Role of Epithelial Cell Death for Re-Establishment of the Gut Barrier During Resolution of Intestinal Inflammation

上皮细胞死亡在肠道炎症消退过程中重建肠道屏障的作用

• 批准号: 536563567
• 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/536563567?language=en
• 关键词: Role; Epithelial; Cell; Death; Re

Chronic intestinal inflammation is driven by a vicious cycle of epithelial cell death leading to barrier dysfunction, microbial translocation and excessive immune cell activation triggering more epithelial cell death. Conversely, resolution of intestinal inflammation is associated with epithelial restitution and restoration of robust barrier function in an attempt to break this vicious cycle. The mechanisms by which the epithelial barrier is restored in the presence of a cytotoxic inflammatory environment during an inflammatory flare of IBD are currently unknown. We have previously shown that dysregulated necroptosis is a driver of chronic intestinal inflammation. More recently, we have shown that the lipid mediator prostaglandin E2 (PGE2), via binding to the EP4 receptor on IEC, is able to induce resolution of intestinal inflammation by suppressing RIPK3-MLKL-induced IEC necroptosis in an inflammatory environment. Strikingly, we have introduced a novel EP4 agonist with therapeutic efficacy in preclinical models and demonstrated a beneficial outcome of high EP4 expression in inflammatory bowel disease patients. In the proposed project, we will continue in this vein, with a focus on unravelling the molecular mechanisms of EP4-mediated resolution of inflammation and the development and evaluation of novel EP4 agonism-based therapeutic approaches. Accordingly, we aim to delineate EP4-dependent barrier protection at the molecular level by deciphering the link between the prostanoid signalling pathway in IECs and necrosome formation and the influence of pro- and anti-inflammatory pathways on this signalling hub, taking advantage of inducible EP4-IEC-specific conditional knockout mice. Since EP4 receptor signalling induces resolution of intestinal inflammation, we aim to develop a gut-tropic EP4 receptor agonist. To achieve this, we will evaluate candidate molecules for efficacy and gut specificity in vivo. In addition, our unpublished data show that PGJ2 blocks necroptosis induction in IECs in addition to PGE2. We will therefore investigate whether PGJ2 is similarly efficient or even complementary to PGE2 in promoting resolution of inflammation, and we will elucidate the cellular source, receptor usage and downstream signalling of these molecules in mediating the protective effects against pathological cell death in an inflammatory context. In summary, our project aims to establish specific prostanoids as key molecules in breaking the vicious cycle of chronic inflammation, epithelial cell death and barrier dysfunction in the gut. We are confident that the proposed project will lead to new insights into the resolution of IBD and new strategies for effective therapies for affected patients.

慢性肠道炎症是由上皮细胞死亡导致屏障功能障碍、微生物易位和过度免疫细胞活化的恶性循环驱动的，从而引发更多的上皮细胞死亡。相反，肠道炎症的消退与上皮恢复和恢复强大的屏障功能有关，试图打破这种恶性循环。目前尚不清楚IBD炎症发作期间在细胞毒性炎症环境存在下恢复上皮屏障的机制。我们先前已经表明，失调的坏死性凋亡是慢性肠道炎症的驱动因素。最近，我们已经表明，脂质介质前列腺素E2（PGE 2），通过结合到IEC上的EP 4受体，能够通过抑制RIPK 3-MLKL诱导的IEC坏死性凋亡在炎症环境中诱导肠道炎症的解决。引人注目的是，我们已经引入了一种新的EP 4激动剂，在临床前模型中具有治疗效果，并证明了炎症性肠病患者中EP 4高表达的有益结果。在拟议的项目中，我们将继续在这方面，重点是解开EP 4介导的炎症消退的分子机制，并开发和评估新的基于EP 4激动剂的治疗方法。因此，我们的目标是描绘EP 4依赖性屏障保护在分子水平上，通过破译前列腺素类信号通路在IEC和坏死体形成和促炎和抗炎通路对这个信号枢纽的影响之间的联系，利用诱导型EP 4-IEC特异性条件性基因敲除小鼠。由于EP 4受体信号传导诱导肠道炎症的消退，我们的目标是开发肠嗜性EP 4受体激动剂。为了实现这一目标，我们将评估候选分子的体内功效和肠道特异性。此外，我们未发表的数据表明，PGJ 2除了PGE 2外，还能阻断IEC中的坏死性凋亡诱导。因此，我们将研究PGJ 2是否同样有效，甚至补充PGE 2在促进炎症的解决，我们将阐明这些分子的细胞来源，受体的使用和下游信号传导介导的保护作用，对病理性细胞死亡的炎症背景。总之，我们的项目旨在建立特定的前列腺素作为打破肠道慢性炎症，上皮细胞死亡和屏障功能障碍的恶性循环的关键分子。我们相信，拟议的项目将为IBD的解决带来新的见解，并为受影响的患者提供有效治疗的新策略。