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

而环孢菌素A治疗克罗恩病的相关性较小。它在治疗溃疡性结肠炎方面有着悠久的历史，特别是在激素难治性与严重恶化相关的情况下，以及在皮质类固醇有禁忌症的情况下。虽然环孢素A的初始治疗成功率很高，但从长远来看，治疗反应会显著下降，导致大约一半的病例无法预防结肠切除术。因此，为了保护IBD患者免受不必要的副作用和治疗犹豫，寻找环孢素A阳性治疗反应的预测标记物是至关重要的。因此，本项目的目的是表征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的阳性结果的关键标记。在本研究中，ITK和NFATc1均被确认为环孢素A治疗的预测因子。在下一组实验中，这些因素将针对人类炎症性肠病的新治疗策略进行评估。在这里，我们建议通过在小鼠系统中建立溃疡性结肠炎模型并与炎症参数相关联，为环孢素A的作用模式提供新的机制见解。此外，该项目旨在填补在确定表明对炎症性肠病患者的环孢素A治疗有积极反应的因素方面的关键空白，总体使命是支持为未来炎症性肠病的治疗开发定制的个性化免疫干预策略。

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.