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CORDIS

Dissecting the molecular mechanisms underlying YAP activation in intestinal tissue repair

Project description

Mechanoresponsive transcription factor in intestinal tissue repair

Inflammatory bowel disease (IBD), namely ulcerative colitis and Crohn’s disease, involves chronic pathologies of the intestines that affect millions of people. Currently, no curative therapies are available, and standard of care is limited to palliative treatments. Improving epithelial regeneration is likely to accelerate recovery and minimise exposure to luminal microbes, preventing inflammation and chronic damage. Recently, the mechanoresponsive transcription factor YAP has been identified as a key mediator of epithelial repair in IBD and is regulated by extracellular matrix rigidity, strain, shear stress and other processes linked to cytoskeletal integrity. The EU-funded InterYAP project proposes to carry out a proteomic study to dissect the mechanisms by which YAP is activated and exerts its functions in intestinal tissue repair.

Objective

Inflammatory bowel diseases (IBDs), such as ulcerative colitis and Crohn’s disease, are chronic and debilitating pathologies of the intestines that affect 2.5-3.0 million patients in Europe and impose an economic burden of approximately €5.0bn/year on European healthcare systems. Currently, no curative therapies are available and standard of care is limited to palliative anti-inflammatory treatments that fail to promote healing of the intestinal lining. Enhancing epithelial regeneration is likely to accelerate functional recovery and reduce exposure to luminal microbes, thereby avoiding further inflammation and, ultimately, chronic damage. However, the cellular and molecular mechanisms underlying regeneration of intestinal epithelium are not yet fully understood, and thus opportunities for pharmacological modulation remain scarce. Recently, the mechanoresponsive transcription factor YAP has been identified as a key mediator of epithelial repair in experimental IBD models. Yet, the molecular details of its function remain elusive. Here, I propose to carry out a proteomic study to dissect the mechanisms by which YAP is activated and exerts its functions in intestinal tissue repair. I will leverage the intestinal stem cell organoid technology and my expertise in CRISPR/Cas9 genome editing to: i) perform a detailed characterisation of YAP post-translational modifications and interacting protein partners using unbiased proteomic approaches; and ii) define the function of identified partners using novel in vitro and animal models of intestinal tissue repair. I envisage the study will provide a clear map of signalling pathways and molecular networks underlying YAP function and uncover potential druggable targets for pharmacological enhancement of intestinal tissue repair. From a professional perspective, execution of the project will equip me a valuable set of technical and transferable skills and ultimately facilitate my transition into a group leader position.

Coordinator

KOBENHAVNS UNIVERSITET
Net EU contribution
€ 207 312,00
Address
NORREGADE 10
1165 Kobenhavn
Denmark

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Region
Danmark Hovedstaden Byen København
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 207 312,00