HIF相关正反馈回路及其信号通路在瘢痕疙瘩发生与发展中的作用及分子机制

瘢痕疙瘩是常见病理性皮肤愈合类型，但发病机制至今未完全明了。近年文献报道累及真皮的创口愈合时常呈缺氧状态及缺氧诱导因子（HIF）激活，上调结缔组织生长因子（CTGF）、TGF-β和诱导型NO合酶表达。我们前期研究发现瘢痕疙瘩HIF-1和HIF-2、TLR4表达及NO水平显著升高，但与瘢痕疙瘩关系及作用机制不明。本项目中我们将从HIF介导缺氧应激反应而导致瘢痕疙瘩发生与发展的思路出发，从临床标本、分子与细胞、动物模型不同层次确定：HIF-1或HIF-2与TGF-β形成正反馈回路激活Smads通路或上调CTGF表达，HIF-1或HIF-2与NO或TLR4形成另一正反馈回路并激活NF-κB、p38MAPK和ERK1/2通路，引起胶原蛋白高表达、粘多糖和ECM过度合成与沉积而引发瘢痕疙瘩分子机制；同时确定不同缺氧程度时HIF-1和HIF-2在瘢痕疙瘩形成中的作用及其差异，具有较高创新性和临床意义。

Keloid is a common type of pathological skin healings, but its pathogenesis remains poorly understood. The recent literatures reported that hypoxia and hypoxia inducible factor (HIF) activation during healing of corium-involved tresis vulnus are frequently presented, and HIF up-regulates the expression of connective tissue growth factor (CTGF), transforming growth factor-beta (TGF-β) and inducible nitricoxide synthase (iNOS). Our preliminary study found that the HIF-1, Toll-like receptor 4 (TLR4) and nitrogen monoxidum levels in keloid tissue were significantly increased, but the correlation and possible active mechanism of these findings referring to keloid generation are unknown. In this project, we presumed that HIF-1 and HIF-2 mediate anoxic stress reaction to cause the generation and development of keloid. We will try to elucidate the molecular mechanism of keloid formation from different levels of clinical specimen, molecule and cell, and animal model. We will determine that the HIF-1 or HIF-2 and TGF-β positive feedback loop to activate Smads pathway and up-regulate CTGF expression, and the HIF-1 or HIF-2 and NO or TLR4 positive feedback loop to activate NF-κB, p38MAPK and ERK1/2 pathways, which cause keloid formation through high expression of collagen proteins and mucoitin, and oversynthesis and deposition of ECM. Moreover, we will also determine the role and diversity of HIF-1 and HIF-2 during keloid formation with different anoxic degrees. The findings of this project will possess high originality and medical significance.