The role of PARP1 in the pathogenesis of fibrotic disorders
The role of PARP1 in the pathogenesis of fibrotic disorders
批准号:
271929393
负责人:
Dr. Clara Dees
金额:
$0.0万
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
项目状态:
已结题
起止时间:
2014-12-31 至 2017-12-31
中文摘要
系统性硬化症(SSc)是一种病因不明的慢性纤维化自身免疫性疾病,它影响皮肤和几个内脏器官。SSc最明显的组织病理学标志是由活化的成纤维细胞合成和释放的细胞外基质蛋白的异常积累,其破坏生理组织结构并损害受影响器官的功能。迄今为止,导致成纤维细胞慢性活化的机制仅部分了解。因此,本项目旨在分析PARP 1在成纤维细胞活化和纤维形成中的作用。PARP蛋白的失调已经涉及几种人类疾病,如肿瘤,心血管和神经系统疾病以及器官纤维化,如肺或肾纤维化,这表明该蛋白质家族也可能对SSc和皮肤纤维化的研究感兴趣。PARP 1的表达在培养的成纤维细胞和SSc患者的皮肤中强烈下调,这也可以由TGF β诱导,TGF β是纤维发生中公认的关键因素。因此,体内阻断PARP 1可有效抑制博来霉素诱导的真皮纤维化。此外,敲除PARP 1会加剧TGF β-Smad信号级联的激活,本项目旨在通过药理学和遗传学方法,在体外和不同的动物模型体内表征PARP 1在皮肤纤维化中的作用。此外,还将评估PARP 1在SSc患者中和TGF β抑制的机制。为了评估PARP 1的抑制是否由表观遗传机制如DNA超甲基化和组蛋白脱乙酰化引起,将使用组蛋白脱乙酰化酶和DNA甲基转移酶的选择性拮抗剂以及siRNA介导的敲低和表达载体。
英文摘要
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.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
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
The role of SOCS3 in the pathogenesis of fibrotic disorders
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批准号:413535976
-
项目类别:Research Grants
-
资助金额:$0.0万
-
财政年份:2018
-
负责人:Dr. Clara Dees
-
依托单位:
Regulation of chromatin remodeling by Notch1 in fibrotic disorders
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批准号:467040214
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项目类别:Research Grants
-
资助金额:$0.0万
-
财政年份:--
-
负责人:Dr. Clara Dees
-
依托单位:
国内基金
海外基金
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