HGF上调Nur77表达抑制循环纤维细胞增殖分化的抗心肌纤维化机制研究

Cardiac fibrosis is the key pathophysiological process leading to heart failure following cardiac injury. Cardiac myofibroblasts have previously been shown to play a predominant role in this process. Recently,circulating fibrocyteshave emerged as a major source of myofibroblasts at the sites of injury. An understanding of the regulatory mechanisms of circulating fibrocyte proliferation and differentiation may provide novel therapeutic strategies against cardiac fibrosis. In a recent work we demonstrated that HGF significantly alleviated fibrosis in a mice MI models. In addition, we found that HGF significantly inhibited the expression of Nur77, which reportedly plays a key role in the regulation of fibroblast proliferation and differentiation. In this project, we propose to evaluate the role of HGF/Nur77 pathways in the proliferation and differentiation of circulating fibrocytes by multiple approaches including bioinformatic analysis, luciferase reporter assay, RNA interference, ChIP. Additionally, the role of key genes in the HGF/Nur77 pathways will be explored in cell and animal models. Conceivably, elucidation of the molecular pathways involved in the regulation of proliferation and differentiation in the pathogenesis of cardiac fibrosis may reveal novel therapeutic targets for fibrotic disorders.

心肌纤维化是心肌损伤后向心衰发展进程中的关键步骤，既往研究证实肌纤维母细胞在此过程中起着主导作用。新近的研究表明，经循环归巢至损伤区域的循环纤维细胞是肌纤维母细胞的重要甚至是最主要的来源。因而，研究循环纤维细胞增殖分化的调控机制并据此制定出相应的对策将有助于抗心肌纤维化的疗效。我们在前期研究中发现，肝细胞生长因子（HGF）能通过上调孤核受体Nur77的表达抑制循环纤维细胞的增殖分化。本项目拟以此为基础，采用生物信息学分析、荧光素酶报告基因、RNA干扰、免疫共沉淀等方法对其机制作进一步的研究探讨；此外，我们还将通过相关的细胞学及动物模型实验等评价HGF/Nur77通路中关键基因对抑制循环纤维细胞增殖分化的作用及其潜在的抗心肌纤维化应用价值。文献检索显示，上述研究内容国内外未见报道。如获成功，不仅有助于更好地阐释HGF抗心肌纤维化的作用机制，而且有望为今后开展抗心肌纤维化治疗研究提供新的靶点。

心肌纤维化是心肌损伤后向心衰发展进程中的关键步骤，既往研究证实肌纤维母细胞在此过程中起着主导作用。新近的研究表明，经循环归巢至损伤区域的循环纤维细胞是肌纤维母细胞的重要甚至是最主要的来源。因而，研究循环纤维细胞增殖分化的调控机制并据此制定出相应的对策将有助于抗心肌纤维化的疗效。我们在前期研究中发现，肝细胞生长因子（HGF）能通过上调孤核受体Nur77的表达抑制循环纤维细胞的增殖分化。通过细胞学实验探索HGF上调Nur77表达抑制循环纤维细胞增殖分化的作用，初步明确了HGF通过促进转录因子cJun表达进而促进Nur77转录表达，从而抑制抑制循环纤维细胞增殖分化； 通过动物模型初步发现HGF-cJun-Nur77 途径表达水平与心梗后心肌纤维化程度的具有相关性。上述结果不仅有助于进一步阐明HGF的抗心肌纤维化作用机制，而且有望为防治心肌及其他组织的纤维化发生和发展提供新的潜在治疗靶点。