YAP通过IGF1R/Akt信号通路调控病理性心肌肥大的机制研究

Cardiac hypertrophy was a maladaptive response to over-load, but the underlying mechanisms were not clear. This study will investigate the role of the mammalian YAP in controlling cell hypertrophy during overloading. Our preliminary results showed expression level of YAP increased after stress stimulation; IGF1R/Akt signal pathway was active, which is very important in regulating cardiac hypertrophy; inhibition of YAP attenuated activation of IGF1R/Akt signal pathway. Thus, our hypothesis is that the mammalian YAP regulates cardiac hypertrophy. In this study, we hypothesize: 1. YAP is activated by phenylephrine (PE) or isoproterenol（ISO）in myocyte, and increased in the nuclear localization. 2. Decreases in the nuclear localization of YAP attenuated myocardial hypertrophy, whereas restoration of YAP expression promotes cardiac hypertrophy. We will address these issues using qRT-PCR, IHC, gain and loss of function mouse models, as well as proteomic approaches. Addressing these issues will allow us to elucidate the role of signaling mechanisms of YAP in mediating cardiac hypertrophy in response to over-load. The knowledge obtained from these experiments should be useful for developing specific therapeutics to prevent or mitigate progression of cardiac hypertrophy.

心肌肥大是心脏对病理刺激的一种适应性反应，其分子机制尚不清楚。本项目将研究YAP在心肌病理性肥大过程中扮演的作用。我们前期的研究工作表明，YAP的表达在细胞、动物心肌肥大模型中升高; 且IGF1R/Akt信号通路被激活；抑制YAP表达明显降低PE诱导的心肌细胞中IGF1R/Akt信号通路激活。因此我们假设，YAP通过IGF1R/Akt信号通路调控病理性心肌肥大。我们将通过以下三个方面进行研究: 1.病理性心肌肥大过程中YAP表达水平升高，核定位增加；2.抑制YAP表达会改善心肌肥大，而过表达YAP会促进心肌肥大的发生；3. YAP入核后可以结合IGF1R启动子促进其表达，通过Akt信号通路促进肥大反应。本研究拟在分子、心肌细胞、 整体水平，综合应用多种分子生物学技术，探讨YAP在心肌肥厚发生中的功能和作用，为心肌肥厚的防治提供新思路。

心肌肥厚是心脏对病理刺激的一种适应性反应，其分子机制尚不清楚。本项目将研究YAP在心肌病理性肥大过程中扮演的作用。首先建立了小鼠、大鼠TAC诱导的心肌肥厚模型，PE诱导的心肌细胞肥大模型。首先在动物水平，我们研究工作表明，YAP的表达水平在心肌肥厚组织中显著升高；通过静脉注射腺病毒质粒实现在体调节YAP表达。我们发现，降低YAP 的表达水平可已改善心肌肥厚。进一步我们在细胞水平，应用 YAP新型小分子抑制剂Verteporfin后也发现，抑制YAP可以缓解PE诱导的心肌肥大。本研究明确了YAP蛋白在小鼠病理性心肌肥厚心肌组织中的表达，通过抑制YAP蛋白，减轻对小鼠病理性心肌肥厚的程度。下一步我们将围绕YAP在小鼠病理性心肌肥厚中的调控靶点、及病理肥厚的不同阶段所发挥的作用进行深入研究。