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。

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.