miR-375及其靶基因MTDH在醛固酮瘤中的表达及机制研究

Our research group is the first to report that the prevalence of primary aldosteronism (PA) in Chinese resistant hypertensive population is 7.1%，and has established diagnosis-to-treatment procedure and tumor tissue bank. During the profiling of miRNA microarray of tumor tissues from patients with aldosterone-producing adenoma(APA)，we found that miR-375 was closely associated with APA. Then by using H295R cell line，we explored the roles of MTDH gene and Wnt/β-catenin pathway in APA. Later in adrenal cortex selectively knock-out mice and miR-375/MTDH double knock-out mice，we further explored the influence of miR-375 and MTDH on the secretion，proliferation and apoptosis of targeted cells. Finally，we analyzed the levels of miR-375 and MTDH in blood samples from AVS as well as pro-and post-operation in patients with APA. This study aims to investigate the expression of miR-375 and its targeted gene including the signaling mechanism in APA，thus to provide prospects of new treatment and biomarkers in classification, prognosis and recurrence of APA.

本课题组首次报道了中国人群难治性高血压中原醛症患病率为7.1%，建立了原醛症的诊治流程及样本数据库，通过原醛症患者手术标本microRNA表达谱分析，发现miR-375与醛固酮瘤发病相关。利用H295R细胞系，检测miR-375及其靶基因MTDH在醛固酮瘤中的表达，探索MTDH基因变化与Wnt/β-catenin通路在醛固酮瘤中的作用，通过进一步建立肾上腺皮质条件性敲除小鼠和miR-375/MTDH双敲除小鼠模型，研究miR-375及 MTDH对于醛固酮瘤的增殖、凋亡以及分泌功能的影响。最后利用原醛症患者双侧肾上腺静脉采血标本及术前术后血清标本检测miR-375及MTDH表达水平。本课题旨在探寻miR-375及其靶基因MTDH在醛固酮瘤中的表达及机制研究，为治疗提供新靶点及新思路，同时对临床分型诊断，判断预后，预测复发提供新的生物标记物。

本课题利用已有的组织标本、临床资源、microRNA芯片结果，检测miR-375及其靶基因MTDH在醛固酮瘤中的表达， 发现MTDH基因变化与Wnt/β-catenin通路在醛固酮瘤中的作用，并建立肾上腺皮质条件性敲除小鼠和双敲除小鼠模型，观察模型老鼠表型（包括血压、血钾、醛固酮、肾素水平）。在临床应用中，利用已留取双侧肾上腺静脉采血（AVS）血清标本及外周血血清标本，检测肾上腺11中激素水平变化，研究激素水平与 miR-375及其靶基因MTDH的关系。此外，我们还对醛固酮瘤标本行KCNJ5 基因检测，分析临床表现与基因型关系。