转录因子Myocardin调控心脏钙通道蛋白表达及其机制研究

Ca2+ influx via Cav1.2 L type calcium channel (LTCCs) is multi-functional signal that triggers myocardial muscle contraction, controls.action potential duration and regulates gene expression in heart. However, Cav1.2 transcriptional regulation mechanisms are still unknown. Our previous studies have shown that myocardin, an co- transcriptional factor of serum response factor (SRF), can activate the expression of LTCC assembly protein Cav1.2 and nuclear transcriptional factor of activated T cells (NFAT) synergistically operates the effect, and microRNA133 driven by myocardin inhibits it. In this study, we will investigate that LTCC Cav1.2 transcriptional mechanisms could be associated with myocardin, which provide the direct evidence of Ca2+-Calcinuerin-NFAT-myocardin-Cav1.2 positive feedback loop and negative feedback pathway of microRNA133 - myocardin-SRF-CarG- Cav1.2 regulation with a variety of cellular and molecular biology technology and transgenic mice in vitro and vivo. Finally, the study will throw up insight into Cav1.2 transcriptional regulation triggered by myocardin and then set up foundation for the development of new drugs and clinical treatment involved in Cav1.2 abnormal regulation.

Ca2+通过心肌细胞膜L型钙通道（LTCC）内流，触发心肌收缩、调控动作电位和基因表达，但组成LTCC 的主要蛋白Cav1.2转录调控机制仍不清。本研究在前期获得SRF辅转录因子myocardin和淋巴细胞核激活转录因子（NFAT）协同激活Cav1.2表达及myocardin可驱动miRNA133表达，并进而负反馈抑制上述过程的基础上，进一步利用各种细胞和分子生物学技术及转基因小鼠，证明myocardin调控LTCC-Cav1.2转录机制，揭示Ca2+-Calciruerin–NFAT-myocardin-Cav1.2正反馈调节环路和miRNA133负反馈调制myocardin-SRF对Cav1.2转录激活。最终，在体内外阐明myocardin调控LTCC转录调控和确切分子机制，提供以Myocardin为中心的LTCC转录调控理论，并为针对其病理机制的新药开发及临床防治心律失常提供基础。

Ca2+通过心肌细胞膜L型钙通道（LTCC）内流，触发心肌收缩、调控动作电位和基因表达，但组成LTCC 的主要蛋白Cav1.2转录调控机制仍不清。本研究发现SRF辅转录因子myocardin和淋巴细胞核激活转录因子（NFAT）都可以激活Cav1.2表达，证明myocardin调控LTCC-Cav1.2转录机制，但是NFATc4通过与myocardin相互作用削弱了myocardin对Cav1.2的转录激活作用。最终，在体外阐明myocardin调控LTCC转录调控和确切分子机制，提供以Myocardin为中心的LTCC转录调控理论，并为针对其病理机制的新药开发及临床防治心律失常提供基础。