Project Details
Projekt
Molecular mechanisms and functional relevance of neuroepithelial circuit formation in the intestine
Applicant
Professor Dr. Thomas Worzfeld
Subject Area
Cell Biology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 564756572
Gut and brain are intimately linked and communicate bidirectionally via the “gut-brain axis”. The gut-brain axis is not only of central importance for gastrointestinal function, but also controls behavior. Moreover, it plays pivotal roles in multiple diseases, in particular in metabolic diseases such as obesity and type 2 diabetes. Therefore, the gut-brain axis represents a promising target for innovative therapies. Recently, a previously unknown gut-brain connection has been identified in mice, which conveys information on the intestinal contents, in particular on orally ingested sugars, directly and rapidly to the brain. This is achieved by specialized intestinal epithelial cells, so-called enteroendocrine cells, which act as sensors and form direct heterotypic cell-cell contacts with vagal sensory neurons to communicate with the brain. This neuroepithelial circuit is decisive for nutrient choices. Despite of its crucial physiological significance, it is entirely unclear how the direct contacts between epithelial enteroendocrine cells and vagal sensory neurons are established, and the responsible molecules and mechanisms, which underlie the communication of enteroendocrine cells and neurons to govern neuroepithelial circuit formation are unknown. Based on extensive preliminary work, we will uncover the critical regulators of neuroepithelial circuit formation by employing enteroendocrine cell- and vagal sensory neuron-specific metabolic labeling of nascent proteomes in vivo, followed by click chemistry, affinity purification and mass spectrometry. This approach will be combined with microfluidic chip and stripe assays, two-dimensional enteroendocrine-neuron-co-culture assays and electrophysiology, three-dimensional intestinal organoid-neuron-co-culture assays, intestinal tissue ex vivo cultures, as well as pharmacological and genetic pertubations in mice. Moreover, we will assess the downstream molecular programmes underlying neuroepithelial circuit formation, and reveal the (patho-)physiological relevance of neuroepithelial circuit regulators for metabolism and behavior.
DFG Programme
Priority Programmes
