Small molecule signaling in C. elegans

项目概要 线虫秀丽隐杆线虫是生物医学最重要的模式生物之一 研究，因为它的生物易处理性以及它的许多生理途径表明 与人类的相应途径有很强的相似性。该项目的目标是补充 高度发达的线虫基因组学和蛋白质组学，具有全面的结构和 其代谢组的功能表征，仅在非常有限的程度上进行了探索。 在最近的工作中，我们表明线虫利用了意想不到的小分子结构 内分泌和外分泌信号的多样性和复杂性控制着生命的几乎各个方面 历史，包括发育、衰老、压力抵抗和广泛的行为。 我们研究的一大重点是阐明生物合成和感知 新发现的控制发育和衰老的小分子信号机制，这将 揭示新陈代谢和保守信号通路如何相互作用来控制生命史。特别是 人们感兴趣的是有效的发育加速器和 dauer 拮抗剂 nacq#1 的作用， 一类新的秀丽隐杆线虫发育调节因子的代表，以及生物合成和模式 蛔苷调节线虫寿命的作用，部分是通过调节类固醇激素 生产。第二个焦点是孤儿核激素受体配体的鉴定 是哺乳动物类固醇受体的同源物（例如肝 X 受体和维生素 D 受体） 介导 nacq#1 和蛔苷感知下游的发育和寿命。中环 拟议的研究是使用已识别的合成衍生物和分子探针 用于化学遗传筛选的信号分子以及基于 HPLC-MS 的方法 （“比较代谢组学”）允许关联代表尚未的光谱特征 直接具有特定遗传背景的未知小分子，大大加速 化合物鉴定及其功能注释。 该项目的成功完成将为C提供部分结构和功能注释。 线虫代谢组，大大增加了我们对控制保守途径的理解 秀丽隐杆线虫的发育、衰老和代谢以及相应的疾病相关途径 哺乳动物。所产生的小分子知识不仅使未来的努力能够实现更多目标 各种化学遗传筛选探索线虫生物学和生态学的其他方面， 还包括与农业或医学相关的线虫物种。此外，方法论 为表征秀丽隐杆线虫信号分子而开发的将促进类似的研究 来自其他模式生物的小分子代谢物的结构和功能表征。

Project Summary The nematode Caenorhabditis elegans is one of the most important model organisms for biomedical research, because of its biological tractability and because many of its physiological pathways show strong analogies to corresponding pathways in humans. The goal of this project is to complement the highly developed genomics and proteomics of C. elegans with a comprehensive structural and functional characterization of its metabolome, which has been explored to only a very limited extent. In recent work we have shown that C. elegans utilizes small-molecule architectures of unanticipated diversity and complexity in endocrine and exocrine signaling that control almost every aspect of its life history, including development, aging, stress resistance, and a wide range of behaviors. One major focus of our investigations will be the elucidation of the biosynthesis and perception mechanisms of newly identified small molecule signals that control development and aging, which will reveal how metabolism and conserved signaling pathways interact to control life history. Of particular interest will be the role of the potent developmental accelerator and dauer-antagonist nacq#1, representative of a new class of C. elegans developmental regulators, and the biosynthesis and mode of action of ascarosides that regulate C. elegans lifespan, in part via modulating steroid hormone production. A second focus forms the identification of ligands of orphan nuclear hormone receptors that are homologs of mammalian steroid receptors (e.g. liver-X receptor and vitamin-D receptor) and mediate development and lifespan downstream of the perception of nacq#1 and ascarosides. Central to the proposed research is the use of synthetic derivatives and molecular probes of the identified signaling molecules for chemical genetic screens, as well as HPLC-MS-based methodology ("comparative metabolomics") that permits correlating spectroscopic features representing yet unknown small molecules directly with a specific genetic background, which greatly accelerates compound identification and their functional annotation. Successful conclusion of this project will provide a partial structural and functional annotation of the C. elegans metabolome, substantially increasing our understanding of conserved pathways that control development, aging and metabolism of C. elegans and corresponding disease-relevant pathways in mammals. The small-molecule knowledge generated will not only enable future efforts aimed at more varied chemical genetic screens exploring additional aspects of the biology and ecology of C. elegans, but also of nematode species relevant in agriculture or medicine. Furthermore, methodology developed for characterizing C. elegans signaling molecules will facilitate similar studies toward structural and functional characterization of small molecule metabolites from other model organisms.