Targeted inhibition of tyrosine-protein phosphatase SHP2 as a potential approach for the treatment of fibrosis

靶向抑制酪氨酸蛋白磷酸酶 SHP2 作为治疗纤维化的潜在方法

• 批准号: 392500703
• 负责人: Professor Dr. Jörg Hans Wilhelm Distler
• 金额: --
• 依托单位: Klinik für Rheumatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/392500703?language=en
• 关键词: Targeted; inhibition; tyrosine; protein; phosphatase

Fibrotic diseases contribute to up to 45% of deaths in the developed world and impose a major socioeconomic burden on modern societies. Systemic sclerosis (SSc) is a prototypical idiopathic systemic fibrosing disease with a high morbidity and mortality rate. As for other fibrotic diseases, SSc is characterized by an accumulation of myofibroblasts, which release excessive amounts of extracellular matrix. Although key factors of fibroblast activation such as transforming growth factor-beta (TGFbeta) have been identified, the molecular mechanisms underlying the persistent activation of myofibroblasts in fibrotic disease are incompletely understood and effective targeted therapies are not available for most fibrotic diseases. We provide first evidence that the tyrosine phosphatase SHP2 might play a central role in the pathogenesis of fibrotic diseases such as SSc. Inactivation of SHP2 signaling prevents the TGF-bata mediated activation of JAK2 / STAT3 signaling to prevent myofibroblast differentiation and collagen release. Inactivation of SHP2 by genetic or pharmacologic approaches inhibits TGF-beta-dependent fibroblast activation and ameliorates experimental fibrosis. We aim to further characterize the molecular mechanisms of SHP2 signaling in fibrotic diseases and to validate the SHP2 as a therapeutic target in fibrotic diseases. We plan to further analyze the anti-fibrotic effects of fibroblast-specific knockdown of SHP2 in complementary mouse models of fibrosis, to identify the molecular mechanisms underlying the differential expression of SHP2 in SSc, to characterize the regulation of JAK2 / STAT3 signaling by SHP2 and to evaluate the anti-fibrotic effects of pharmacologic inhibition of SHP2. Our findings may have translational implications as small molecule inhibitors of SHP2 are currently evaluated for clinical use in cancer.

纤维化疾病导致发达国家高达45%的死亡，并对现代社会造成重大的社会经济负担。系统性硬化症（SystemicSclerosis，SSc）是一种典型的特发性系统性纤维化疾病，具有较高的发病率和死亡率。至于其他纤维化疾病，SSc的特征在于肌成纤维细胞的积累，其释放过量的细胞外基质。虽然成纤维细胞活化的关键因素如转化生长因子-β（TGF β）已被确定，但纤维化疾病中肌成纤维细胞持续活化的分子机制尚未完全了解，大多数纤维化疾病无法获得有效的靶向治疗。我们提供的第一个证据表明，酪氨酸磷酸酶SHP 2可能在纤维化疾病，如SSc的发病机制中发挥核心作用。SHP 2信号传导的失活阻止了TGF-β介导的JAK 2/STAT 3信号传导的活化，从而阻止了肌成纤维细胞分化和胶原蛋白释放。通过遗传或药理学方法灭活SHP 2抑制TGF-β依赖性成纤维细胞活化并改善实验性纤维化。我们的目标是进一步表征SHP 2信号转导在纤维化疾病中的分子机制，并验证SHP 2作为纤维化疾病的治疗靶点。我们计划进一步分析成纤维细胞特异性敲低SHP 2在互补小鼠纤维化模型中的抗纤维化作用，以确定SSc中SHP 2差异表达的分子机制，表征SHP 2对JAK 2/STAT 3信号传导的调节，并评估SHP 2药理学抑制的抗纤维化作用。我们的研究结果可能具有翻译意义，因为目前正在评估SHP 2的小分子抑制剂在癌症中的临床应用。