Enteroendocrine regulation of signaling pathways governing homeostasis. The balance between proliferation and differentiation in the intestine is essential for homeostasis. We recently demonstrated that EECs are essential regulators of cellular metabolism in the crypt, and that in their absence, intestinal stem cell activity and cellular proliferation is increased (McCauley et al, bioRxiv 2022). This led us to hypothesize that enteroendocrine cells may influence the master signaling pathways Wnt and BMP which regulate cellular proliferation and differentiation. Because increased proliferation and imbalance in the signaling pathways that maintain intestinal homeostasis could potentially drive tumor formation, we will investigate the role of EECs in a mouse model of colorectal cancer driven by an activating mutation in the Wnt pathway. This is primarily a mouse project with opportunities for histology, biochemistry, and single-cell sequencing.
Enteroendocrine regulation of enterocyte function. We previously found that EECs influenced ion transport and therefore glucose and peptide absorption in enterocytes (McCauley et al, 2020). Ion transport and nutrient availability are linked to cellular metabolism and mitochondrial function, which afford enterocytes the capacity to absorb sufficient nutrients to survive. The role of EECs in regulating these processes has been difficult to study due to absence of good model systems – until now. This project will use metabolomics, gene expression analysis, and functional uptake assays in both mouse models and PSC-derived human intestinal organoids to identify the roles for individual EEC-derived hormones in this complex physiological mechanism.
EEC regulation of crypt metabolism. We recently found that EECs are required to restrict intestinal crypt cells, including stem, progenitor, and Paneth cells, from adopting a fatty acid metabolic program (McCauley et al, bioRxiv 2022). This project will delve deeper into metabolic profiling of crypts with and without EECs and establish roles for individual EEC peptides or metabolites in the regulation of crypt metabolism and homeostasis, in both mouse and in human PSC-derived human intestinal organoids.
EEC regulation of enteric neuron development. The enteric nervous system (ENS) innervates the intestine, controlling important processes like gut motility and water resorption. The gut is also innervated by vagal afferents which signal directly to the brain. EECs and enteric and vagal neurons form synaptic connections that allow for rapid communication between these essential cell types in the intestine. In addition to producing hormones, EECs also produce neurotrophic factors, raising the possibility that EECs help attract neurons to the right place in the developing intestinal epithelium and instruct them to become the right type of neuron. This project uses in vivo and in vitro modeling in mouse and human PSC-derived organoids.
Open to your ideas! The McCauley Lab believes in intellectual equity, meaning the best ideas can come from anyone. Pitch your project and we’ll see if we can get it off the ground using the tools we have!