Characterising the molecular and cellular basis of enteric nervous system alterations in the inflamed gut

Descrizione del progetto

Cambiamenti del sistema nervoso intestinale in condizioni infiammatorie

Il sistema nervoso enterico (ENS, enteric nervous system) è una complessa rete di neuroni nelle pareti del tratto gastrointestinale, spesso definita «secondo cervello». I cambiamenti nel sistema nervoso enterico sono stati associati alle malattie infiammatorie intestinali, ma i meccanismi precisi rimangono elusivi. Finanziato dal programma di azioni Marie Skłodowska-Curie, il progetto NeurogENSity si propone di studiare la specificazione dell’identità neuronale nel sistema nervoso enterico durante l’infiammazione. I ricercatori utilizzeranno un modello di colite ulcerosa e studieranno gli eventi molecolari nel sistema nervoso enterico infiammato e le interazioni sistema nervoso enterico-immunità responsabili delle alterazioni neurogeniche. Il lavoro potrebbe portare a trattamenti mirati per la disfunzione del sistema nervoso enterico nelle malattie infiammatorie intestinali.

Obiettivo

Inflammatory Bowel Disease (IBD) encompasses two gastrointestinal conditions - Crohn’s disease and ulcerative colitis - which currently lack satisfactory treatment. IBD is associated with alterations to the enteric nervous system (ENS) of the gut, including the formation of new neurons (‘neurogenesis’) and changes in the properties of existing neurons (‘neuroplasticity’). Growing evidence suggests an interplay between acute inflammation and ENS pathology. Despite this, detailed characterisation of ENS alterations, their underlying molecular mechanisms, and how inflammation may induce them during IBD, is not well understood.
The Marklund laboratory has recently uncovered a stepwise diversification model of enteric neurogenesis, suggesting that during embryonic development, subtype identities are specified through identity conversions in post-mitotic neurons. This work leads to the intriguing possibility that the identity of terminally-differentiated enteric neurons may, in fact, be flexible. However, whether stepwise diversification is present during adult inflammation-induced neurogenesis, and whether neuronal identity can be altered by extrinsic stimuli such as inflammation, remains to be assessed. Using a colitis model of IBD, single cell RNA sequencing of ENS and immune cells and spatial transcriptomics, NeurogENSity will characterise the composition of the inflamed ENS, revealing the cellular changes occurring as a result of acute inflammation. Pseudotime trajectory analysis, in combination with lineage tracing experiments, will address the nature of adult enteric neuronal identity specification. ENS-immune interactions which may underlie neurogenic and neuroplastic alterations will be identified, and their relevance assessed using cell depletion assays. Together, NeurogENSity will identify mechanisms underlying inflammation-induced alterations to the ENS, paving the way for targeted treatments of ENS dysfunction during IBD.