Investigation Of Small Molecule Signaling In The Model Organism Caenorhabditis Elegans

Abstract

Caenorhabditis elegans is an important model for the study of aging and disease. The worm has traditionally been used to explore gene function. Notably, one of the first genes shown to extend lifespan was discovered in C. elegans and was found to be conserved in humans. In the past ten years, though, it has been shown that this nematode utilizes a diverse class of small molecules called ascarosides that affect a variety of biological phenomena including development, aging, and mating. Yet many aspects of ascaroside biosynthesis and function remain incomplete. A second class of steroidal small molecules, the dafachronic acids, has also been recently discovered to be endogenous regulators of C. elegans physiology. It is clear that C. elegans is becoming established as a model for chemists. The work presented here highlights recent progress in our understanding of small molecule signaling in C. elegans. My Ph.D. research has contributed novel discoveries in the areas of sex-specific ascaroside biosynthesis, ascaroside modulation of lifespan, and ascaroside based immune system activation. My research has also led to discovery of a small molecule detoxification mechanism in C. elegans and utilized an established 2D NMR-based metabolomics method to investigate a host-pathogen interaction. Finally, this thesis presents a novel statistically powerful 2D NMR metabolomics tool to take small molecule research in C. elegans and higher organisms into the 21st century.