Small molecule signaling in Caenorhabditis elegans

描述(申请人提供)：线虫秀丽线虫是生物医学研究中最重要的模式生物之一，因为它具有生物可控性，而且它的许多生理途径与人类的相应途径有很强的相似性。该项目的目标是对线虫高度发达的基因组学和蛋白质组学进行补充，对其代谢组进行全面的结构和功能表征，令人惊讶的是，这方面的探索仅限于非常有限的程度。这一努力是由一系列证据推动的，这些证据表明，结构基本上未知的小分子在线虫的内分泌和外分泌信号中发挥重要作用，特别是在调节寿命、发育和新陈代谢的关键途径中。这一更新的具体焦点是最近发现的一种模块化的小分子语言的生物合成和功能，即蛔虫苷，它几乎调控线虫生活史的方方面面，包括 寿命。对蛔虫苷生物合成的阐明将揭示初级代谢和保守的信号通路如何整合，以产生调节发育、衰老、抗逆性和一系列行为的小分子信号。尤其令人感兴趣的是，通过sirtuins，一类保守的组蛋白脱乙酰酶家族和胰岛素信号，蛔虫苷在调节线虫寿命中的作用。第二个焦点是核激素受体DAF-12的胆汁酸样配体的生物合成，DAF-12是脊椎动物维生素D受体的同系物，在调节蛔虫苷感知下游的发育和寿命方面发挥关键作用。拟议研究的中心是使用已识别的信号分子的合成衍生物进行化学遗传筛选，以及核磁共振光谱方法，该方法允许分析复杂的小分子混合物，并极大地加快了被检测化合物的结构阐明过程和功能表征。该项目的成功完成将提供线虫代谢组的部分结构和功能注释，大大增加我们对控制线虫发育、衰老和代谢的保守途径以及哺乳动物相应的疾病相关途径的了解。产生的小分子知识不仅将使今后的努力能够针对更多样化的化学遗传筛选，探索线虫生物学和生态学的其他方面，而且还将有助于农业或医学上相关的线虫物种的研究。此外，为表征线虫信号分子而开发的方法将有助于类似的结构和 其他模式生物小分子代谢物的功能表征。

DESCRIPTION (provided by applicant): 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, surprisingly, has been explored to only a very limited extent. This effort is motivated by several lines of evidence indicating that small molecules of largely undetermined structure play important roles in C. elegans endocrine and exocrine signaling, specifically in key pathways regulating lifespan, development, and metabolism. Specific focus of this renewal form the biosynthesis and functions of a recently identified modular "language" of small molecules, the ascarosides, which regulate virtually every aspect of the life history of C. elegans, including lifespan. Elucidation of ascaroside biosynthesis will reveal how input from primary metabolism and conserved signaling pathways are integrated to create small-molecule signals that regulate development, aging, stress resistance, and a wide range of behaviors. Of particular interest will be the role of ascarosides in regulating C. elegans lifespan via sirtuins, a family of conserved histone deacetylases, and insulin signaling. A second focus forms the biosynthesis of bile acid-like ligands of the nuclear hormone receptor DAF-12, a homolog of vertebrate vitamin D receptors, which plays a key role in the regulation of development and lifespan downstream of ascaroside perception. Central to the proposed research is the use of synthetic derivatives of the identified signaling molecules for chemical genetic screens, as well as NMR-spectroscopic methodology that permits the analysis of complex small molecule mixtures and greatly accelerates both the structure elucidation process and the functional characterization of the detected compounds. 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.