Comparative Behavioral Metabolomics in Nematodes

描述（由申请人提供）：本提案是对来自两个属的九种线虫的分泌化学物质和调节行为的受体进行比较研究。利用在模式生物秀丽隐杆线虫中引起交配行为或能量形成的几个分子的最新知识，将从另外八个横纹虫物种中鉴定和表征新的化合物：C. briggsae， C. remanei， C. brenneri， C. japonica，太平洋Pristionchus pacificus， P. lheritieri， P. uniformis和P. pauli。本研究将扩大我们对化学信号的认识，并为这些具有多种生态位和繁殖方式的线虫的行为化学控制提供重要的生物学基础。这项工作将通过在特定的发育阶段隔离蠕虫条件水来完成。这种蠕虫水基本上不含细菌化合物，将用于核磁共振和质谱法的靶向和活性引导结构测定。有针对性的分析将集中在所有物种中含有双脱氧糖蛔虫糖的化合物，它附着在所有已知秀丽隐杆线虫信息素中不同的脂肪酸衍生基团上。在活性导向鉴定中，将对蠕虫条件水进行分离和生物测定，以确定其交配和交配活性。通过靶向靶标鉴定的化合物将在相同的方案中分离和重复，以便在活性引导靶标中只研究独特的化合物。来自这两个目标的新化合物将被合成并测试其生物活性，无论是在源物种中还是在所有物种之间。这一目标不仅将提供每个物种交配和产卵的详细信息，而且将为更好地了解横纹肌线虫的生态和行为提供基础。最后，利用已知的用于交配和交配活动的化合物，这些分子的受体将通过基因筛选和分析细胞中交配活动所必需的cdna来确定。对受体的了解将有助于将化学和行为与秀丽隐杆线虫的遗传和交配途径的广泛现有知识联系起来。相关性：线虫是地球上数量最多的动物，寄生物种感染数十亿人、包括家养宠物和农场牲畜在内的其他动物，以及包括主要农业食物来源在内的植物。从这一建议中获得的知识可能为控制寄生线虫的药物发现提供新的起点，寄生线虫对世界上数十亿人的健康产生不利影响。公共卫生相关性：线虫是地球上数量最多的动物，寄生物种感染数十亿人、包括家养宠物和农场牲畜在内的其他动物以及包括主要农业食物来源在内的植物。从这一建议中获得的知识可能为控制寄生线虫的药物发现提供新的起点，寄生线虫对世界上数十亿人的健康产生不利影响。

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.