多层次系统研究SMN2基因表达的调控以开发治疗脊肌萎缩症的新途径

项目名称： 多层次系统研究SMN2基因表达的调控以开发治疗脊肌萎缩症的新途径

项目编号： No.81471298

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 华益民

作者单位： 苏州大学

项目金额： 70万元

中文摘要： 脊肌萎缩症（SMA）是婴儿中常见致死性运动神经元退化疾病，因SMN蛋白表达量不足引起。人类有两个平行同源基因SMN1和SMN2皆编码SMN。两基因的关键不同在于SMN2外显子7的一个沉默碱基变化（C6T）导致其RNA剪接缺陷,约90%的转录终产物没有外显子7，而产生的截短蛋白没有功能。SMA病人由于SMN1基因发生突变不能表达正常蛋白，但皆携带至少一个拷贝的SMN2；SMN2表达的少量全长SMN尽管不足以补偿SMN1的缺陷，对患者的生存至关重要。同时，病人SMN2的存在为药物干预提供了一个理想的靶点。近年来，以SMN2为靶点、通过高通量筛选提高转录或纠正剪接缺陷的分子一直是SMA药物开发的热点。但至今尚未有对SMN2基因表达在转录、RNA剪接、RNA稳定性和蛋白稳定性多层次进行系统研究的报道。本项目我们拟用最新技术对SMN2表达在上述几个层面进行全面系统的研究,以期发现治疗SMA的新途径。

中文关键词： 脊肌萎缩症；运动神经元生存基因2；基因表达；转录调控；RNA剪接

英文摘要： Spinal muscular atrophy (SMA), a fatal motor neuron degeneration disorder, is the most common genetic killer of infants.It is caused by reduced expression of the survival of motor neuron (SMN) protein. Humans have two paralogous genes SMN1 and SMN2 that encode SMN. The key difference between these two genes lies in a translationally silent nucleotide transition in SMN2 exon 7 (C6T)that reults in splicing defect of this exon; about 90% of SMN2 mature transcripts skip exon 7. The exon7-skipped transcript produces a truncated dysfunctional protein.In SMA patients, SMN1 is unable to express functional SMN due to point mutations or deletions in the gene; however, all patients still carry at least one copy of SMN2.The limited amount of full-length SMN produced by SMN2 cannot fully compensate for the loss of SMN1 but is essential for viability. Meanwhile, the presense of SMN2 in patients provides an ideal target for therapeutic intervention. Indeed, it has been a central theme in SMA drug development in recent years to identify molecules that promote SMN2 transcription or correct its exon 7 splicing through high-throughput screens. However,so far SMN2 expression regulation at levels including transcription,RNA splicing, RNA stability, and protein stability has never been systematically studied. In this project, we will conduct a comprehensive and systematic study of SMN2 expression at multiple levels using modern molecular technologies to develop new approaches to treating SMA.

英文关键词： spinal muscular atrophy;survival of motor neuron 2;gene expression;transcription regulation;RNA splicing