ECCO Grant Study Synopsis: Celia Escudero-Hernández
Celia Escudero-Hernández , ECCO Grant Awardee
Intestinal epithelial cell stress modulates enteric fibroblastic and neuronal profiles in Inflammatory Bowel Disease
© Celia Escudero-Hernández
Background & aim of research
Genetic studies have implicated the autophagy gene ATG16L1 and the endoplasmic stress (ER) gene XBP1 in the pathogenesis of Inflammatory Bowel Disease (IBD). Indeed, spontaneous inflammation develops in mice lacking ATG16L1 or XBP1 expression in intestinal epithelial cells (IEC). Because of the dominant role of failing autophagy and ER stress in IBD, we hypothesise that IEC stress contributes to intestinal fibrosis, gut dysmotility and pain during colitis.
This project aims, for the first time, to thoroughly comprehend the role of crucial IBD epithelial stress factors (i.e. ATG16L1 and XBP1 impairments) in enteric fibroblasts and neurons and to explore potential future intervention points.
Methodology/experiments that will be used
We have implemented organ-on-a-chip technology to reasonably model the gut and explore epithelia–fibroblast and epithelial–neuron crosstalk separately. In addition, we are combining these in vitro assays with established techniques in our lab, such as organoid-derived IEC cultures, in vivo colitis models in genetically modified mice and high-throughput single-cell RNA sequencing. For specific intervention in signalling pathways of relevance for IBD, we will use knock-out organoids and/or pharmacological and genetic blockage of pathways (drugs and small interference RNA/CRISPR, respectively).
Anticipated main impact
In the short term, this study will define the functional contribution of IBD intestinal epithelial risk genes ATG16L1 and XBP1 to enteric fibroblast and neuronal homeostasis. More generally, we will clarify the genetic and molecular mechanisms underlying intestinal fibrosis, gut dysmotility and pain in IBD, thereby laying the groundwork for subsequent therapeutical interventions. Going forward, our results might help to, for example, predict clinical complications in IBD patients and treat them more efficiently compared with current therapies. They might also contribute to the understanding of other common gut disorders (e.g. irritable bowel syndrome and functional diarrhoea).
This project is part of a multi-year enterprise that started in 2020 with the implementation of all relevant technologies. Thus, we expect to produce results shortly.