miRNA-200c在海马神经元衰老退化中的作用和分子机制

Abstract：microRNA involved in neural development, differentiation, it is also participate in the occurrence and development of central nervous system (CNS) related major diseases such as neurodegenerative diseases. It has been reported that the important signaling molecules, CREB1 and Bcl2 activity are inhibited in the aging process. Preliminary miRNA microarray found, miR-200c expression increased significantly in hippocampus in the aging process, and bioinformatics analysis found that there were predicted miR-200c binding sites on CREB1 and Bcl2 mRNA 3'-UTR sequences. We speculated that miR-200c inhibit the expression of CREB1 and Bcl2 through an interaction with CREB1 and Bcl2 mRNA 3'-UTR, and then involved in the aging process of hippocampal neurons. To confirm the research hypothesis, the molecular mechanism of miR-200c function, and its effect on the growth of hippocampal neurons and the LTP of elderly hippocampal slices were researched with molecular biology, dual luciferase detection etc. technologies in vivo and vitro. This project will provide new diagnostic and therapeutic targets for effective prevention and treatment of neurodegenerative diseases.

摘要：miRNA 参与了神经系统发育、分化，它也与神经退行性疾病等中枢神经系统重大疾病的发生发展相关。有文献报道，在衰老过程中，重要的信号分子CREB1和Bcl2的活性受到抑制。前期的miRNA芯片检测发现，在老龄化进程中，海马组织中miR-200c的表达明显增加，而且，生物信息学分析发现，CREB1和Bcl2的mRNA 3'-UTR序列上存在着miR-200c的预测结合位点。我们推测miR-200c通过与CREB1和Bcl2的mRNA 3'-UTR序列结合，抑制CREB1和Bcl2的表达，进而参与海马神经元的衰老进程。为证实这一研究假想，我们采用分子生物学，双荧光素酶检测等技术，从在体到细胞两个层次，检测、研究miR-200c作用的分子机制，及miR-200c对海马神经元生长和老年海马脑片LTP的影响。本课题将为神经退行性疾病的有效防治提供新的诊断和治疗的靶点。

miRNA 参与了神经系统发育、分化，它也与神经退行性疾病等中枢神经系统重大疾病的发生发展相关。此项研究采用分子生物学、双荧光素酶检测、免疫荧光检测等技术，从在体到细胞两个层次，研究miRNAs作用的分子机制。首次发现：1）miR-200c通过结合CREB1 mRNA 3'-UTR抑制CREB1表达；2）miR-200c-3p通过结合Bcl2 mRNA 3'-UTR抑制Bcl2表达；3）miR-15b-5p通过结合BDNF mRNA 3'-UTR抑制BDNF表达。上述结果证实，miR-200c、miR-200c-3p和miR-15b-5p参与与老龄化相关的神经退行性疾病的发生、发展。miR-200c、miR-200c-3p和miR-15b-5p可作为探索老龄化相关疾病的诊断和治疗及神经元功能保护的新靶点。