MBD2基因对DNA加合物诱导的肺动脉平滑肌细胞异常增殖的影响及机制

在国家自然科学基金项目（81070044和81370156）的资助下，我们发现香烟烟雾在体内产生的DNA加合物BPDE等，可通过影响DNA甲基化和组蛋白乙酰化来调控细胞外信号调节激酶（ERK）和蛋白激酶C（PKC）等表达，从而促进肺动脉平滑肌细胞(PASMCs)异常增殖。同时，我们发现DNA甲基化CpG结合蛋白2(MBD2)通过表观遗传学影响某些基因的表达。在上述研究基础上，本课题拟探究MBD2在BPDE诱导的PASMCs异常增殖的作用及机制。我们先探究MBD2对PASMCs表观遗传学的影响，然后研究甲基转移酶（DNMT1）及HDAC1的抑制性蛋白MASPIN在BPDE诱导PASMCs异常增殖的作用，进而阐明MBD2对PASMCs异常增殖的影响及其机制。这是我们近十年研究的纵向延伸，更深层次探索BPDE致PASMCs异常，对阐明吸烟致肺血管损伤、修复、重构的机制具有重要的意义。

Abstract: Funded by the National Natural Science Foundation Project (NO. 81070044, 81370156), our previous studies have demonstrated benzo[a]pyrene diol epoxide (BPDE), one of DNA adducts induced by cigarette smoke in the body, could enhance proliferation of pulmonary artery smooth muscle cells (PASMCs) by regulating the expression of extracellular signal-regulated kinase (ERK) and protein kinase C (PKC) through epigenetic modifications, including DNA methylation and histone acetylation. In the meantime, we identified that methyl-CpG-binding domain protein 2 (MBD2) affected gene expression through epigenetic changes. Based on the above, this study intends to explore the role and mechanism of MBD2 in abnormal PASMCs proliferation induced by BPDE. In this study, we will evaluate the impact of MBD2 on PASMCs’ epigenetic change first. Subsequently, we will conduct our research on the role of DNA methyltransferase 1 (DNMT1) and MASPIN in abnormal PASMCs proliferation induced by BPDE. Finally, we are going to investigate the role and mechanism of MBD2 in abnormal proliferation of PASMCs induced by BPDE. This study, which extends our previous research longitudinally, provides a novel insight into the deeper mechanism of BPDE-induced proliferation of PASMCs and is crucial for elucidating the mechanism of cigarette smoke-induced pulmonary vascular injury, repair and remodeling.