characterizing the action mechanism of the highly active antagonists. Results of the research could improve our understanding of the functions of far-1 in the development of parasitic nematodes, and facilitate to develop drugs against parasitic nematode diseases.