Pharmacological Blockade of Canonical Wnt Signaling for the Treatment of Systemic Sclerosis and Other Fibrotic Diseases

药理学阻断经典 Wnt 信号转导治疗系统性硬化症和其他纤维化疾病

• 批准号: 227045208
• 负责人: Dr. Christian Beyer
• 金额: --
• 依托单位: Medizinische Klinik 3 - Rheumatologie und Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/227045208?language=en
• 关键词: Pharmacological; Blockade; Canonical; Wnt; Signaling

Fibrosis results from the excessive accumulation of extracellular matrix, which leads to the disruption of the physiologic tissue architecture and failure of the affected organs. In systemic sclerosis (SSc), a prototypical fibrotic disease, fibrosis of the skin, lungs, gastrointestinal tract and the cardiovascular system leads to high morbidity and mortality among patients. Canonical Wnt signaling has a central role in the development of fibrosis. We have shown that overexpression of Wnt-1 and Wnt-10b leads to accumulation of beta-catenin and increased transcription of pro-fibrotic target genes in SSc. The development of massive fibrosis of the skin and internal organs upon overexpression of Wnt-10b or stabilization of beta-catenin in fibroblasts further highlights the crucial role of canonical Wnt signaling in fibrogenesis. By contrast, fibroblast-specific deletion of beta-catenin significantly inhibits experimental dermal fibrosis suggesting a therapeutic potential of canonical Wnt signaling. The canonical Wnt signaling pathway offers several therapeutic targets that we will study in the proposed project. This includes inhibition of Wnt secretion by porcupine inhibitors, stabilization of Axin via Tankyrase inhibitors, inhibition of beta-catenin-cofactor-binding and blockade of beta-catenin-dependent transcription of target genes. The major goal of this pre-clinical project is selecting potent and tolerable therapies to block pro-fibrotic Wnt signaling in future clinical studies. We will test both the potency and tolerability of the above-mentioned therapeutic strategies in in vitro- and in vivo-models for different clinical scenarios, including (1) treatment of different fibrotic diseases (SSc, lung fibrosis, chronic Graft-versus-Host Disease), (2) early and inflammation-dependent stages as well as late and non-inflammatory stages of fibrotic diseases, and (3) prevention and treatment of fibrosis. Using genetic knock-out models as well as pharmacological inhibitors we will analyze the molecular signaling pathways in detail. As pharmacological inhibitors are available for all of the selected Wnt targets, with some of them having already entered clinical trials in oncology, our project has a great translational potential. Potent anti-fibrotic therapies to treat SSc and other fibrotic diseases are not available in clinical routine. Because of the high morbidity and mortality among patients suffering from these diseases, however, the clinical need is tremendous. Our comprehensive project shall path the way for clinical studies with Wnt inhibitors to treat fibrosis.

纤维化是由于细胞外基质的过度积累，导致生理组织结构的破坏和受影响器官的衰竭。在系统性硬化症（SSc）中，一种典型的纤维化疾病，皮肤、肺、胃肠道和心血管系统的纤维化导致患者的高发病率和死亡率。 经典Wnt信号传导在纤维化的发展中具有核心作用。我们已经表明，Wnt-1和Wnt-10 b的过表达导致β-连环蛋白的积累和SSc中促纤维化靶基因的转录增加。在成纤维细胞中Wnt-10 b过表达或β-连环蛋白稳定化后皮肤和内脏的大量纤维化的发展进一步突出了经典Wnt信号传导在纤维发生中的关键作用。相比之下，成纤维细胞特异性β-连环蛋白缺失显著抑制实验性真皮纤维化，表明经典Wnt信号传导的治疗潜力。 经典的Wnt信号通路提供了几个治疗靶点，我们将在拟议的项目中进行研究。这包括通过豪猪抑制剂抑制Wnt分泌，通过端锚聚合酶抑制剂稳定Axin，抑制β-连环蛋白-辅因子结合和阻断靶基因的β-连环蛋白依赖性转录。 该临床前项目的主要目标是在未来的临床研究中选择有效且可耐受的疗法来阻断促纤维化Wnt信号传导。我们将在体外和体内模型中测试上述治疗策略对于不同临床情况的效力和耐受性，包括（1）治疗不同的纤维化疾病（SSc、肺纤维化、慢性移植物抗宿主病），（2）纤维化疾病的早期和炎症依赖性阶段以及晚期和非炎症阶段，和（3）预防和治疗纤维化。使用基因敲除模型以及药理学抑制剂，我们将详细分析分子信号通路。由于药理学抑制剂可用于所有选定的Wnt靶点，其中一些已经进入肿瘤学临床试验，因此我们的项目具有很大的转化潜力。 治疗SSc和其他纤维化疾病的有效抗纤维化疗法在临床常规中不可用。然而，由于患有这些疾病的患者的高发病率和死亡率，临床需求是巨大的。我们的综合项目将为Wnt抑制剂治疗纤维化的临床研究开辟道路。