Our research is dedicated to facilitating systematic structural and functional annotation of small biogenic molecules – the metabolome – in model organisms, integrating expertise in molecular biology, bioinformatics, and analytical chemistry. Structurally diverse but yet unidentified metabolites play central roles as information carriers in most biological processes and represent an increasingly recognized source for new drug leads, e.g., the treatment of metabolic disease and cancer. Moreover, detailed knowledge of small-molecule structures, their biosynthetic pathways, and their interactions with other biomolecules is essential for advancing our understanding of endocrine and exocrine signaling pathways.  

Combining NMR-spectroscopic and MS-based comparative metabolomics with phenotypic screens and genetic approaches, we have engaged in a comprehensive effort to characterize structures and functions of the metabolomes of animal model organisms, focusing on metabolites that control development, lipid metabolism, and interactions with the microbiota. Our research has led to the identification of several 100 new metabolites that function as signaling molecules in C. elegans regulating virtually all aspects of physiology. This large diversity of metabolites is derived from the modular assembly of building blocks from conserved metabolic pathways, presenting a new paradigm of small molecule biosynthesis in metazoans.  

Encouraged by the initial success of our methods in the model system C. elegans, we engaged in a major effort toward a systematic characterization of mammalian metabolomes, with a focus on changes in response to alteration of the composition of the gut microbiome. These studies indicate that mammals employ similarly extensive small molecule-based signaling networks that rely to a significant extent on not yet annotated metabolites. 

Many of the newly identified molecules, including a new class of bile acid conjugates, have entirely unexpected structures or biological activities, and the elucidation of their roles in signaling pathways regulating metabolic homeostasis has become a major focus of my lab. This includes elucidation of the biosynthetic pathways that regulate abundance of the identified signaling molecules, identification of corresponding receptors, and their associated physiological phenotypes.  

To accelerate detection and functional characterization of new metabolites my lab has developed a suite of software tools (“Metaboseek”) for the research community that facilitate comparative metabolomic analysis of high-resolution MS data to detect metabolites associated with specific mutations, developmental stages, or environmental conditions. As a necessary component of the chemical biology-related aspects of our research, my lab has extensive experience with syntheses of newly identified metabolites (for phenotypic assays) and related compounds, e.g. probes to identify receptors or interrogate biosynthetic pathways. 

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