CSE/H2S系统去谷胱甘肽化修饰SIRT1促进肝组织修复与再生的机制研究

SIRT1蛋白活性水平的降低是肝组织修复与再生障碍发生的主要原因之一，尚无有效的治疗策略。H2S具有显著促进肝组织修复与再生的作用，但是，其作用的靶点和机制是未知的。我们前期研究发现H2S可以打开二硫键，提示H2S具有还原氧化状态硫原子的能力。近期发现，SIRT1蛋白中某些半胱氨酸发生可逆性谷胱甘肽化修饰，从而提高SIRT1蛋白活性水平。谷胱甘肽化修饰的本质是一种特殊的二硫键，因此，我们推测H2S很可能也同样具有解除SIRT1蛋白中谷胱甘肽化修饰的能力。外源性H2S无法应用于临床治疗，团队利用急慢性肝损伤动物模型，聚焦研究肝组织内源性CSE/H2S系统的调控；在阐明Leonurine上调肝组织内源性CSE/H2S生成水平的基础上，深入研究SIRT1蛋白是否是内源性CSE/H2S的靶分子，发挥促进肝组织修复与再生的作用。课题研究成果将为肝组织修复与再生障碍的治疗提供理论依据，具有潜在的临床应用价值。

The decrease of SIRT1 protein activity level is one of the main causes of liver tissue repair and regeneration disorders, and there is no effective treatment strategy. H2S has a significant role in promoting liver tissue repair and regeneration, but its target and mechanism are unknown. Our previous study found that H2S can open the disulfide bond, suggesting that H2S has the ability to reduce and oxidize sulfur atoms in the state. Recently, reversible glutathionylation of some cysteines in SIRT1 protein was found to enhance the activity of SIRT1 protein. The nature of glutathionization modification is a special disulfide bond, so we speculate that H2S may also have the ability to remove glutathione modification from SIRT1 protein. Exogenous H2S could not be applied to clinical treatment. The team focused on the regulation of endogenous CSE/H2S system in liver tissues by using acute and chronic liver injury animal models. On the basis of elucidate that Leonurine up-regulates endogenous CSE/H2S generation level in liver tissues, the SIRT1 protein is further studied to determine whether it is the target molecule of endogenous CSE/H2S and play a role in promoting the repair and regeneration of liver tissues. The results of this study will provide theoretical basis for the treatment of liver tissue repair and regeneration disorders and have potential clinical application value.