Descrizione del progetto
Cellule enterocromaffini e secrezione di serotonina
Le difficoltà nella comunicazione tra il tratto gastrointestinale, il sistema nervoso enterico e il cervello sono state implicate nella patogenesi di molteplici disturbi, tra cui obesità, diabete, dolore viscerale e malattia infiammatoria intestinale. Le cellule enteroendocrine, in particolare le cellule enterocromaffini, che funzionano come meccano- e chemorecettori nella secrezione di serotonina, sono fondamentali per questa comunicazione e mostrano caratteristiche molecolari e morfologiche che ricordano le sinapsi neuronali nel cervello. Il progetto SynGut, finanziato dall’UE, impiega un approccio multidisciplinare per svelare i meccanismi molecolari che mediano la secrezione ormonale dalle cellule enterocromaffini e comprenderne le conseguenze funzionali; inoltre, farà luce sul processo di trasferimento delle informazioni al sistema nervoso enterico e al cervello.
Obiettivo
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’.
Campo scientifico
- natural sciencesbiological sciencesneurobiology
- medical and health sciencesclinical medicinegastroenterologyinflammatory bowel disease
- natural sciencesphysical sciencesopticsmicroscopyelectron microscopy
- medical and health sciencesclinical medicineendocrinologydiabetes
- medical and health scienceshealth sciencesnutritionobesity
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF-EF-ST - Standard EFCoordinatore
1165 Kobenhavn
Danimarca