Prenylation and prenylated proteins as key player for epithelial integrity
Intestinal epithelium plays a crucial role for the maintenance of tissue homeostasis in the gut. Rather than a simple physical barrier against the invasion of luminal components, specialized intestinal epithelial cells perform sophisticated innate immune functions, which allow tolerance against nutrients and protection against potentially pathogenic microorganisms.
Therefore, epithelial integrity is a key component of the gut mucosa in order to avoid the breakdown of tissue homeostasis and the development of pathologies, such as chronic intestinal inflammation. Indeed epithelial leakage and defects on intestinal permeability are associated with IBD, and even postulated as primary mechanisms in IBD pathogenesis. Thus, innovative therapy strategies based on epithelial barrier function restoration are currently being investigated and tested in chronic intestinal inflammation. In physiological conditions, the tightness of the epithelial barrier is warranted by a complex and highly regulated epithelial cell turnover, as well as by the intimate intercellular communication between adjacent epithelial cells. Both mechanisms are highly dependent of an adequate cytoskeleton network within the cell. Small GTPases belonging to the Ras superfamily, and especially Rho proteins, are key molecular switches playing an important role in cytoskeleton regulation. Accordingly, we could recently demonstrate that epithelial prenylation is essential for epithelial integrity and intestinal homeostasis in vivo. In summary, we think that the identification of molecular mechanisms regulating prenylation and the subsequent function of Rho proteins might contribute to the current knowledge on the association between breakdown of epithelial integrity and pathogenesis of IBD. The aim of this project is the identification of single small GTPases as key players in intestinal epithelial integrity in vivo, as well as the description of the molecular mechanisms behind. In the future, this knowledge could be exploited in epithelial restitution strategies for the benefit of IBD patients.
Prenylation and prenylated proteins in the context of colorectal cancer
Representing one of the major causes of death in developed countries, colorectal cancer appears as an inflammation-dependent complication in IBD patients. Patients suffering from chronic intestinal inflammation present increased risk of developing colon tumors. Inflammation-associated epithelial stress is postulated as one of the main drivers of tumorigenesis in IBD. Interestingly, prenylation and small GTPases (Ras, as main example) has been also associated with tumor development. Together, we are investigating the in vivo association between alteration of prenylation and/or small GTPase function and the development of colorectal cancer in the context of chronic intestinal inflammation.
Identification of prenylome in the context of Inflammatory Bowel Disease
Based on the role of prenylation and prenylation targets for intestinal epithelial cell biology in the context of IBD, we are interested in the description of prenylated protein profile (prenylome) in different cell types within the gut mucosa. Therefore, we are developing innovative methods for the identification, separation and quantification of prenylated proteins. We will then take advantage of these techniques to identify disease-specific alterations of the prenylome in human IBD and Colorectal Cancer.