致肥大刺激介导的细胞核转录异常是心肌肥大重要病理机制。PARP-1是聚ADP核糖聚合酶家族主要成员，可通过催化底物蛋白的聚ADP核糖基（PAR）化参与心肌肥大。我们在ISO刺激致肥大的心肌细胞检测到PARP-1活性上调，并通过与FoxO3结合介导其PAR化修饰，使FoxO3转录活性下降、磷酸化增加、核内聚集减少；抑制PARP-1活性可明显减弱此反应，减轻心肌肥大。本课题拟利用心肌肥大的细胞及大鼠模型，进一步确定FoxO3的PAR化修饰，鉴定出修饰的确切位点，并构建此位点缺失的腺病毒载体转染心肌细胞及大鼠心室壁注射方式，研究心肌肥大过程中：1）PAR化修饰对FoxO3转录活性的影响及调控其出核转运的机制；2）FoxO3的PAR化修饰是直接调节FoxO3功能还是通过对磷酸化修饰的影响。本课题将从FoxO3 的PAR化修饰角度研究PARP-1与心肌肥大的密切关系，为防治心肌肥大提供新的理论依据。

The abnormality of nuclear transcription induced by pro-hypertrophic stimuli is the important pathological mechanism underlying cardiac hypertrophy. PARP-1 is the primary member of an enzyme family termed poly(ADP-ribose) polymerases. It catalyzes the poly(ADP-ribose) (PAR) modification of protein substrates, thereby contributing to cardiac hypertrophy. Previously, we have detected that the activity of PARP-1 is up-regulated in cardiomyocytes hypertrophy stimulated by ISO. Through physically interaction with FoxO3, PARP-1 promotes the poly(ADP-ribosyl)ation of FoxO3, which leads to the decline in FoxO3 transcriptional activity, as well as elevated phosphorylation and attenuated nuclear accumulation of FoxO3. In contrast, the suppression of PARP-1 activity can ameliorate these changes and suppress cardiac hypertrophy. The present study is aimed to further confirm the poly(ADP-ribosyl)ation of FoxO3 and identify the exact modification sites by using cell and animal models of cardiac hypertrophy. Based on the construction of adenovirus vector with specific depletion of these identified sites and transfection by ventricular injection, we will investigate the following aspects during the progress of cardiac hypertrophy: (1) the mechanisms underlying poly(ADP-ribosyl)ation-induced changes in FoxO3 activity and its nuclear export; (2) whether the poly(ADP-ribosyl)ation directly affect the roles of FoxO3 or it functions via influencing phosphorylation. In brief, our study will investigate the substantial link between PARP-1 and cardiac hypertrophy from the perspective of FoxO3 poly(ADP-ribosyl)ation, and thereby provide new theoretical basis for the intervention of cardiac hypertrophy.