Investigation of the role of Par4-associated cell polarity and associated barrier defects in Inflammatory Bowel Diseases
© Federica Branchi
Aim of the research
In Inflammatory Bowel Diseases (IBD), epithelial barrier defects occur as a consequence of chronic inflammation. Recent research has suggested that cell polarity alterations may be upstream of barrier defects and additionally play a role in IBD-associated carcinogenesis (colitis-associated and small intestinal carcinoma). Par4 is a gene encoding a protein crucial in the development of cell polarity. LKB1, its human homologue, is mutated in Peutz-Jeghers syndrome (PJS), a genetic condition characterised by a higher risk of epithelial cancers. Considering the pivotal role of Par4/LKB1 in the development of epithelial cell polarity, this project aims to assess its involvement in IBD-associated barrier defects and carcinogenesis.
The project is structured as follows:
- Comparative investigation of the expression and the mucosal (i.e. crypt/villi) and subcellular localisation of Par4/LKB1 in the gut mucosa of patients with IBD and PJS: endoscopic bowel mucosa samples from patients with Crohn’s Disease (CD), Ulcerative Colitis (UC), PJS and controls will be analysed to assess the expression and localisation of Par4/LKB1, other cell polarity-relevant proteins and junctional proteins. Results will be correlated to functional data assessing epithelial barrier function.
- Evaluation of Par4/LKB1 function in intestinal epithelial cells (IECs) by means of a cell model: a Par4-deficient IEC model will be established. It will provide data on the function of Par4/LKB1 in polarity, barrier function and cell invasion (with and without inflammatory conditions).
- Assessment of the possible role of Par4/LKB1-related polarity processes in IBD-associated carcinomas: genetic data from colitis-associated carcinomas will be scanned for potential Par4-related mutations and altered Par4/LKB1 expression in IBD.
The project officially started in March 2018 and will be carried out for one year, with 3–6 months for the analysis of results and elaboration of a final report. We plan to present our results at the Annual Congress of ECCO in 2020.