CD39+成纤维细胞亚型促进瘢痕增生的分子机制研究

成纤维细胞（Fb）是增生性瘢痕的主要效应细胞。探究关键细胞亚型及致病机制，可以形成精准的靶向治疗。项目组发现：CD39+Fb在增生性瘢痕中增加，并与瘢痕增生的严重程度呈正相关；基因表达趋势分析表明IL-11在CD39+Fb中表达显著增高；而抑制CD39能降低IL-11的表达、减少瘢痕增生。最新研究提示：CD39下游特定腺苷受体的激活可促进IL-11分泌，加重组织纤维化。据此，提出假说：CD39+Fb激活特定腺苷受体及其下游通路，促进IL-11分泌，导致瘢痕增生。拟采用CD39过表达/敲减细胞、转基因小鼠等模型，研究CD39+Fb在IL-11分泌、肌成纤维细胞激活和瘢痕增生中的作用；利用受体激动剂、PCR芯片和siRNA等手段，筛选激活IL-11表达的腺苷受体亚型，探寻其调控IL-11表达的信号通路和可能的治疗靶点。本项目从细胞亚型的新视角揭示瘢痕增生机制，将有助于形成新的靶向治疗策略。

Fibroblasts(Fb) are the main effector cells of hypertrophic scars. The discovery of more precise targeted therapies may be facilitated by the investigation of critical cell subtype and its related pathogenesis. The preliminary research of our group show that the fraction of CD39+ Fb is increased in hypertrophic scars and is positively correlated with the scar severity; the expression of IL-11 is increased significantly in CD39+ Fb according to the gene expression trend analysis; and the inhibition of CD39 could effectively downregulate the expression of IL-11 and impede the formation of hypertrophic scar. Recent researches showed that the activation of specific adenosine receptors in CD39 downstream signaling pathway could promote the secretion of IL-11, leading to exacerbation of tissue fibrosis. Based on these findings, we propose that CD39+ Fb may promote the secretion of IL-11 by activating those specific adenosine receptors and their downstream signaling pathways, which ultimately leads to the formation of hypertrophic scars. In this study, we intend to explore the role of CD39+ Fb on IL-11 secretion, myofibroblast activation and hypertrophic scar development via the gene overexpression and knockdown cell lines and the transgenic mice model. Further, the main types of adenosine receptor responsible for the regulation of IL-11 expression will be screened and their mechanisms to facilitate IL-11 expression along with the possible therapeutic targets will be investigated by means of adenosine receptor agonists, PCR array and siRNA interference. This project is expected to uncover the mechanism of hypertrophic scar formation from a new perspective of cell subtypes, which may contribute to the development of new targeted therapies.