Identification and Characterization of Nutrient-Sensing Metabolite GPCRs

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My research investigates molecular endocrinology: the ways in which cells communicate with one another on a molecular level. In order to survive and perform their intended functions, neighboring cells must continuously sense changes in environmental conditions and nutrient availability and respond through finely tuned alterations in cellular function. Nutrient status signals such as proteins, fats, sugars, metabolites, and hormones orchestrate this dynamic communication through activation of specialized receptors on the surface of cells. The G protein-coupled receptor (GPCR) superfamily constitutes greater than 800 unique cell-surface receptors capable of detecting these diverse signals in order to continuously adjust to environmental conditions and demand. My students and I seek to understand how these receptors control cell function during nutrient shortage and nutrient excess. In the short term, we are focusing on a subset of these receptors, the so-called metabolite GPCRs. We ask (1) are these receptors essential for cell survival and metabolic function? (2) What cellular mechanisms do these receptors use to modulate cell function? To answer these questions, we study multiple hormone-secreting and -sensitive cell types (e.g., liver, pancreas, brain) using receptor deletion or addition techniques, in combination with standard molecular biology lab analyses to measure cellular health and function under different metabolic stress conditions. Using these means, we will answer the biological question: How do cell surface GPCRs contribute to cellular nutrient sensing and survival during environmental stress? - a fundamental function for cells and whole animal survival. By comparing and contrasting receptor use in a variety of cell types, these studies will provide insight into tissue-specific mechanisms of nutrient detection and will highlight those essential mechanisms that span multiple tissues and represent fundamental processes in metabolic regulation.