组蛋白去乙酰化酶介导下的miRNA在JAK2V617F突变阴性的骨髓增殖性疾病中的功能研究

项目名称： 组蛋白去乙酰化酶介导下的miRNA在JAK2V617F突变阴性的骨髓增殖性疾病中的功能研究

项目编号： No.81200350

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 高申孟

作者单位： 温州医科大学

项目金额： 23万元

中文摘要： JAK2V617F突变导致JAK2/STAT信号通路的异常活化是骨髓增殖性疾病（MPDs）发病机制中的关键因素，然而JAK2V617F突变阴性的MPDs发病机制尚未明确。课题组前期实验发现两种miRNAs：miR-101/miR-375 在JAK2V617F 突变阴性MPDs 患者中表达明显低于突变阳性患者，而miR-101/miR-375本身低表达又可能受组蛋白去乙酰化酶(HDACs)调控。我们拟进一步通过体外靶基因实验、集落形成实验、裸鼠移植肿瘤等实验观察过表达的miR-101/miR-375 对JAK2/STAT通路抑制作用；用HDACs特异性抑制剂验证miR-101/miR-375是否受HDACs调控。本研究分别从细胞、动物模型、临床标本三个方面来阐述miR-101/miR-375在MPDs中的作用机制，为JAK2V617F突变阴性的MPDs诊断和治疗提供新思路和新策略。

中文关键词： 骨髓增殖性肿瘤；微小RNA；组蛋白去乙酰化酶抑制剂；；

英文摘要： The constitutive activation of the Janus kinase 2/singal transducer and activator of transcription(JAK2/STAT) signaling pathway, which is activated by JAK2V617F mutation, is the key factor leading to myeloproliferative diseases (MPDs).However the mechanism of MPDs without JAK2V617F mutation is still unknown. Explaining the factors which result in the constitutive activation of JAK2/STAT signaling pathway is the hot and difficult points in the mechanism of MPDs without JAK2V617F mutation. Our previous study showed that miR-101/miR-375 were significantly downregulated in patients without JAK2V617F mutation than those with JAK2V617F mutation. Moreover the downregulation of miR-101/miR-375 is possibly regulated by overexpression of histone deacetylases (HDACs) in MPDs. We are planning to take software predication, MTT test, clonogenic activity, and nude mice xenograft tumor formation to test the inhibition of JAK2/STAT signaling pathway through the overexpression of miR-101/miR-375. Moreover the specific inhibitors of HDACs will be taken to prove whether miR-101/miR-375 are modulated by HDACs. Our study contributes to explore the functional role of miR-101/miR-375 in MPDs. Furthermore these study will also provide the new strategy for the diagnosis and treatment of MPDs without JAK2V617F mutation. Finally we

英文关键词： myeloproliferative neoplasm；miRNA；histone deacetylases inhibitor；；