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.
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, endogenous compounds called ascarosides and dafachronic acids 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 in humans.
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