基于miR-375/LDHB/PDHK1调控心肌能量代谢的机制及早期压力负荷性心肌肥厚的可视化研究

压力负荷性心肌肥厚（POH）是引起心衰的主要原因，目前尚无POH早期诊断方法，传统影像技术诊断POH往往已是晚期，失去有效治疗时机。课题组前期研究表明miR-375在POH早期高表达，对心肌肥厚起重要调控作用。本课题拟在前期体外实验基础上，进一步在大鼠POH模型中验证高表达的miR-375负调控靶基因LDHB/PDHK1影响心肌能量代谢，进而引起心肌肥厚的机制；在此基础上对miR-375表达进行可视化研究，引入报告基因行生物发光显像监测miR-375表达；构建病毒载体调控miR-375，行心肌荧光显像验证分子表达水平与心肌肥厚程度的相关性;构建99mTc标记靶向miR-375的反义核苷酸探针（99mTc-NH3-MAG3-AMO-375）行在体核素反义显像，探究该分子探针的生物学分布、血液动力学变化及基因表达显像。项目顺利实施能为POH早期分子影像诊断和有效干预提供分子靶点及科学依据。

Pressure overload hypertrophy (POH) is the main cause of heart failure. Currently, there is no effective method for early diagnosis of POH and the traditional imaging technology is often late in the diagnosis of POH, and the time for effective treatment is lost. Our previous studies showed that miR-375 was highly expressed in the early stage of POH, and played an important regulatory role in myocardial hypertrophy. On the basis of previous results in vitro experiments, we intend to further verify that high-expressed miR-375 negatively regulates the target gene LDHB/PDHK1 to affect the myocardial energy metabolism in the rat POH model, thus causing myocardial hypertrophy. On this basis, we performed the visualization of miR-375. The reporter genes were introduced to dynamically monitor the expression of miR-375 by bioluminescence imaging. The expression of miR-375 was regulated by the viral vector, proving that the degree of myocardial fluorescence imaging was correlated with the degree of myocardial hypertrophy. A 99mTc labeled antisense nucleotide probe targeting miR-375 (99mTc-NH3-MAG3-AMO-375) was constructed and radionuclide imaging was performed to explore the biological distribution, hemodynamic change and imaging of the probe. The successful implementation of this project can provide molecular targets and scientific basis for early molecular imaging diagnosis and effective intervention of POH to improve the prognosis of POH.