OSMR基因在压力负荷致小鼠心肌肥厚中的作用及其机制

The prevalence rate of primary hypertension in Xinjiang Uygur Autonomous Regionat is at a high level, however, the Uygur population hypertension prevalence rate is lower than the Han and Kazakh population, which may be associated with certain gene polymorphisms. At present, there is no further study on the function of such genes in the development of hypertension and its complications. Our preliminary data indicated that OSMR gene was involved in the development of cardiac hypertrophy, the common complications of hypertension. In order to clarify the underlying mechanisms, we aim to construct the pressure overload induced cardiac hypertrophy models in wild-type and OSMR gene knockout mice, and observe the different process of changes in the phenotype of cardiac hypertrophy. Then, we explore the effect of OSMR on the expression of IL-6 family cytokines and their receptors , the signaling pathways on gp130, MAPKs, PI3k/Akt/GSK3β andJAK/stat signaling pathways. In addition,we also investgate the effect of OSMR gene on cardiac myocytes hypertrophy, and the changes of signaling pathways related to OSMR gene in vitro by using primary neonatal rat cardiac myocytes with silence or over-expression of OSMR gene, which are stimulated by AngⅡ and OSM. These studies are designed to provide new targets for the prevention and treatment of cardiac hypertrophy.

新疆维吾尔族自治区高血压病患病率在全国处于高水平，其中维吾尔族人群高血压病患病率较汉族和哈萨克族人群低，可能与某些基因多态性相关，目前尚无对此类基因在高血压病及其并发症发生发展过程中功能学机制方面的深入研究。本项目以高血压病常见并发症心肌肥厚发生机制为研究对象，以可能参与心肌肥厚的抑瘤素受体(OSMR)基因为研究靶点，用野生型、OSMR基因敲除小鼠构建压力负荷诱导的心肌肥厚模型，观察心肌肥厚表型变化，探讨OSMR基因对IL-6家族细胞因子及其受体表达以及MAPKs、PI3k/Akt/GSK3β和JAK/STAT在内的多条心肌肥厚相关信号通路的影响。同时建立OSMR基因沉默和过表达OSMR基因的大鼠原代心肌细胞模型，以AngⅡ和OSM分别刺激以及共刺激，观察OSMR基因对心肌细胞形态、相关蛋白表达和信号通路的的影响，阐明其机制，并建立高血压病并发症相关靶基因功能学机制的系统研究模式。

新疆维吾尔族自治区高血压病患病率在全国处于高水平，其中维吾尔族人群高血压病患病率较汉族和哈萨克族人群低，可能与某些基因多态性相关，目前尚无对此类基因在高血压病及其并发症发生发展过程中功能学机制方面的深入研究。本项目以高血压病常见并发症心肌肥厚发生机制为研究对象，以可能参与心肌肥厚的抑瘤素受体(OSMR)基因为研究靶点，用野生型、OSMR基因敲除小鼠构建压力负荷诱导的心肌肥厚模型，观察心肌肥厚表型变化，探讨OSMR基因对IL-6家族细胞因子及其受体表达以及MAPKs、PI3k/Akt/GSK3β和JAK/STAT在内的多条心肌肥厚相关信号通路的影响。研究发现OSMR基因缺失促进压力负荷诱导的心肌肥厚，恶化压力负荷诱导的小鼠心功能障碍，主动脉缩窄术后四周，OSMR KO小鼠心肌组织中OSM、p-stat3 s727、p-stat3 s705、LIFR的蛋白表达均有明显增加，提示OSMR基因缺失对压力负荷诱导的心肌肥厚的影响可能是通过对JAK/STAT信号途径调节而实现的。