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

Rac1 介导的炎症肠道上皮完整性调节的分子机制

• 批准号: 389909293
• 负责人: Privatdozentin Dr. Rocío López Posadas, Ph.D.
• 金额: --
• 依托单位: Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/389909293?language=en
• 关键词: Molecular; mechanisms; Rac1; mediated; regulation

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.

由于肠道炎症反复发作，炎症性肠病 (IBD) 患者的生活质量急剧下降。我们对 IBD 潜在机制的理解仍然不完整。因此，目前的治疗基于使用非特异性药物，这些药物常常伴随着不良副作用。进一步了解 IBD 发病机制的需要证明了当前在该领域进行的密集科学努力是合理的。基础研究将有助于确定未来可利用的新 IBD 治疗靶点。此外，改善 IBD 患者的生活质量反过来也会对社会和经济产生富有成效的影响。人体不断受到环境因素的威胁。在这种情况下，肠道在防御有害异物方面发挥着重要作用。复杂的肠道结构和几种特殊细胞类型的共存使得屏障功能受到严格调节，从而削弱微生物的入侵。特别是，肠道的最外层，肠上皮，建立了针对环境的最佳物理和免疫屏障。最近，上皮屏障功能调节与 IBD 的发展有关。针对上皮修复的新型治疗药物在 IBD 患者中显示出有希望的结果。因此，我相信调节肠道上皮屏障功能的分子的鉴定可能有助于更好的 IBD 临床管理。在此框架中，我们最近发现肠上皮细胞（IEC）内的异戊二烯化是维持组织完整性的关键机制。异戊二烯化是一种翻译后修饰，包括将脂质部分附着到蛋白质结构上，导致目标蛋白质的理化性质和功能发生变化。作为分子开关，Rho 蛋白表现为异戊二烯化蛋白，有助于上皮完整性。根据我的初步数据，我认为在 Rho 蛋白中，Rac1 是在上皮完整性方面值得利用的有吸引力的候选者。该项目的主要目的是表征 Rac1 控制体内肠上皮功能的分子机制。此外，我将评估 Rac1 功能的调节，以及体内 IEC 内 Rho 家族不同成员之间的功能相互作用。最终目标是为未来基于 GTP 酶的治疗策略建立科学支柱，以逆转上皮通透性增加。因此，我还将致力于将肠道炎症方面的主要发现转化为人体系统。总之，我相信本项目将有助于上皮完整性领域的基础和转化研究，并有助于确定上皮源性肠道病理学（例如 IBD）的新治疗策略。