Summary
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.
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.
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| Web resources: | https://cordis.europa.eu/project/id/101149960 |
| Start date: | 01-09-2025 |
| End date: | 31-08-2027 |
| Total budget - Public funding: | - 206 887,00 Euro |
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Original description
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.
Status
SIGNEDCall topic
HORIZON-MSCA-2023-PF-01-01Update Date
22-11-2024
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