RNA结合蛋白HuR在COPD状态下气道上皮细胞功能形态异常的地位、作用及干预策略

Airway epithelial cells dysfunction is the key pathgenic event underlying chronic obstructive pulmonary disease (COPD), along with the overexpression of relative genes. Related studies suggested mRNA stability regulation mechanism might be involved in airway epithelial cells dysfunction in COPD. Human antigen R (HuR) is an ubiquitously expressed RNA-binding protein, and is known to modulate mRNA stability of various proteins, including several growth factors, inflammatory cytokines, extracellular matrix regulating proteins, etc. Our previous studies have shown that HuR-mediated mRNA stability control participated in PDGF-induced Cyclin D1 overexpression in airway smooth muscle cells. The present study aims to explore whether HuR is also be involved in airway epithelial cells dysfunction in COPD using both in-vivo and in-vitro methods. The alterations of HuR expression and activities in airway epithelial cells will first be investigated. Then, the role of HuR in airway epithelial cells dysfunction in COPD will be studied using RNA inference and transgenic methods. Finally, the protective effects of AMPK-activation on airway epithelial cells dysfunction will be explored by using AICAR. The present study will not only help to deepen our current understanding of airway epithelial cells dysfunction in COPD, but also be of significance in searching novel intervention methods for COPD.

气道上皮细胞形态功能异常是COPD发生发展的重要机制，多种功能蛋白过表达是关键细胞内事件。气道上皮细胞功能蛋白过表达过程有mRNA稳定性调控机制参与。人抗原R(HuR)作为广泛存在的RNA结合蛋白，参与调控包括炎症因子、细胞外基质调节蛋白在内多种因子的基因表达。项目组前期研究证实，HuR介导的mRNA稳定性调控机制参与PDGF诱导的气道平滑肌细胞Cyclin D1过表达和细胞增殖。据此我们推测，HuR介导的mRNA稳定性调控机制很可能也参与COPD状态下气道上皮细胞功能蛋白的过表达。本课题拟采用体内和体外实验相结合的方法，观察COPD状态下气道上皮细胞HuR表达及活性的变化，应用RNA干扰技术和转基因技术验证HuR在气道上皮细胞功能蛋白过表达过程中的地位和作用，观察AMPK激活剂能否通过抑制HuR，对COPD气道上皮细胞形态、功能异常机制的认识，以及寻找干预COPD的新靶点均具有重要意义。