Stat3抑制myocardin诱导心肌肥厚的机制研究

Interactions of different tanscriptional factors can provide precise transcriptional regulation in human physiology and pathophysiology, but make it to be more complex.Myocardin is poweful co-transcriptional factor of serum response factor(SRF) and can activate the related genes of cardiac hypertrophy to mediate cardiac hypertrophy in vitro. Signal transduction and activation of factor 3 (Stat3), also can trigger cardiac hypertrophy. But when they work in cardiomyocytes together, Stat3 may repress the the cardiac hypertrophy gene activation drived by myocardin.On the basis of our previous these findings, this study will further investigate their interaction and effects on cardiac hypertrophy in vivo. Mechanisms that stat3 inhibits the cardiac hypertrophy mediated by myocardin will be clarified by a variety of cellular and molecular biology methods, which stat3 can reduce myocardin binding with SRF because of their protein - protein interaction, inhibit Myocardin expression and enhance its phosphorylation to inhibit its transactivation.Stat3 may also activate miR-133 transcription and expression to strengthen the inhibitive effect of miR-133 on SRF feedback.Eventually, novel evidence will be provided to prove that Stat3 suppress the cardiac hypertrophy triggered by myocardin in vitro and in vivo.

蛋白质转录因子间相互作用为机体提供了更精细的转录调节，但也使转录调控更为复杂。Myocardin是血清反应因子（SRF）强力辅助转录因子，可激活心肌肥厚基因转录，诱发心肌肥厚。信号转导和激活因子3（Stat3）也可促发心肌肥厚。但二者共同作用时，Stat3却抑制Myocardin对心肌肥厚基因的激活。在我们先前这些发现基础上，本研究将进一步在转基因整体动物水平上，证明其相互作用，并利用各种细胞分子生物学手段，阐明Stat3抑制Myocardin介导的心肌肥厚机制。包括Stat3与Myocardin蛋白-蛋白相互作用，降低其与SRF结合；抑制Myocardin表达并使其磷酸化降低其活性；激活miR-133转录和表达，加强miR-133对SRF反馈抑制等。最终，在分子-细胞-整体水平上，证明Stat3抑制Myocardin触发的心肌肥厚最新分子机制。

蛋白质转录因子间相互作用为机体提供了更精细的转录调节，但也使转录调控更为复杂。Myocardin是血清反应因子（SRF）强力辅助转录因子，可激活心肌肥厚基因转录，诱发心肌肥厚。信号转导和激活因子3（Stat3）也可促发心肌肥厚。但二者共同作用时，Stat3却抑制Myocardin对心肌肥厚基因的激活。在我们先前这些发现基础上，本研究将进一步在转基因整体动物水平上，证明其相互作用，并利用各种细胞分子生物学手段，阐明Stat3抑制Myocardin介导的心肌肥厚机制。包括Stat3与Myocardin蛋白-蛋白相互作用，降低其与SRF结合；抑制Myocardin表达并使其磷酸化降低其活性；激活miR-133转录和表达，加强miR-133对SRF反馈抑制等。最终，在分子-细胞-整体水平上，证明Stat3抑制Myocardin触发的心肌肥厚最新分子机制。