糖尿病心肌病（DCM）是糖尿病的高危并发症之一。细胞周期依赖性激酶9（CDK9）是正性转录延长因子β（P-TEFβ）复合物的关键组成部分，是抗肿瘤和抗病毒的重要靶点之一；近年来，少量研究发现CDK9参与心脏发育和压力性心肌肥大的调节，但它在DCM中的作用尚无报道。我们前期发现，糖尿病小鼠心肌中CDK9异常激活；CDK9抑制剂可以显著缓解DCM，且转录因子GATA4可能参与该过程。基于此我们提出假设：心肌细胞CDK9通过调节GATA4介导DCM。本项目将利用原代心肌细胞和条件性心肌细胞CDK9敲除小鼠，阐明高血糖（高糖）通过促进P-TEFβ抑制蛋白解离而活化CDK9，随后招募GATA4形成CDK9-GATA4复合物后入核，激活核内RNAPII并促进心肌肥大和纤维化相关基因的转录表达这一分子机制。旨在证实心肌细胞CDK9在DCM发生发展中的重要作用，提出CDK9可能成为DCM防治的新靶点。

Diabetic cardiomyopathy (DCM) is one of the most severe complications of diabetes. Cell cycle-dependent kinase 9 (CDK9) is a key component of the positive transcription elongation factor beta (P-TEFβ) complex, and is an important anti-tumor and anti-viral target. In recent years, a few studies have found that CDK9 is involved in the regulation of cardiac development and stress-induced myocardial hypertrophy, but its role in DCM is still unknown. Our previous study found that CDK9 was abnormally activated in the myocardium of diabetic mice. In addition, CDK9 inhibitors could significantly alleviate DCM, which might be achieved by regulation of the transcription factor GATA4. These previous results indicate that cardiomyocyte CDK9 contributes to DCM by regulating GATA4. We propose the hypothesis that hyperglycemia activates CDK9 by promoting the dissociation of P-TEFβ inhibitor. Activated CDK9 forms a complex with GATA4 and translocate to the nucleus, leading to the activation of RNAPII and the subsequent transcription of genes associated with myocardial hypertrophy and fibrosis. In this project, we will use primary myocardial cells and myocardial cell-specific CDK9 knockout mice to confirm the hypothesis. In this way, we show that cardiomyocyte CDK9 plays an important role in the development of in DCM, and may become a novel therapeutic target for DCM.