PHLDA3在病理性心肌肥厚中的功能及机制研究

Cardiac hypertrophy is a dynamic, complex process regulated by multiple signaling pathways, which ultimately leads to heart failure but without effective treatment strategies. PHLDA3 is a tumor suppressor that inhibits the activation of Akt by competitively binding to PIP3. Studies have shown that down-regulation of PHLDA3 is associated with various tumorigenesis. While the function of PHLDA3 in cardiac fields has not been reported. Our previous studies showed that PHLDA3 is down-regulated in stress-induced cardiac hypertrophy, and that cardiomyocyte-specific PHLDA3-knockout mice showed a more pronounced phenotype of cardiac hypertrophy under pressure loading. In this project, we intend to combine cardiomyocyte-specific PHLDA3 transgenic and knockout mice subjected to cardiac hypertrophy with in vitro cell models, to ① clarify the role for PHLDA3 in pathological cardiac hypertrophy; ② investigate the underline mechanism from upstream DNA methylation and downstream signaling pathways; ③ explore the therapeutic effect of PHLDA3 in cardiac hypertrophy by using AAV9 overexpression vector. The outcomes of this project will provide a new target for the treatment of heart failure caused by cardiac hypertrophy, which is of great clinical value.

心肌肥厚是一个受多种信号调控的动态复杂过程，最终会导致心力衰竭，而目前却无有效的治疗策略。PHLDA3是一个肿瘤抑制因子，通过竞争性结合PIP3抑制Akt的激活。研究表明PHLDA3表达下调与多种肿瘤发生相关，但它在心脏领域的功能尚无报道。我们前期初步研究显示，PHLDA3在压力负荷诱导的小鼠心肌肥厚模型中表达下调，且心肌细胞特异性PHLDA3敲除小鼠在压力负荷下产生更明显的心肌肥大。本项目拟用心肌细胞特异性PHLDA3转基因和敲除小鼠，结合病理性心肌肥厚动物模型和体外细胞模型，①明确PHLDA3在病理性心肌肥厚中的功能；②从甲基化修饰和下游信号通路两方面探讨PHLDA3对心肌肥厚的调节机制；③利用AAV9过表达载体探索PHLDA3高表达对心肌肥厚的治疗作用。本项目预期成果有望阐释PHLDA3在心肌肥厚中的重要生物学功能和机制，并为心肌肥厚引起的心衰治疗提供新的靶点，具有深远的临床价值。

心肌肥厚是一个受多种信号调控的动态复杂过程，最终会导致心力衰竭，而目前却无有效的治疗策略。肿瘤抑制因子PHLDA3的表达下调与多种肿瘤发生相关，但它在心脏领域的功能尚无报道。本项目研究通过心脏特异性敲除和过表达PHLDA3的小鼠，以及体外腺病毒载体敲低和过表达实验，证实PHLDA3通过抑制Akt-mTOR-GSK3β信号的异常激活负调控主动脉缩窄导致的病理性心肌肥厚和心脏纤维化。我们进一步发现Akt抑制剂可以有效抑制动物模型中PHLDA3缺失引起的病理性心脏肥大。本研究揭示了PHLDA3在病理性心肌肥厚导致的心衰过程中发挥重要作用，并且为靶向Akt的持续激活抑制心肌肥厚和心衰提供理论依据。本项目资金还支持完成另一项工作，发现NLK是血糖稳态调控的重要激酶，通过磷酸化和出核调控糖异生关键转录及调节因子Foxo1和CRTC2，抑制糖异生基因表达和肝脏葡萄糖生成，从而达到降低空腹血糖、改善糖尿病表型的作用。本研究揭示了NLK在调控肝脏糖异生的关键分子机制和作用，以及其作为T2DM治疗靶标的极大潜力。