炎症致硬皮病纤维化的分子机制

项目名称： 炎症致硬皮病纤维化的分子机制

项目编号： No.81470254

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王久存

作者单位： 复旦大学

项目金额： 75万元

中文摘要： 硬皮病是以皮肤及内脏纤维化为特征的自身免疫性疾病，炎症是硬皮病发展的初期特征，是引起硬皮病纤维化的关键因素，但目前对炎症导致硬皮病纤维化的机制知之甚少。申请人前期研究发现，促炎因子S100A9在硬皮病患者中的高表达与硬皮病肺纤维化正相关，可单独或协同低剂量博莱霉素引起小鼠皮肤炎症和纤维化反应。此外，具抗炎作用的小分子药物白藜芦醇及丹酚酸B均可阻断硬皮病小鼠中纤维化的发生、发展，并显著缓解其皮肤和肺纤维化。为揭示炎症导致硬皮病纤维化的分子机制，本项目拟构建不同时间点和不同浓度的博莱霉素诱导的小鼠模型以模拟硬皮病不同发病时期的表型，比较其目标组织中基因的表达差异，筛选导致纤维化的关键炎症成分，并在处于不同时期的硬皮病患者的临床样本中进行验证，进一步利用体内体外实验研究其作用机理，发现炎症对胶原蛋白产生的调控机制，揭示炎症因子在硬皮病纤维化发生中的作用，为开发抗纤维化药物奠定基础。

中文关键词： 炎症；硬皮病纤维化；胶原蛋白；差异表达基因；炎症因子

英文摘要： Scleroderma (syetemic sclerosis, SSc) is an autoimmune disease characterized by the fibrosis of skin and internal organs. Inflammation is the main feature of scleroderma at the early stage and plays critical roles in the fibrosis of scleroderma. Our previous study revealed that the proinflammatory factor S100A9 could induce mouce skin inflammation and fibrosis. The elevated expression of S100A9 was positively correlated with disease severity and serological abnormalities in SSc patients. Furthermore, the anti-inflammatory compounds resveratrol and salvianolic acid B can reduce the formation of collagen and significantily ameliorate the pulmonary fibrosis in the scleroderma-associated lung fibrosis mouse model. The goal of this proposal is to identify the key inflammaory mediators partcipanted in the fibrogenesis of scleroderma-associated fibrosis and determine the molecular mechanisms of inflammation induced fibrosis. We will simulate different phases of scleroderma-associated skin fibrosis and scleroderma-associated pulmonary fibrosis in scleroderma mice models. Genomewide study at transcriptional level will be conducted to identify the key inflammatory factors involed in the modulation of collagen prodution. Those factors will be validated by using clinical samples from scleroderma patients at different disease stages. The molecular mechanisms of inflammatory mediators involved in the occurrence and development of scleroderma fibrosis will be investigated. These studies will lead to a better understanding of the role of inflammation in the development of scleroderma-associated fibrosis, as well as specific targets for therapeutic interventions against fibrosis.

英文关键词： Inflammation;Scleroderma-associated fibrosis;Collagen proteins;Differentially expressed genes;Inflammatory cytokines