miRNA在肌萎缩侧索硬化发病机制中的研究

Amyotrophic lateral sclerosis (ALS）is a fatal neurodegenerative disease that mainly affects pyramidal upper motor neurons in the motor cortex and lower motor neurons in the brainstem and spinal cord. A majority of patients suffering from the disease will develop limb-weakness symptoms at the initial onset and die from respiratory failure within 5 years. ALS is a devastating, progressive, incurable disease, which has a significant impact on the lives of the patients, their families and the community. The characteristics of the disease and the absence of effective treatment throw a large burden onto the family group, society, and health care resources. Although the pathogenic mechanism of ALS remains unclear, misregulation of microRNAs has emerged as a new mechanism involved in ALS pathogenesis. In the present project, we plan to fully explore the aberrant miRNA expression in ALS based on the tissues from ALS patients and animals. By detecting the specific miRNA disease-related changes in the skeletal muscles and the peripheral blood leukocytes from ALS patients,we are hoping to get the fingerprint of ALS and provide more evidence on developing new targets for therapeutic approaches of ALS. Furthermore, we will conduct the miRNA expression profiles in the skeletal muscles and the peripheral blood leukocytes from transgenic ALS mice overexpressing the human mutant SOD1G93A. By comparing the two set of miRNA expression profiles, we can get the specific miRNA expression in the peripheral system of both ALS patients and mice. We will also identify the aberrant expressed miRNAs in central system of SOD1G93A mice. Using bioinformatic database search, we will screen out the principle targets of these specific miRNAs. Once the principle targets are identified, we will induce the simulator and inhibitor to the cultured primary motor neurons to figure out that if the specific miRNA directly regulate the principle target. The expression of the principle targets in both mRNA and protein level in SOD1G93A mice at different stages of the disease will be also detected to verify the correlation of aberrant miRNAs expression with disease progression. Overall, the results of the present project will propose a possible scenario that certain miRNAs aberration is invovled in the pathogenesis of ALS by regulating some principle targets in ALS.

肌萎缩侧索硬化（ALS）是一种严重致死性神经系统变性疾病，目前该病的病因和发病机制尚不明确。最近研究表明miRNA异常在神经退行性疾病的发病中起了重要作用。申请者前期工作也发现SALS患者骨骼肌及外周血白细胞中存在miRNA差异性表达。本项目拟通过患者和动物模型两方面研究miRNA在ALS发病机制中的作用。通过检测SALS患者和SOD1G93A小鼠这一经典的ALS模型的骨骼肌及外周血白细胞中miRNA表达谱的变化，有望获得ALS的指纹码，为开发药物作用新靶点从而改善ALS患者骨骼肌功能提供新的理论依据。同时运用激光捕获显微切割技术，检测不同生长时期的SOD1G93A小鼠脊髓运动神经元细胞中miRNA表达，筛选确定miRNA-靶mRNA-目标蛋白-蛋白功能的完整通路，明确外周系统与中枢系统miRNA变化的可比性及一致性，对进一步阐明miRNA变化对运动神经元退变的影响具有指导意义。

研究背景：肌萎缩侧索硬化(ALS)是一种严重致死性神经系统变性疾病，目前该病的病因和发病机制尚不明确。最近研究表明 miRNA 异常在神经退行性疾病的发病中起了重要作用。主要研究内容：本项目通过对ALS患者外周血白细胞的miRNA表达谱进行了分析，探究了差异miRNA在ALS患者中的相关性研究及在动物中的可比性，探讨了hsa-miR-193对神经母细胞瘤细胞的生物学特性的影响，进一步深入探讨了hsa-miR-193在运动神经元样细胞中的作用及功能。主要研究结果：1）成功筛选并验证了has-miR-183, has-miR-193b, hsa-miR-451 and has-miR-3935这 4个在ALS患者中差异表达的miRNA；2）发现了差异表达miRNA与ALS患者的临床表现相关；3）同时发现了hsa-mir-183，hsa-mir-193 and hsa-mir-451这3个miRNA在SOD1G93A小鼠中差异表达；4）发现hsa-miR-193影响了SH-SY5Y细胞的生物学特性及可能的机制，下调hsa-miR-193后SH-SY5Y细胞增殖抑制；5）miR-193b-3p可能通过调控TSC1/mTOR信号通路而调控细胞自噬，进而影响神经元的存活和凋亡。本项目发现了miRNA的异常表达在ALS发病中具有重要的作用，并深入探讨了miR-193在ALS发病中的具体作用机制，为ALS新的治疗药物的开发提供了新的思路。.

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