Functional characterization of prenylated Rho proteins in the pathogenesis of Inflammatory bowel diseases

异戊二烯化 Rho 蛋白在炎症性肠病发病机制中的功能表征

• 批准号: 273811926
• 负责人: Privatdozentin Dr. Imke Atreya, 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: Clinical Research Units
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/273811926?language=en
• 关键词: Functional; characterization; prenylated; Rho; proteins

Our recent data identified prenylated Rho-A in intestinal epithelial cells (lECs) as a crucial player in gut homeostasis. Accordingly, a spontaneous development of mild intestinal inflammation could be observed in mice lacking Rho-A in lECs. Further supported by decreased expression levels of the prenylation-catalyzing enzyme GGTase-lß and a cytosolic redistribution of Rho-A In lECs of IBD patients, our findings strongly suggest prenylated Rho-A as an important target protein in IBD pathogenesis. In the proposed project we therefore aim at the functional characterization of Rho-A in lEC biology and in the context of chronic gut inflammation. In particular, we will take advantage of genetically engineered mouse strains in order to investigate the impact of lEC-specific Rho-A deficiency on the course of chronic colitis. Analyzing the activation profile and downstream signaling cascades of Rho-A under steady state conditions as well as in the context of mucosal inflammation in murine and human IBD tissue samples will allow us to define its exact role and pathogenic relevance in lEC function. Furthermore, our project will deal with the role of epithelial protein prenylation in IBD. In particular, we will focus on the identification of new prenylated target proteins with potential relevance for IBD, characterized by an altered prenylation status under inflammatory conditions, which would represent interesting candidate proteins for intensified translational investigations.

我们最近的数据确定了肠上皮细胞（IEC）中的异戊二烯化Rho-A是肠道稳态的关键参与者。因此，在lEC中缺乏Rho-A的小鼠中可以观察到轻度肠道炎症的自发发展。进一步通过降低异戊二烯化催化酶GGT酶-γ的表达水平和Rho-A在IBD患者的lEC中的胞质再分布来支持，我们的研究结果强烈表明异戊二烯化Rho-A是IBD发病机制中的重要靶蛋白。因此，在所提出的项目中，我们的目标是Rho-A在lEC生物学和慢性肠道炎症背景下的功能表征。特别地，我们将利用基因工程小鼠品系来研究lEC特异性Rho-A缺乏对慢性结肠炎病程的影响。在稳态条件下以及在小鼠和人IBD组织样本的粘膜炎症背景下分析Rho-A的激活谱和下游信号级联反应将使我们能够定义其在lEC功能中的确切作用和致病相关性。此外，我们的项目将处理上皮蛋白异戊二烯化在IBD中的作用。特别是，我们将专注于识别新的异戊二烯化的靶蛋白与IBD的潜在相关性，其特征在于在炎症条件下改变的异戊二烯化状态，这将代表感兴趣的候选蛋白，用于强化翻译研究。