Research Group: Prenylated proteins and Cytoskeleton dynamics in the gut mucosa
Projects
Research topic
Inflammatory Bowel Diseases (IBD) describe a group of disorders characterized by a chronic and relapsing inflammation of the gastrointestinal tract. Crohn’s disease (CD) and ulcerative colitis (UC) represent the two main forms of IBD; and they show an increasing incidence and high prevalence in Europe and North America. Patients suffering from IBD develop clinical symptoms such as diarrhea, abdominal pain, rectal bleeding, fever, weight loss, fatigue and a considerable loss of life quality. Despite an intensive scientific effort during the last decades, our understanding of the molecular pathogenesis underlying inflammatory bowel diseases still remains incomplete and current drug therapy therefore often aims at an unspecific down-regulation of the overwhelming immune response. Due to a significant number of therapy-refractory patients and undesirable side effects of pharmacotherapy, there is a well-recognized need for the identification of innovative and disease-specific therapeutic target molecules within the inflamed tissue of IBD patients.
Chronic and relapsing inflammation of the gastrointestinal tract in IBD patients is pathogenetically based on a complex interaction between genetic, immunological and environmental factors. In this context, the intestinal mucosa represents a complex system in which immune and non-immune cells work together in a tightly regulated manner. In this system, the intestinal epithelium builds up a first physical barrier facing the environment and 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.
Epithelial integrity in the gut has to be tightly regulated 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.
Prenylation and prenylated proteins as key player for epithelial integrity
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. The function of Rho GTPases is regulated via lipid post-translational modification, namely prenylation. Interestingly, 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 our research 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. We believe that this knowledge could be exploited in epithelial restitution strategies for the benefit of IBD patients in the future.
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.
Epithelial cell shedding in the gut
Being the last step of the epithelial turnover in the gut, cell shedding or cell extrusion occurs at the villus tip in order to discard old or damaged cells to maintain epithelial cell numbers and the tightness of the intestinal epithelium. We aim at providing a more detailed description of molecular mechanisms driving epithelial cell shedding in the gut. In particular, we are interested in the contribution of physiological/pathological cell shedding and the functional consequence of these phenomena for gut homeostasis. Thereby, we would like to contribute to an improved understanding of intestinal epithelial integrity which contribute to therapy aimed at epithelial restoration in IBD patients.