1型多聚ADP核糖合成酶调控心肌自噬在心肌重构中的作用和机制研究

Myocardial remodeling is a pathological feature common to numerous forms of heart disease. It has been demonstrated that myocardial autophagy is important for maintaining myocardial function, and autophagy anomalies are associated with the increased risk for myocardial remodeling. Poly (ADP-ribose) polymerase 1 (PARP1) is the major cellular stimulus-response manner and a key regulator of autophagy. It has been reported that PARP1 takes great part in the development of myocardial remodeling. We therefore hypothesize that PARP1 participates in the process of myocardial remodeling by modulating myocardial autophagic signalling. We preliminary data show that short term starvation-induced autophagy in cardiac myocytes promotes PARP1 activation. Activated PARP1 mediates transactivity of FOXO3 and increases the expression of autophagy-related (ATG) genes, promoting the starvation-induced autophagy. By clinical trial, animal studies and cell research, we will investigate the relationship between PARP1 and FOXO3, mTOR signaling and its target protein, or other autophagy-related transcription factors in the process of myocardial remodeling. We will further explore the role of PARP1 in this process, and find the new PARP1 co-factor. This project will explore the new role of PARP1 in myocardial remodeling, providing experimental evidence and theoretical basis for targeted intervention on this disease

心肌重构是许多心脏疾病共同的病理环节。心肌细胞自噬对维持心肌功能具有重要的作用，自噬的异常会促进心肌重构的发生发展。1型多聚ADP核糖合成酶(PARP1)作为细胞应对各种应激的主要反应方式，是一种关键的自噬调节因子，在心肌重构发生发展过程中起重要作用。我们的前期研究发现，短期饥饿诱导心肌细胞自噬时，活化的PARP1可调控FOXO3转录活性，并上调其下游心肌细胞自噬基因核心蛋白ATG家族的表达，从而诱导心肌细胞自噬。因此我们假设：PARP1可通过调控心肌细胞自噬相关蛋白来参与心肌重构的发生发展。本课题拟通过临床、动物和细胞模型实验，研究在心肌重构不同阶段PARP1与FOXO3、mTOR通路与靶蛋白、以及其他自噬相关转录因子的关系，寻找与自噬相关的新的PARP1“合作者蛋白质”。研究有助揭示PARP1调控心肌重构的新机制，为靶向干预心肌重构提供实验依据和理论基础。

心肌重构是许多心脏疾病共同的病理环节。心肌细胞自噬对维持心肌功能具有重要的作用，自噬的异常会促进心肌重构的发生发展。1型多聚ADP核糖合成酶(PARP1)作为细胞应对各种应激的主要反应方式，是一种关键的自噬调节因子，在心肌重构发生发展过程中起重要作用。我们的研究发现，短期饥饿诱导心肌细胞自噬时，活化的PARP1可调控FOXO3转录活性，并上调其下游心肌细胞自噬基因核心蛋白ATG家族的表达，从而诱导心肌细胞自噬。因此我们假设：PARP1可通过调控心肌细胞自噬相关蛋白来参与心肌重构的发生发展。本课题通过临床、动物和细胞模型实验，研究了PARP1与FOXO3、mTOR通路与靶蛋白、以及其他自噬相关转录因子的关系,通过调控作用促进心肌自噬促进心室重塑。研究有助揭示PARP1调控心肌重构的新机制，为靶向干预心肌重构提供实验依据和理论基础。