Leptin信号传导通路调控区功能性SNP与冠心病复发和预后相关研究

leptin is a peptide hormone which was secreated from adipocyte. High level leptin promote oxygen free radical creation thus induces cell damage, platelet aggregation and the occurrence and development of atherosclerosis. But for the target regulation mechanism is still not clear. We have studied using the predict software of miRNASNP and TRANSFACR○R and the database of Regulome-db、NCBI-SNP and Hapmap-SNP to screening the functional SNP in minor allele frequency over 10% in the whole sequence of signal transduction gene regulatory region with Chinese population. In this study, we observe the allele frequency of SNP and the level of Leptin and TNF-α，to investigate the effect of genetic and enviroment factor interaction on the CAD and the rate of revascularization 2 year after percutaneous coronary intervention through luciferase assay, CHIP and western blot methods detect miRNA on target and investigate the control effect of miRNA on different genotype. This will provide the theoretical basis for early screening of high risk population, primary prevention of coronary artery disease, and the early clinical intervention.

Leptin是属于脂肪细胞分泌的肽类激素，高水平Leptin促进氧自由基生成，使细胞遭到损伤，促进血小板的聚集，诱发血栓形成的同时促进动脉粥样硬化的发生和发展。但对靶标调控作用机制尚不清楚。课题组前期应用TRANSFACR○R、miRNASNP预测软件以及Regulome-db、NCBI-SNP和Hapmap-SNP数据库，在Leptin信号传导通路基因整体调控区序列中筛选出汉族人群中次要等位基因频率大于10%的功能性SNP。本研究观察上述SNP基因分布频率、血浆Leptin和TNF-α等水平，调查上述遗传和环境因素的交互作用对冠心病经皮冠状动脉介入治疗后疗效和2年无病生存率的影响，并通过荧光素酶检测、CHIP和蛋白印迹等方法鉴定转录因子和miRNA对靶标的影响，探讨对不同基因型的调控作用，为筛选冠心病复发高危人群、一级预防以及早期临床干预和个体化治疗提供理论基础。

冠心病是世界范围内的主要死亡原因之一，仅在美国就造成了17%的死亡。冠心病带来的挑战不仅对工业化国家至关重要，而且对发展中国家来说仍然是公共卫生问题。课题组前期应用TRANSFACR○R、miRNASNP预测软件以及Regulome-db、NCBI-SNP和Hapmap-SNP数据库中筛选出汉族人群中次要等位基因频率大于10%的功能性SNP。本实验从候选基因位点最终筛选4个基因位点并通过病例对照研究发现4个基因位点与冠心病相关，为筛选冠心病复发高危人群、一级预防以及早期临床干预和个体化治疗提供理论基础。此外我们还进行了细胞功能学的研究，阐述了NERP-1间接地抑制PVN MNCs的活动的影响机制。提示了NERP-1间接的抑制下丘脑室旁核神经分泌大细胞的活动与分泌；以及促肾上腺皮质激素释放因子调节小鼠小脑浦肯野细胞的活性机制。