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

Descripción del proyecto

Cambios del sistema nervioso entérico en afecciones inflamatorias

El sistema nervioso entérico (SNE) es una compleja red de neuronas situada en las paredes del tracto gastrointestinal, a menudo denominado «segundo cerebro». Los cambios en el sistema nervioso central se han asociado a las enfermedades inflamatorias intestinales (EII), pero los mecanismos precisos siguen siendo inciertos. Financiado por las Acciones Marie Skłodowska-Curie, el equipo del proyecto NeurogENSity pretende investigar la especificación de la identidad neuronal en el SNE durante la inflamación. Los investigadores emplearán un modelo de colitis ulcerosa e investigarán los acontecimientos moleculares en el SNE inflamado, así como las interacciones entre el SNE y el sistema inmunitario responsables de los cambios neurogénicos. Este trabajo podría permitir tratamientos específicos de la disfunción del sistema nervioso central en las EII.

Objetivo

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.