The role of PARP1 in the pathogenesis of fibrotic disorders

PARP1 在纤维化疾病发病机制中的作用

• 批准号: 271929393
• 负责人: Dr. Clara Dees
• 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: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/271929393?language=en
• 关键词: role; PARP1; pathogenesis; fibrotic; disorders

Systemic sclerosis (SSc) is a chronic fibrotic autoimmune disease with unknown etiology, which affects the skin and several internal organs. The most obvious histopathological hallmark of SSc is an aberrant accumulation of extracellular matrix proteins synthesized and released by activated fibroblasts, which destroys the physiological tissue architecture and impairs the function of the affected organs. The mechanisms leading to the chronic activation of fibroblasts are only partially understood to date. Therefore, the present project aims to analyze the role of PARP1 in fibroblast activation and fibrogenesis. Deregulation of PARP proteins has already been implicated in several human diseases like tumors, cardiovascular and neurological disorders as well as organ fibrosis such as lung or kidney fibrosis, suggesting that this protein family may be also of interest for research in SSc and skin fibrosis. The expression of PARP1 is strongly downregulated in cultured fibroblasts and in the skin of SSc patients, which can also be induced by TGFbeta, an accepted key-player in fibrogenesis. Consistently, blockade of PARP1 in vivo potently aggravates bleomycin-induced dermal fibrosis. In addition, knockout of PARP1 exacerbates the activation of the TGFbeta-Smad signalling cascade.Using both pharmacological and genetic approaches, this project aims to characterize the role of PARP1 in skin fibrosis in vitro and in different animal models in vivo. In addition, the mechanism by which PARP1 is repressed in SSc patients and by TGFbeta will be evaluated. In order to evaluate whether the repression of PARP1 is caused by epigenetic mechanisms like DNA hypermethylation and histone deacetylation, selective antagonists of histone deacetylases and DNA methyltransferases as well as siRNA-mediated knockdown and expression vectors will be employed.

系统性硬化症(SSC)是一种病因不明的慢性纤维性自身免疫性疾病，影响皮肤和多个内脏器官。SSC最明显的组织病理学特征是由激活的成纤维细胞合成和释放的细胞外基质蛋白异常聚集，破坏生理组织结构，损害受影响器官的功能。导致成纤维细胞慢性激活的机制到目前为止还只有部分了解。因此，本项目旨在分析PARP1在成纤维细胞激活和纤维化形成中的作用。PARP蛋白的解除调控已经被认为与多种人类疾病有关，如肿瘤、心血管和神经疾病，以及器官纤维化，如肺或肾纤维化，这表明该蛋白家族可能也是SSc和皮肤纤维化研究的兴趣所在。在培养的成纤维细胞和SSC患者的皮肤中，PARP1的表达强烈下调，这也可以被公认的纤维化形成中的关键角色TGFbeta诱导。一直以来，体内阻断PARP1会有效地加重博莱霉素诱导的皮肤纤维化。此外，PARP1基因的敲除加剧了转化生长因子β-Smad信号通路的激活。本项目旨在利用药理学和遗传学方法，在体外和体内不同的动物模型中表征PARP1在皮肤纤维化中的作用。此外，PARP1在SSC患者中被抑制的机制和TGFbeta被抑制的机制也将被评估。为了评估PARP1的抑制是否是由DNA高甲基化和组蛋白去乙酰化等表观遗传机制引起的，将使用组蛋白去乙酰酶和DNA甲基转移酶的选择性拮抗剂以及siRNA介导的基因敲除和表达载体。

项目成果

Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators

蛋白激酶 G 是 sGC 刺激剂抗纤维化作用的重要下游介质

• DOI: 10.1136/annrheumdis-2017-212489
• 发表时间: 2018
• 期刊: Annals of the Rheumatic Diseases
• 影响因子: 27.4
• 作者: Matei AE;Beyer C;Györfi AH;Soare A;Chen CW;Dees C;Bergmann C;Ramming A;Friebe A;Hofmann F;Distler O;Schett G;Distler JHW
• 通讯作者: Distler JHW