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.
The pervasive physiological changes associated with aging are reflected in age-dependent increases in the incidence of many diseases, including, diabetes, cancer, neurological disorders, heart disease, and osteoporosis. In nematodes, several different classes of small molecules have been shown to significantly retard the effects of ageing and increase lifespan. The proposed study aims to investigate the biological mechanisms through which these and other endogenous compounds modulate lifespan and development in nematodes, which will contribute to our understanding of the causes of ageing and age-related decline in humans.
