p53乳酸化修饰水平异常致糖尿病心肌病中心肌损伤的机制及黄芩苷的干预作用研究

糖尿病心肌病（DCM）是糖尿病患者死亡的主要原因之一，但发病机制尚未明确，缺乏有效干预药物。前期研究发现：DCM中蛋白组乳酸化修饰水平发生整体改变，其中p53乳酸化修饰增加可导致心肌损伤及代谢紊乱；基于清热解毒之法筛选出的黄芩及其主要成分黄芩苷（Baicalin, BAI）可发挥抗DCM作用；BAI可减少p53乳酸化修饰，该作用依赖AMPK发挥；BAI增加AMPK与SIRT3结合及SIRT3与p53结合。据此本课题提出以下假设：DCM中，高血糖通过抑制AMPK/SIRT3通路，增加p53乳酸化修饰，激活p53靶基因转录，从而抑制心肌糖酵解，促进心肌凋亡，诱发心肌损伤，黄芩苷能通过直接结合AMPK并增加其稳定性有效逆转这一过程。本课题拟构建转基因动物，采用RNA-seq等技术阐明p53乳酸化修饰影响DCM进展的上下游调控机制及BAI的调控机制，为系统防治DCM提供新靶点及有效药物。

Diabetic cardiomyopathy (DCM) is one of the major causes of death in diabetic patients, but the pathogenesis is not yet clear, and there is a lack of effective drugs. Previous studies showed that the proteome lactylation profile were altered, and the increase of p53 lactylation led to myocardial damage and metabolic disorders; Based on the theory of clearing heat and detoxification Scutellaria baicalensis and its main component Baicalin (BAI) were identified as the anti-DCM medicine; BAI downregulated the lactylation of p53, which depended on AMPK. BAI increased the binding of AMPK with SIRT3, and the binding of SIRT3 with p53. Based on this, this study proposes the following hypothesis: under DCM conditions, hyperglycemia inhibits AMPK/SIRT3 pathway, increases the lactylation of p53, activates p53 target gene transcription, thereby inhibiting myocardial glycolysis, promoting cardiomyocyte apoptosis, and inducing myocardial damage, Baicalin effectively reverses this process by directly binding AMPK and increasing its stability. In this study we will construct transgenic animals, adopt molecular biology techniques such as RNA-seq to clarify the upstream and downstream regulatory mechanisms of p53 lactylation on the progress of DCM and the regulatory mechanism of BAI, providing the new strategies and the effective drug for the prevention and treatment of DCM.