Small molecule signaling in Caenorhabditis elegans

描述（由申请人提供）：线虫秀丽隐杆线虫是生物医学研究中最重要的模式生物之一，因为它具有生物学上的易处理性，而且它的许多生理途径与人类中的相应途径具有很强的相似性。该项目的目的是补充高度发达的C.线虫具有其代谢组的全面结构和功能特征，令人惊讶的是，其仅在非常有限的程度上进行了探索。这一努力的动机是由几条证据表明，在很大程度上不确定的结构的小分子在C。elegans内分泌和外分泌信号，特别是在调节寿命，发育和代谢的关键途径。这种更新的具体焦点是最近确定的小分子模块化“语言”的生物合成和功能，即Ascarosides，它几乎调节C.优雅，包括 寿命阐明Ascaroside生物合成将揭示如何从初级代谢和保守的信号传导途径的输入整合，以创建小分子信号，调节发育，衰老，抗应激和广泛的行为。特别令人感兴趣的将是在调节C. elegans寿命通过sirtuins，一个保守的组蛋白脱乙酰酶家族，和胰岛素信号。第二个焦点是形成核激素受体的胆汁酸样配体的生物合成，该受体是脊椎动物维生素D受体的同系物，其在蛔虫苷感知下游的发育和寿命调节中起关键作用。拟议研究的核心是使用已识别信号分子的合成衍生物进行化学遗传筛选，以及NMR光谱方法，该方法允许分析复杂的小分子混合物，并大大加快了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为C. elegans代谢组，大大增加了我们对控制C.线虫和哺乳动物中相应的疾病相关途径。产生的小分子知识不仅将使未来的努力，旨在更多样化的化学遗传筛选探索的生物学和生态学的其他方面的C。线虫，但也与农业或医学相关的线虫物种。此外，还建立了C. elegans信号分子将促进类似的研究， 来自其他模式生物的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.