HDAC2 双酶协同致修复细胞增殖和凋亡失衡在病理性瘢痕形成中的作用及分子机制研究

修复细胞增殖和凋亡失衡是病理性瘢痕形成之关键环节，但机制不清。预实验显示正常创面HDAC2呈动态表达，病理性瘢痕则持续高表达，且其敲出小鼠创面愈合速度减慢，提示其在创面修复调控中起重要作用，但机制不清。已知HDAC2可通过去乙酰化酶功能，在转录水平沉默抗增殖和促凋亡基因的表达。而我们发现，其兼有SUMO E3连接酶功能而促进eIF4E的SUMO化修饰，在翻译水平激活促增殖和抗凋亡基因的表达。由此提出“HDAC2通过双酶协同，致转录抑制和翻译激活，选择性调节细胞增殖和凋亡基因的表达，导致修复细胞增殖和凋亡失衡，在病理性瘢痕形成中发挥重要作用”的假设。为此，本研究拟通过结构域基因回补HDAC2敲出小鼠致伤皮肤和成纤维细胞，以及特异性抑制患者病理性瘢痕来源成纤维细胞和猪增生性瘢痕中HDAC2的表达或双酶活性，探讨其在病理性瘢痕形成中的作用和机制，为靶向阻断其双酶活性抗瘢痕策略的应用奠定基础。

The disequilibrium between cellular proliferation and apoptosis plays an important role in the formation of pathologic scars.Unfortunately the mechanism of which remains unclear. The expression of HDAC2 is a dynamic process in normal wound healing, however, high and persistent at pathologic scars. The wound-healing was significantly slow in HDAC2 knock-out mice shown in our previous experiments. It suggested that HDAC2 plays a key role in regulating wound healing, but its mechanism requires elucidation. Previous studies have shown that HDAC2 is able to silent the expression of genes related to anti-proliferation and pro-apoptosis at the transcription level through the reaction of deacetylase. In addition, we found that, similar to SUMO E3 ligase, HDAC2 is able to up-regulate the sumolation of eIF4E, which in turn boosts the translation of genes related to pro-proliferation and anti-apoptosis and thus controls the balance between cellular proliferation and apoptosis. Here we propose that through the synergic action of dual enzyme, HDAC2 selectively suppresses transcription or promotes translation of cap-dependent mRNA, and thus regulates accordingly the expression of genes related to proliferation and apoptosis. Therefore, HDAC2 plays an important role in normal wound healing and formation of pathologic scars by regulating the balance/disqquilibrium between cellular proliferation and apoptosis. In order to test for this hypothesis, we will rescue the functional structure domain gene of HDAC2 to damaged skin in HDAC2-/- KO mice as well as its fibroblast cells, and specifically inhibit the expression or activities of HDAC2 in pig hyperplastic scar tissue and fibroblast cells from patients’ pathologic scars. This study is going to explore the synergic effect of HDAC2 dual enzyme on the formation of pathologic scars as well as its mechanism of action, finally aiming to provide novel insights and approaches to improve the treatment and prevention of pathologic scars by targeting HDAC2.