Characterization and function of OPA1 in intestinal epithelial homeostasis and the pathogenesis of inflammatory bowel disease

OPA1 在肠上皮稳态中的特征和功能以及炎症性肠病的发病机制

• 批准号: 510624836
• 负责人: Professor Dr. Christoph Becker
• 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
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/510624836?language=en
• 关键词: Characterization; function; OPA1; intestinal; epithelial

Inflammatory Bowel Diseases (IBD, Crohn’s disease and ulcerative colitis) are common inflammatory diseases affecting more than 400.000 patients in Germany alone. Since the cause of IBD is largely unknown, there is currently no causative therapy available for IBD patients. Our previous studies provided functional evidence that a primary defect in cell death regulation of the intestinal epithelium can cause barrier dysfunction, microbial translocation into the bowel wall and chronic gut inflammation with similar features as seen in IBD patients. We also demonstrated that epithelial cells death pathways are tightly regulated by both signals from the microbiome and the immune system in the steady state gut. Mitochondria play a crucial role in cell death regulation and the dynamics of mitochondrial fission and fusion in cells has recently been shown to be connected to immune and tissue homeostasis. Although functional data regarding the role of these processes in gut immune homeostasis and IBD are sparse, our unpublished data imply an important role for OPA1, a key regulator of mitochondrial fusion, for intestinal immune homeostasis and the pathogenesis of IBD. Our preliminary data provide evidence of mitochondrial alterations in epithelial cells of IBD patients. Moreover, OPA1 was found to be downregulated in both experimental colitis in mice and human IBD. In support of an important functional role of OPA1, newly generated mice specifically deficient in OPA1 in the intestinal epithelium spontaneously developed chronic intestinal inflammation associated with increased epithelial cell death. Based on these preliminary data, we hypothesize that OPA1 has a profound impact on the development of intestinal inflammation and that modulating OPA1 and mitochondrial dynamics might have therapeutic potential in IBD. To evaluate this hypothesis and to decipher the consequences of diminished OPA1 expression on mitochondrial dynamics, epithelial cell homeostasis and intestinal inflammation, we aim to study the functional role of epithelial OPA1 for intestinal tissue homeostasis and gut inflammation using mice with altered OPA1 expression. Further, we will focus on revealing the functional role of OPA1 for epithelial barrier functions and assess changes on the level of mitochondria caused by OPA1 deficiency. Finally, we will evaluate the impact of OPA1 on the development and progression of human IBD and further explore the potential therapeutic value of preclinical modulation of OPA1 expression and function. Our long-term goal is to evaluate the innovative concept that a dysfunction in mitochondrial dynamics is a driver of IBD pathogenesis.

炎症性肠病(炎症性肠病、克罗恩病和溃疡性结肠炎)是常见的炎症性疾病，仅在德国就有400.000多名患者受到影响。由于IBD的病因在很大程度上是未知的，目前还没有针对IBD患者的病因治疗方法。我们以前的研究提供了功能性证据，表明肠上皮细胞死亡调控的初级缺陷可导致屏障功能障碍、微生物移位到肠壁和慢性肠炎，这些特征与IBD患者相似。我们还证明，在稳定状态的肠道中，上皮细胞死亡途径受到微生物组和免疫系统信号的严格调控。线粒体在细胞死亡调节中起着至关重要的作用，细胞内线粒体分裂和融合的动力学最近被证明与免疫和组织动态平衡有关。尽管这些过程在肠道免疫动态平衡和IBD中的作用的功能数据很少，但我们未发表的数据表明OPA1在肠道免疫动态平衡和IBD的发病机制中发挥着重要作用。OPA1是线粒体融合的关键调节因子。我们的初步数据提供了IBD患者上皮细胞线粒体改变的证据。此外，OPA1在小鼠实验性结肠炎和人类IBD中都被发现下调。为了支持OPA1的重要功能作用，新生的小鼠在肠上皮中特异性地缺乏OPA1，自发地发展成与增加的上皮细胞死亡相关的慢性肠炎。基于这些初步数据，我们假设OPA1对肠道炎症的发展具有深远的影响，调控OPA1和线粒体动力学可能在IBD中具有治疗潜力。为了评估这一假说，并破译OPA1表达减少对线粒体动力学、上皮细胞稳态和肠道炎症的影响，我们的目标是利用OPA1表达改变的小鼠来研究OPA1在肠道组织稳态和肠道炎症中的功能作用。此外，我们将重点揭示OPA1在上皮屏障功能中的功能作用，并评估OPA1缺乏引起的线粒体水平的变化。最后，我们将评估OPA1在人类IBD发生发展中的作用，并进一步探讨临床前调控OPA1表达和功能的潜在治疗价值。我们的长期目标是评估这一创新概念，即线粒体动力学功能障碍是IBD发病的驱动因素。