血清反应因子在慢性阻塞性肺疾病相关骨骼肌消耗发病中的变化及机制研究-changes and mechanism of serum response factors in the pathogenesis of skeletal muscle consumption associated with chronic obstructive pulmonary disease.docx

差异有统计学意义（P0.05），RhoA、RhoGDI 和 SRF 未见明显变化。3. CCG-1423（0，20um/ml）干预 C2C12 细胞 48h 后，SRF 蛋白表达明显减少，IGF-1（P0.001）、Myh2（P0.001）、Acta1（P0.001）mRNA 表达明显减少。 总结：1. 成功建立 COPD 小鼠模型：该模型具备 COPD 基本生理（肺阻力升高、肺顺 应性下降）及病理（肺部炎症细胞浸润、肺气肿）改变，存在血清炎症因子 水平升高和骨骼肌消耗。PM10 可作为稳定可靠的 COPD 建模监测指标；2. 转录因子活性谱芯片筛选：通过对 COPD 小鼠和对照组小鼠股肌核蛋白进行 转录因子活性谱芯片的筛选，发现了多个差异表达的转录因子，其中，SRF 在 COPD 小鼠股肌中活性下调；3. SRF 的表达、定位及下游靶基因检测：COPD 小鼠骨骼肌内 SRF 活性降低， 表现在核定位变化，磷酸化 SRF 减少。SRF 靶基因 IGF-1、Myh2 和 Acta1 mRNA 表达减少，SRF 活性改变可能参与 COPD 相关骨骼肌消耗发生；4. SRF 核定位变化的可能机制：TNF-α 可能通过抑制 STARS/Rho 信号，引起SRF 定位变化。全文结论：全身炎症反应可能通过下调 STARS/Rho/SRF 通路参与 COPD 骨骼肌萎缩的 发生。关键词：慢性阻塞性肺疾病动物模型；骨骼肌消耗；转录因子；血清反应因子； 核定位；STARS；RhoA；RhoGDI。Reduced nuclear translocation of serum response factor is associated with skeletal muscle wasting in a cigarette smoke-induced mouse model of chronic obstructive pulmonary diseaseAbstractBackgroud:Chronic obstructive pulmonary disease is a common complex of diseases defined by persistent airflow limitation and progressive lung function decline. Globally, it is almost the primary burden of disease and a major cause of death. Besides of the desease state in lung, COPD is often complicated with skeletal muscle atrophy, which also attributes to reduced quality of life, increased healthcare utilization and mortality in COPD. The mechanisms underlying skeletal muscle wasting in COPD are largely unknown. It is thought that the dysregulations of multiple functional related genes might be involved in this process. We speculated there might be a pannel of transcription factors that dominate these dysregulations. Therefore, we used a oligonucleotide array-based transcription factor assay (OATFA) to screen the differential expression of various transcription factors in the skeletal muscle from COPD and control mice, and found that serum responsive factor (SRF) was differentially expressed.SRF is known as a crucial transcriptional factor for muscle-specific gene expression, thus playing a central role in the regulation of skeletal muscle d