长链非编码RNAH19在瘢痕疙瘩形成中的功能及分子机制研究

Abnormal proliferation of keloid fibroblasts is the central link of keloid growth and the key target of research on anti-scarring therapy. lncRNA is another hotspot next to miRNA in biological medicine. It is reported to be associated with fibrosis of multiple tissues. However, there are few studies reporting the association of lncRNA with keloid tissue. H19 is an early discovered LncRNA and believed to be associated with the development of multiple diseases and liver fibrosis. The previous study of the applicant found that the expression of H19 was increased markedly in keloid tissue, and inhibition of H19 could inhibit the proliferation of keloid fibroblasts remarkably. Further research revealed that inhibition of H19 could down-regulate the activity of Smad2 and Smad3, two key proteins in the TGF-β/Smad signaling pathway. Therefore, we postulated that H19 could promote keloid formation by activating the TGF-β/Smad pathway. The present study was intended to further clarify the role of H19 in promoting keloid fibrosis and its regulatory mechanism, and observe the effect of H19-targeted anti keloid fibrosis treatment in vivo. It is expected that the result of the present study could provide insights into the mechanism of keloid formation and offer a new way of thinking in research and development of drugs against keloid formation.

瘢痕疙瘩成纤维细胞异常增殖是瘢痕疙瘩生长的中心环节和抗瘢痕纤维化治疗研究的关键靶标。长链非编码RNA（lncRNA）是继miRNA后生物医学领域又一热点，迄今已有报道LncRNA与多种组织纤维化有关，但与瘢痕疙瘩相关性报道甚少。H19是较早发现的LncRNA，与多种疾病发生及肝纤维化相关。申请人前期研究发现，H19在瘢痕疙瘩组织中表达明显增高，抑制H19则显著抑制瘢痕疙瘩成纤维细胞增殖；进一步研究发现，抑制H19可下调TGF-β/Smad信号通路关键蛋白Smad2、Smad3活性。故推测H19可通过激活TGF-β/Smad通路，促进瘢痕疙瘩的形成。因此，本研究拟通过过表达及RNA干扰技术进一步明确H19的促瘢痕疙瘩纤维化作用，阐明其调节机制，并在体内观察以H19为靶点的抗瘢痕疙瘩纤维化效应。预期成果将为明确瘢痕疙瘩形成机制提供线索，并为抗瘢痕疙瘩药物研发提供新的思路。

瘢痕疙瘩成纤维细胞异常增殖是瘢痕疙瘩生长的中心环节和抗瘢痕纤维化治疗研究的关键靶标。长链非编码RNA（lncRNA）是继miRNA后生物医学领域又一热点，迄今已有报道LncRNA与多种组织纤维化有关，但与瘢痕疙瘩相关性报道甚少。H19是较早发现的LncRNA，与多种疾病发生及肝纤维化相关。通过体内及体外实验发现，瘢痕疙瘩组织中H19表达明显较高，干扰H19时，可抑制细胞增殖。 H19过表达时，Collagen I和Collagen III表达明显升高，Smad2、Smad3和TGF-β1明显升高，Smad7表达明显下降。因此，本研究证明 H19可以作为抑制瘢痕疙瘩的一个重要潜在靶点，在瘢痕疙瘩形成过程中，H19通过激活Smad2和Smad3，抑制Smad7的表达，正反馈作用于TGF-β/Smad通路，促使瘢痕疙瘩的形成，为明确瘢痕疙瘩形成机制提供线索，并为抗瘢痕疙瘩药物研发提供新的思路。