Complex organisms adapt to changes of internal and external conditions by modulating a network of coordinated endocrine signals. These endocrine pathways are classically associated with well-defined organs or organ structures (e.g., adrenal and pituitary glands, pancreatic islets, or parathyroid). Some important endocrine functions are, however, performed by specialized cells scattered throughout several organs such as heart, lung, or the gastrointestinal tract. These cells define the Diffuse Neuro-Endocrine System (DNES), which modulates multiple physiological events ranging from heart rate regulation to breathing and appetite control. This modulation is achieved by secretion of a number of hormones, most of which are peptides. Our goal is to purify these very rare secretory cells in order to identify novel secreted factors and to understand how hormone secretion may be controlled. This approach is enabled by strong expertise in GPCR pharmacology and signalling as well as transgenic mice. Using a combination of technologies, including RNASeq and CRISPRs, we have developed efficient strategies to match bioactive ligands to their corresponding receptors, which is paramount to understanding the endocrine networks. Our current efforts focus on the enteroendocrine cells (EECs), with which we aim to be able to modulate pancreatic function, regulate appetite, and stimulate epithelial gut regeneration.
Target identification for a Hedgehog pathway inhibitor reveals the receptor GPR39. Bassilana F, Carlson A, DaSilva JA, Grosshans B, Vidal S, Beck V, Wilmeringwetter B, Llamas LA, Showalter TB, Rigollier P, Bourret A, Ramamurthy A, Wu X, Harbinski F, Plonsky S, Lee L, Ruffner H, Grandi P, Schirle M, Jenkins J, Sailer AW, Bouwmeester T, Porter JA, Myer V, Finan PM, Tallarico JA, Kelleher JF 3rd, Seuwen K, Jain RK, Luchansky SJ. Nat Chem Biol. 2014 May;10(5):343-9.