Molecular mechanisms of Rac1-mediated regulation of epithelial integrity in the inflamed gut

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Patients suffering from Inflammatory Bowel Disease (IBD) experience a dramatic loss of quality of life, due to recurrent episodes of gut inflammation. Our understanding of the mechanism underlying IBD still remains incomplete. Hence, current therapy is based on the use of unspecific drugs which often are accompanied by undesirable side effects. The need of further understanding of IBD pathogenesis justifies the current intensive scientific effort in the field. Basic research would aid to identify new IBD therapy targets which could be exploited in the future. Additionally, improving the life quality of IBD patients would in turn have a fruitful impact on Society and Economy. The human body is continuously exposed to the threat of environmental agents. In this context, the gut plays an essential role for the defence against harmful foreign substances. The complex gut structure and the coexistence of several specialized cell types enable a tightly regulated barrier function which impairs the invasion of microorganisms. In particular, the most external layer of the gut, the intestinal epithelium, builds up an optimal physical and immune barrier against the environment. Recently, epithelial barrier function regulation has been associated to IBD development. Novel therapy agents aiming at epithelial restoration show promising results in IBD patients. Thus, I believe that the identification of molecules regulating epithelial barrier function in the gut might contribute to a better clinical management of IBD. In this framework, we recently identified prenylation within Intestinal Epithelial Cells (IECs) as a key mechanism for the maintenance of tissue integrity. Prenylation is a post-translational modification consisting of the attachment of a lipid moiety to the protein structure, resulting in changes in physicochemical properties and function of target proteins. As molecular switches, Rho proteins appear as prenylated proteins which could contribute to epithelial integrity. Based on my preliminary data, I assume that among Rho proteins, Rac1 is an attractive candidate to be exploited in the context of epithelial integrity. The main aim of this project is the characterization of the molecular mechanism by which Rac1 controls function of intestinal epithelium in vivo. Furthermore, I will assess the regulation of Rac1 function, as well as the functional interplay between different members of the Rho family within IECs in vivo. The ultimate aim is to create a scientific backbone for future GTPase-based therapy strategies to reverse increased epithelial permeability. Therefore, I will also aim at the translation of major findings into the human system in the context of intestinal inflammation. Together, I believe that the present project will contribute to the basic and translational research in the field of epithelial integrity and to the identification of novel therapy strategies for epithelial-derived gut pathology, such as IBD.