CHK1激酶通过磷酸化修饰组蛋白H3启动心肌梗死后心肌再生的功能及相关机制研究

心肌梗死是目前导致人类死亡的主要疾病之一，梗死后心肌的再生治疗成为近年来研究热点。哺乳动物心脏在出生后7天内保持完全再生能力，为探索启动成年心肌再生机制提供了较好的研究平台。CHK1激酶通过磷酸化组蛋白H3途径促进细胞增殖和癌症发生。目前，我们通过定量磷酸化蛋白组学技术筛选获得CHK1，该激酶在新生心脏再生过程中被广泛激活，而在成年心脏中表达丢失；抑制其活性显著降低心肌细胞增殖水平。我们推测CHK1激酶通过磷酸化修饰组蛋白H3途径参与启动新生心脏再生程序。为此在前期工作基础上，将运用CHK1激酶特异性抑制剂和心肌过表达CHK1转基因小鼠，双向验证其对新生心脏再生能力的影响及可能的磷酸化修饰组蛋白H3途径；并在成年小鼠心脏中过表达CHK1，探索其对成年心脏梗死后的治疗作用；最后在人胚胎干细胞系进行初步功能验证，为临床转化提供依据。本研究将为临床心梗后心肌修复的再生治疗提供新的理论依据和方向。

Myocardial infarction is one of the leading causes to human death, and regeneration of myocardial cells after myocardial Infarction has become a research topic of high interest in recent years. Mammalian hearts maintain potential for regeneration within 7 days after birth, which provides a good study platform for exploring the mechanism of adult cardiac regeneration. CHK1 kinase promotes cell proliferation and cancer induction through phosphorylated histone H3. CHK1 kinase is screened out using quantitative phosphoproteomics technology. CHK1 kinase is activated during neonatal cardiac regeneration, while a loss of its expression occurs in the adult heart. Inhibition of CHK1 kinase activity could significantly reduce the level of myocardial cell proliferation. These findings suggest CHK1 kinase might effect myocardial regeneration that occurs after neonatal cardiac injury. In this study, we will verify the regeneration function of CHK1 kinase on newborn and adult myocardium post myocardial infarction by kinase-specific inhibitor, and construct myocardium over-expression transgenic mice based on previous research works, and discuss the correlated mechanism of inducing cardiomyocyte proliferation by phosphorylated histone H3. Finally, preliminary functional verification will be taken in human fetal cardiomyocyte to provide relevant evidence for clinical application. This study will explore a new theoretical basis and direction for the regeneration of myocardial repair post myocardial infarction.