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

患有炎症性肠病(IBD)的患者由于反复发作的肠道炎症，生活质量急剧下降。我们对IBD发病机制的了解仍然不完全。因此，目前的治疗方法是基于使用非特异性药物，这些药物往往伴随着不良的副作用。进一步了解IBD发病机制的需要证明了目前该领域密集的科学努力是合理的。基础研究将有助于确定未来可以开发的新的IBD治疗目标。此外，提高IBD患者的生活质量将反过来对社会和经济产生丰硕的影响。人体不断地暴露在环境毒剂的威胁下。在这种情况下，肠道在防御有害外来物质方面发挥着至关重要的作用。复杂的肠道结构和几种特殊细胞类型的共存使一种受到严格调控的屏障功能减弱了微生物的入侵。特别是，肠道的最外层，即肠道上皮，建立了对抗环境的最佳物理和免疫屏障。近年来，上皮屏障功能的调节与IBD的发生发展密切相关。针对上皮修复的新型治疗药物在IBD患者中显示出良好的效果。因此，我认为肠道中调节上皮屏障功能的分子的识别可能有助于更好地临床治疗IBD。在这个框架中，我们最近发现肠上皮细胞(IECS)内的戊烯基化是维持组织完整性的关键机制。预基化是一种翻译后修饰，包括将脂类部分附着到蛋白质结构上，导致目标蛋白质的物理化学性质和功能发生变化。作为分子开关，Rho蛋白以前烯基化蛋白的形式出现，可能有助于上皮的完整性。根据我的初步数据，我认为在Rho蛋白中，rac1在上皮完整性方面是一个有吸引力的候选蛋白。本项目的主要目的是在活体内表征rac1控制肠上皮功能的分子机制。此外，我还将在体内评估Rho家族不同成员在IECS中对rac1功能的调节以及功能的相互作用。最终目的是为未来基于GTPase的治疗策略创造一个科学的支柱，以逆转增加的上皮通透性。因此，我还将致力于在肠道炎症的背景下将主要发现转化为人类系统。总之，我相信本项目将有助于上皮完整性领域的基础和翻译研究，并有助于确定上皮源性肠道病理的新治疗策略，如IBD。

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.