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CORDIS

Molecular, morphological, and functional requirements for gastrointestinal serotonin release

Project description

Enterochromaffin cells and serotonin secretion

The impairments in communication between the gastrointestinal tract, the enteric nervous system (ENS) and the brain have been implicated in the pathogenesis of multiple disorders, including obesity, diabetes, visceral pain and inflammatory bowel disease. The enteroendocrine cells, particularly enterochromaffin (EC) cells, functioning as mechano- and chemoreceptors in serotonin secretion, are central to this communication and display molecular and morphological features that are reminiscent of neuronal synapses in the brain. The EU-funded SynGut project employs a multidisciplinary approach to unravel the molecular mechanisms mediating hormone secretion from EC cells and understand its functional consequences; moreover, it will shed light on the information transfer process to the ENS and the brain.

Objective

Communication between the gastro-intestinal (GI) tract, the enteric nervous system (ENS), and the brain plays an important role in regulating our behaviour, and accordingly, impairments in this communication have been implicated in the pathogenesis of multiple disorders including obesity, diabetes, visceral pain, and inflammatory bowel diseases. A better understanding of the molecular and cellular mechanisms of gut-to-brain signalling will be critical for treating these disorders. An important group of cells in this context are enteroendocrine cells (EECs), and most notably enterochromaffin (EC) cells, which function as mechano- and chemoreceptors and signal by secreting serotonin, however the release process is poorly understood. Strikingly, these cells show molecular and morphological features that are highly reminiscent of neuronal synapses in the brain, raising the intriguing hypothesis that they may form synapse-like contacts that lie at the heart of their communication mechanism. To date, however, this hypothesis has been difficult to test due to the low spatial density of EC cells along the GI tract. Using a multidisciplinary approach combining intestinal 3D-organoid cultures, correlative light- and electron microscopy, electrophysiology, and single-cell RNA sequencing, this project aims to address the questions i) which molecular mechanisms mediate hormone secretion from EC cells, ii) what are the functional properties of the release process, and iii) how are local circuits organized to signal information to the ENS and brain. The results from this study will allow me to answer the fundamental question whether EC cells form functional synaptic connections, as well as providing a comprehensive overview over the functional and molecular properties of these ‘synapses’.

Coordinator

KOBENHAVNS UNIVERSITET
Net EU contribution
€ 207 312,00
Address
NORREGADE 10
1165 Kobenhavn
Denmark

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Region
Danmark Hovedstaden Byen København
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 207 312,00