缺血性脑血管病的发病率逐年增加，成为世界性重大公共卫生问题。转录因子KLF11和PPARγ在缺血性脑血管病的发病过程中起着关键的调控作用，然而有关两者在缺血性脑血管病发病过程中的共调节作用研究甚少，且局限于单个蛋白或分子水平的基础研究，缺乏系统的人群流行病学研究。mRNA水平受到miRNAs的干扰会导致蛋白表达水平的差异，基于KLF11和PPARγ基因miRNAs的人群流行病学报道尚处空白，本课题拟开展病例-对照研究，从蛋白及miRNAs水平，采用多因素Logistic回归、叉生分析和交互作用分析，探索KLF11、PPARγ单独和联合作用乃至同环境交互作用与缺血性脑血管病易感性的关系。阐明KLF11和PPARγ在缺血性脑血管病发生、发展中的作用，寻找较特异的与缺血性脑血管病发病风险相关的分子标记物，为缺血性脑血管病的早期防治提供新的思路。

With the population aging, the incidence of ischemic cerebrovascular disease increased year by year, to become an important public health problem in the world. Transcription factor KLF11 and PPARγ plays a key regulatory role in the development of ischemic cerebrovascular diseases. Currently KLF11 and PPARγ and ischemic cerebrovascular diseases, mostly focused on the development of protein and molecular level of basic research, the crowd is still a lack of systematic epidemiological studies. The mRNA level by the interference of miRNAs could lead to differences in the levels of protein expression. Epidemiological reports based on KLF11 and PPARγ miRNAs is still blank. From the perspective of epigenetics, the subject carried out population-based Case-control study of ischemic cerebrovascular disease. Using multivariate logistic regression analysis, crossover analysis and interaction analysis, the subject will explore KLF11 and PPARγ alone and combined effect and environmental interactions as well as with ischemic cerebrovascular diseases susceptibility on the level of protein and miRNAs. Clarify occurrence and development functions of KLF11 and PPARγ in ischemic cerebrovascular diseases, search for more specific molecular markers associated with risk of ischemic cerebrovascular disease, provide experimental evidence and theoretical reference for early prevention, diagnosis and treatment of ischemic cerebrovascular disease.

缺血性脑血管病具有发病率高、致残率高和死亡率高的特点。随着当今社会人口老龄化，缺血性脑血管病的发病率呈逐年上升趋势，目前已成为世界公认的重要公共卫生问题。阐明缺血性脑血管病发病机制、寻找较特异的与缺血性脑血管病发病风险相关的分子标记物，做到早期诊断及有效的干预治疗是提高脑中风患者生存率、提高生活质量的关键。鉴于转录因子KLF11 和PPARγ在缺血性脑血管病的发病过程中起着关键的调控作用，结合我们已完成的国家自然科学基金项目结果显示局灶性脑缺血损伤可以导致大鼠脑组织miRNA表达广泛改变，并通过生物信息学分析，我们提出在脑缺血损伤发病过程中可能存在miR138-5p/KLF11/PPARγ这一新的调控通路。本研究以缺血性脑中风患者血清样本为基础，应用实时定量PCR和酶联免疫吸附实验检测病例组与对照组外周血中miRNA138-5p的含量和KLF11、PPARγ的蛋白表达情况。应用荧光酶素报告基因检测方法验证核转录因子KLF11对PPARγ基因转录调控作用。利用过表达技术和靶向封闭技术在体外神经细胞拟缺血损伤模型上确认miR138-5p对KLF11 的调控作用，通过荧光酶素报告基因检测方法确认miR138-5p对KLF11 调控作用的靶位点。综合分析miRNA138-5p/ KLF11/PPARγ缺血损伤调控通路与缺血性脑血管病发生发展的关系。研究结果表明，miRNA138-5p/ KLF11/PPARγ损伤调控通路在脑缺血损伤发病机制中具有重要的作用，抑制神经细胞内miRNA138-5p的表达，可上调其靶蛋白KLF11的表达，进而增强其下游基因PPARγ的表达，最终有效对抗脑缺血性损伤。提示miR138-5p可能成为与脑缺血损伤发病风险相关的分子生物学标志，为脑缺血损伤临床筛查以及预后判断提供新的切入点，为临床个体化治疗方案的制定提供实验依据及理论参考。