Comparative Behavioral Metabolomics in Nematodes

描述（由申请人提供）：本提案旨在对调节两属9种线虫行为的分泌化学物质和受体进行比较研究。利用最近的几种分子的知识，导致交配行为或dauer形成的模式生物秀丽隐杆线虫，新的化合物将被确定和表征的8个额外的小杆种：C。布里格塞角remanei，C. brenneri，C. japonica、太平洋食心虫、莱氏食心虫、单形食心虫和保利食心虫。这项研究将扩大我们的化学信号的知识，并提供了一个重要的生物学基础的化学控制的行为，在这些线虫，有各种生态位和生殖模式。这项工作将通过在规定的发育阶段隔离蠕虫调节水来完成。这种蠕虫水将基本上不含细菌化合物，并将用于使用NMR和质谱法进行靶向和活性指导的结构测定。有针对性的分析将集中在所有物种的化合物，含有双脱氧糖ascarylose，这是连接到不同的脂肪酸衍生基团在所有已知的C。线虫信息素在活动指导鉴定中，将对蠕虫调节水进行分级，并对幼虫和交配活动进行生物测定。通过有针对性的目标识别的化合物将在相同的方案中分级分离并去复制，以便在活性指导的目标中仅研究独特的化合物。将合成来自这两个目标的新型化合物，并在源种属和所有种属之间测试其生物活性。这一目标不仅将提供详细的信息，交配和dauer形成在每一个单独的物种，但也将提供基础，以更好地了解生态和行为的杆线虫。最后，利用已知的用于交配和交配活性的化合物，将通过遗传筛选和分析细胞中交配活性所必需的cDNA来鉴定这些分子的受体。受体的知识将有助于连接化学和行为与广泛的现有知识的遗传学的dauer和交配途径在C。优雅相关性：线虫是地球上最丰富的动物，寄生物种感染数十亿人，其他动物包括家养宠物和农场牲畜，以及植物包括主要的农业食物来源。从这一提议中获得的知识可能为药物发现提供新的起点，以控制对世界上数十亿人的健康产生不利影响的寄生线虫。公共卫生相关性：线虫是地球上最丰富的动物，寄生物种感染数十亿人，其他动物包括家养宠物和农场牲畜，以及植物包括主要的农业食物来源。从这一提议中获得的知识可能为药物发现提供新的起点，以控制对世界上数十亿人的健康产生不利影响的寄生线虫。

DESCRIPTION (provided by applicant): This proposal is to perform a comparative study of the secreted chemicals and receptors that regulate behavior in nine species of nematodes from two genera. Using recent knowledge of several molecules that cause mating behavior or dauer formation in the model organism Caenorhabditis elegans, new compounds will be identified and characterized from eight additional Rhabditid species: C. briggsae, C. remanei, C. brenneri, C. japonica, Pristionchus pacificus, P. lheritieri, P. uniformis, and P. pauli. This study will expand our knowledge of chemical signaling and provide an important biological foundation for the chemical control of behavior in these nematodes that have a variety of ecological niches and reproductive modes. The work will be accomplished by isolating worm-conditioned water at defined developmental stages. This worm water will be essentially free from bacterial compounds and will be used in both targeted and activity-guided structure determination using NMR and mass spectrometry. The targeted analysis will focus on compounds from all species that contain the dideoxysugar ascarylose, which is attached to different fatty-acid derived groups in all known C. elegans pheromones. In the activity-guided identification, worm conditioned water will be fractionated and bioassayed for both dauer and mating activities. Compounds identified through the targeted aim will be fractionated in identical protocols and dereplicated so that only unique compounds will be studied in the activity-guided aim. Novel compounds from both aims will be synthesized and tested for biological activity, both in the source species and between all species. This aim will not only provide detailed information about mating and dauer formation in each individual species but also will provide the basis to better understand the ecology and behavior of rhabditid nematodes. Finally, with the known compounds for both dauer and mating activities, receptors for these molecules will be identified through genetic screens and profiling cDNAs in cells that are necessary for mating activity. Knowledge of the receptors will help connect chemistry and behavior with the extensive existing knowledge of genetics of dauer and mating pathways in C. elegans. Relevance: Nematodes are the most abundant animal on earth, and parasitic species infect billions of humans, other animals including domestic pets and farm stock, and plants including major agricultural food sources. Knowledge gained from this proposal might provide new starting points for drug discovery to control parasitic nematodes that adversely impact the health of billions of people in the world. PUBLIC HEALTH RELEVANCE: Nematodes are the most abundant animal on earth, and parasitic species infect billions of humans, other animals including domestic pets and farm stock, and plants including major agricultural food sources. Knowledge gained from this proposal might provide new starting points for drug discovery to control parasitic nematodes that adversely impact the health of billions of people in the world.