InterYAP · Dissecting the molecular mechanisms underlying YAP activation in intestinal tissue repair
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-09-01 → 2023-08-31
- EU contribution
- €207,312
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Dissecting the molecular mechanisms underlying YAP activation in intestinal tissue repair
During intestinal organogenesis, equipotent epithelial progenitors mature into phenotypically distinct stem cells that are responsible for lifelong maintenance of the tissue. While the morphological changes associated with the transition are well characterized, the molecular mechanisms underpinning the maturation process are not fully understood. In this project, the main goal was to define transcriptional and epigenetic landscapes that define the embryonic and adult cellular states in order to identify cell-intrinsic mechanisms regulating tissue maturation. This project generated a comprehensive datasets that provide a framework for investigation of determinants of epithelial maturation, allowing scientists in the field to further investigate and better understand the developmental processes and associated congenital disorders of the intestinal epithelium. Given the emerging evidence that similar mechanisms operate in the context of tissue repair and cancer, the findings of the project are also of interest for regenerative medicine and oncology research fields. Finally, the identification cell-intrinsic mechanisms regulating cellular maturation might also assist the development of more robust embryonic stem cell/induced pluripotent stem cell differentiation in vitro protocols, which often result in the generation of immature cell types that are ill-suited for functional studies or cell-replacement therapies for a variety of human disorders. Thus, in summary, the knowledge generated in the project might assist the future development of more effective therapies for a variety of conditions affecting the gastrointestinal tract (e.g congenital disorders, inflammatory bowel diseases, colorectal cancer) and, therefore, benefit society at large.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- KOBENHAVNS UNIVERSITET · KOBENHAVNCoordinatorDenmark
Links
Data: CORDIS, © European Union