Analysis of the molecular mode of action of Cyclosporin A in inflammatory bowel disease

环孢素A在炎症性肠病中的分子作用模式分析

• 批准号: 206965563
• 负责人: Privatdozent Dr. Benno Weigmann
• 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: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/206965563?language=en
• 关键词: Analysis; molecular; mode; action; Cyclosporin

While cyclosporine A therapy in Crohn's disease is of minor relevance. It has a long standing history in the treatment of ulcerative colitis especially in the setting of steroid-refractory associated with massive exacerbation as well as when there are contraindications for corticosteroids. Although the initial rate of treatment success in response to cyclosporine A is high, in long term a significant drop of the treatment response can be observed, resulting in the fact that a colectomy in about half the cases cannot be prevented. Therefore it is of critical relevance to find predictive markers for a positive treatment response to cyclosporine A, with the aim to protect IBD patients from unnecessary side effects and treatment hesitation. The aim of this project is therefore to characterize the cellular and molecular mechanisms involved in the action of cyclosporine in order to identify critical markers that are suited to predict a positive outcome upon cyclosporine application. In the present work, both Itk and NFATc1 were identified as predictive mariners of cyclosporine A therapy. In a next set of experiments, these factors will be evaluated with regard to new therapeutic strategies in human inflammatory bowel disease. Here, we propose to provide novel mechanistic insights into the mode of action of cyclosporine A by the use of well-established models of ulcerative colitis in the murine system and in correlation with inflammatory parameters. In addition, the project aims to fill a critical gap in the need to identify factors indicating a positive response upon cyclosporine A treatment in patients with inflammatory bowel disease with the overall mission to support the development of tailored personalized immune intervention strategies for the treatment of inflammatory bowel disease in the future.

而环孢素A治疗克罗恩病的相关性较小。它在溃疡性结肠炎的治疗中有着悠久的历史，特别是在类固醇难治性溃疡性结肠炎伴大面积加重以及糖皮质激素禁忌症的情况下。尽管对环孢霉素A的初始治疗成功率很高，但从长期来看，可以观察到治疗反应的显著下降，导致约一半病例的结肠切除术无法预防。因此，找到对环孢菌素A的阳性治疗反应的预测标志物至关重要，目的是保护IBD患者免受不必要的副作用和治疗犹豫。因此，本项目的目的是表征参与环孢素作用的细胞和分子机制，以确定适合预测环孢素应用后阳性结果的关键标志物。在目前的工作中，Itk和NFATc1都被确定为环孢素A治疗的预测水手。在下一组实验中，将评估这些因素对人类炎症性肠病的新治疗策略的影响。在这里，我们建议提供新的机制的见解环孢素A的作用模式，通过使用完善的模型，溃疡性结肠炎的小鼠系统和炎症参数的相关性。此外，该项目旨在填补一个关键的空白，即需要确定炎症性肠病患者接受环孢素A治疗后出现积极反应的因素，其总体使命是支持开发定制的个性化免疫干预策略，用于未来炎症性肠病的治疗。