CTMP对心肌肥厚发生发展的影响及其机制研究

Cardiac hypertrophy, an enlargement and fibrosis of the heart caused by hypertension and myocardial infarction, can cause heart failure, arrhythmiasand sudden death. Although many signal transduction cascades are demonstrated as important regulators to facilitate the induction of cardiac hypertrophy, the signaling pathways for suppression hypertrophic remodeling remain largely unexplored. We focus on a negative regulator of AKT protein, CTMP, which is a carboxyl terminal modulator protein. Its principal role has been determined in the anti-apoptotic activity and regulation of signal transduction. However, the role of CTMP in cardiac hypertrophy is still unclear. Our preliminary results indicated that CTMP may play an important role in cardiac hypertrophy, but further study is needed to investigate the exact role and molecular mechanisms of CTMP in cardiac hypertrophy. In the first part of this research, we explore the effects of CTMP on cardiac hypertrophy and fibrosis by using CTMP knockout mice and cardiac-specific transgenic mice through evaluate the pathological and molecular analyses. In addition, our research will use the cultured neonata rat cardiomyocytes to explore the mechanisms of CTMP on cardiac hypertrophy. The present study is designed to investigate the role and underlying mechanisms of CTMP in cardiac hypertrophy, and provide new experimental evidence and targets for clinical intervention in cardiac hypertrophy and heart failure.

心肌肥厚是多种心血管疾病发展为心衰的共同病理生理过程，AKT信号通路及线粒体介导的细胞凋亡与心肌肥厚关系密切。羧基末端调节蛋白（CTMP）是一种新发现的 AKT 激酶的负性调节因子，CTMP通过调控AKT激酶和线粒体介导的细胞凋亡发挥生物学功能，但CTMP是否参与心肌肥厚的发生发展，目前尚无研究报道。我们的预实验发现 CTMP可能对压力负荷诱导的心肌肥厚具有保护作用，然而其内在机制尚未明确。本项目拟用CTMP基因敲除和CTMP心脏特异性转基因小鼠建立压力负荷诱导的心肌肥厚模型，并从心脏功能、整体形态、组织病理、分子标志物表达等多个层面研究CTMP对心肌肥厚的影响，探讨CTMP对心肌肥厚作用可能的分子机制；然后在细胞水平进一步探讨 CTMP沉默或过表达对心肌细胞肥大、纤维化、凋亡及相关信号通路的影响，力图明确 CTMP 对心肌肥厚的作用，阐明其根本机制，探寻防治心肌肥厚的新靶点和新策略。

心肌肥厚是多种心血管疾病发展为心衰的共同病理生理过程。羧基末端调节蛋白（CTMP）是一种新发现的AKT激酶的负性调节因子，CTMP与癌症、脑损伤和肥胖有关。然而，CTMP在病理性心肌肥厚中的作用尚未被证实。本课题研究发现CTMP在人心力衰竭和小鼠心肌肥厚的心脏中表达水平下降。为了进一步探讨CTMP在病理性心肌肥厚中的作用，我们选用CTMP基因敲除和CTMP心脏特异性转基因小鼠建立压力负荷诱导的心肌肥厚模型。体内实验表明，CTMP基因敲除加重了压力超负荷引起的心肌肥厚、纤维化和功能，而CTMP的过表达则减轻了对肥厚刺激的反应。与体内实验结果一致，腺病毒介导的功能获得或功能缺失实验进一步表明，CTMP在体外对血管紧张素II诱导的心肌肥大也有保护作用。此外，机制方面，我们发现CTMP通过阻断AKT信号通路改善病理性心肌肥厚。我们的研究首次表明，增加心肌CTMP的表达可能是治疗病理性心肌肥厚的一种新方法，为探寻防治病理性心肌肥厚提供了可能的新靶点和新策略。项目资助发表SCI论文4篇。本研究持续进行中培养研究生4名，其中3名已毕业，1名还在学习中。项目投入经费17.5万元，已支出14.174万元，各项支出与项目计划相符。剩余经费3.326万元，剩余经费将用于本项目研究后续支出。