Small molecule signaling in C. elegans

项目摘要 秀丽线虫是生物医学中最重要的模式生物之一 研究，因为它的生物易驯化，因为它的许多生理途径显示 与人类相应的通路有很强的相似性。该项目的目标是补充 线虫高度发达的基因组学和蛋白质组学具有全面的结构和 其代谢体的功能特征，这方面的探索仅限于非常有限的程度。 在最近的工作中，我们已经证明线虫利用出乎意料的小分子结构 内分泌和外分泌信号的多样性和复杂性，几乎控制着它生活的方方面面 历史，包括发育、衰老、抗逆性和广泛的行为。 我们研究的一个主要焦点将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的机制，这将 揭示新陈代谢和保守的信号通路如何相互作用来控制生活史。特别的 人们感兴趣的将是强大的发育加速器和达尔拮抗剂NACQ#1的作用， 一类新的线虫发育调节剂的代表及其生物合成和模式 部分通过调节类固醇激素调节线虫寿命的蛔虫皂苷的作用 制作。第二个焦点是孤儿核激素受体配体的识别。 是哺乳动物类固醇受体(如肝X受体和维生素D受体)的同源物，以及 调节NACQ#1和蛔虫苷的下游发育和寿命。中环 对拟开展的研究是利用合成的衍生物和分子探针进行鉴定 用于化学遗传筛选的信号分子以及基于高效液相色谱-质谱仪的方法学 (“比较代谢组学”)允许将光谱特征关联起来 直接具有特定遗传背景的未知小分子，这大大加速了 复合标识及其功能注解。 该项目的圆满完成将为C。 线虫的代谢组，大大增加了我们对保守的控制途径的理解 线虫的发育、衰老和代谢及其与疾病相关的途径 哺乳动物。所产生的小分子知识不仅将使未来的努力瞄准更多 探索线虫生物学和生态学的其他方面的各种化学遗传屏幕， 也包括与农业或医药相关的线虫物种。此外，方法论 为表征线虫信号分子而开发的将有助于类似的研究 其他模式生物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.