心肌组织CTRP9基因转录调控的机制研究

CTRP9（C1q/TNF related protein 9）is an newly discovered adiponectin (APN) analogue protein, which has the ischemia myocardial protection and more remarkable vasorelaxation compared with APN. What's more, our previous study found that the expression of CTRP9 in heart is 100 times higher than that of APN but is decreased in obese mice and ischemia/reperfusion myocardial injury exacerbated. While I/R myocardial injury decreased when CTRP9 was replenished. Which implied that decreased CTRP9 has important pathological effect in the increased diabetic ischemia/reperfusion myocardial injury. Our further research found that TNFα significantly inhibited CTRP9 expression in H9c2 cell. We identified the basic activity area of CTRP9 promoter and binding sites for FOXO3, PPARγ and CREB. On the basis of our previous study, this project is to investigate the regulation of CTRP9 gene expression in physiologic and obese pathologic condition. The aims of the project are 1.to determined the transcription factor which participate the CTRP9 transcription regulation; 2.to explore the mechanism of the decreased CTRP9 gene expression by TNFα; 3. to determine whether overexpression or knockdown the gene expression of special transcription factors can reverse the inhibition of CTRP9 induced by TNFα and the decrease of CTRP9 in obesity and insulin resistance. So, the clarification of the mechanisms of CTRP9 gene transcription and the decreased CTRP9 gene expression in myocardium is to find a novel therapeutic target for the treatment of insulin resistance and diabetic ischemic cardiovascular diseases.

CTRP9是新发现的一个脂联素（APN）类似物，具有保护缺血心肌和更强的扩张血管作用。更重要的是我们前期发现，正常心肌组织CTRP9的表达量是APN的100倍，而糖尿病小鼠心肌CTRP9表达降低且缺血/再灌注心肌损伤加重，外源补充CTRP9显著保护缺血心肌，提示CTRP9下降在糖尿病I/R心肌损伤中发挥重要作用。进一步研究发现，TNFα显著抑制H9c2细胞CTRP9的转录和表达，软件预测CTRP9基因启动子区存在FOXO3，PPARγ和CREB等转录因子的结合位点。本项目拟在上述发现的基础上，探讨生理和病理状态CTRP9基因的转录调控机制。明确参与CTRP9基因表达的转录因子；TNFα下调CTRP9基因表达的机制；过表达或抑制特定转录因子的表达是否可逆转TNFα诱导的和胰岛素抵抗时的CTRP9下调。阐明CTRP9的转录调控及其下调机制，为临床治疗胰岛素抵抗及糖尿病心肌缺血寻找新的治疗靶点。

CTRP9 是新发现的一个脂联素（APN）类似物，具有保护缺血心肌和更强的扩张血管作用。我们前期研究发现，正常心肌组织CTRP9 的表达量是APN 的100 倍，而糖尿病小鼠心肌CTRP9 表达降低且缺血/再灌注心肌损伤加重，外源补充CTRP9 显著保护缺血心肌，提示CTRP9 下降在糖尿病I/R心肌损伤中发挥重要作用。本项目在上述发现的基础上，探讨生理状态CTRP9 基因的转录调控机制。结果发现，转录因子PPARγ和CREB 可能参与了 CTRP9 基因转录调控，TNF-α显著抑制CTRP9基因启动子的活性及其蛋白转录和表达，且TNF-α抑制转录因子PPARγ在其中发挥重要作用。