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Genome-wide CRISPR/Cas9 screen in intestinal organoids for identification and molecular characterization of therapeutic targets to enhance tissue regeneration

Project description

CRISPR/Cas9 screening to identify regulators of tissue regeneration in inflammatory bowel disease

Inflammatory bowel disease is a devastating chronic inflammatory condition of the digestive tract characterised by severe damage to the intestinal epithelium. Therapeutic strategies have to promote epithelial repair to restore tissue integrity in addition to relieving symptoms of inflammation. The EU-funded ScrIntOR project aims to elucidate the cellular and molecular mechanisms involved in epithelial regeneration. The study will employ a unique in vitro organoid system that captures epithelial cells in a regenerative state in combination with large-scale CRISPR/Cas9 screening to identify novel regulators of intestinal regeneration. Moreover, ScrIntOR will validate key pathways in intestinal repair and dissect the interplay of molecular pathways that orchestrate tissue healing.

Objective

Around 3 million people in Europe are affected by inflammatory bowel disease (IBD), a devastating condition characterized by chronic inflammation of the digestive tract causing severe damage to the intestinal epithelium. Current medication strategies aim to relieve symptoms by reducing the inflammatory burden without promoting epithelial repair to restore tissue integrity. It is therefore of great importance to enhance the current understanding of intestinal regeneration and thus facilitate the development of novel pharmaceutical compounds to improve tissue recovery in IBD patients. However so far, only few regulators of intestinal regeneration with quite distinct cellular functions have been identified, suggesting an interplay of various molecular pathways that orchestrate intestinal repair. This therefore raises the question of which cellular and molecular mechanisms safeguard epithelial regeneration. To address this issue, I will combine a unique in vitro organoid system, developed in the host lab that captures epithelial cells in a regenerative state, with my expertise in large-scale screening approaches to: (1) perform an unbiased genome-wide CRISPR/Cas9 screen to identify novel regulators of intestinal regeneration, (2) validate essential pathways in intestinal repair in vitro and in vivo, and (3) dissect the molecular events coordinating tissue healing. The outcome of this project will on one hand provide a comprehensive list of factors and their molecular function controlling this cellular process and on the other hand uncover novel druggable pathways in IBD to enhance the regenerative capacity of the intestinal epithelium. Executing this MSCA fellowship proposal will equip me with expert knowledge in epithelial biology and associated pathologies, cutting-edge technologies and an essential set of transferable skills, which all together will ensure my successful establishment as an independent group leader in the field of regenerative stem cell biology.

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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
Other funding
€ 0,00