通过集成分析小RNA和基因组高通量测序数据识别人类和灵长类疾病模型 microRNA的编辑和突变

Parkinson’s disease (PD) and Alzheimer's Disease (AD) are chronic neurodegenerative diseases with increasing incidence when people age. The exact causes of PD/AD are still not well-understood. And there are no cure for PD/AD. When the population of China is getting aged in a fast pace, it becomes an urgent task to carry out basic researches for PD/AD. MicroRNA (miRNA) are endogenous small regulatory non-coding RNAs and organized in different families. MiRNAs play important roles in PD/AD and almost all biological processes. Editing and mutations in miRNAs may change the complementarities between miRNAs and their targets, or change the secondary structures of their precursors that consequently lead to the deregulated expression levels of mature miRNAs. Thus, some editing and mutations in miRNAs lead to severe consequences and result in diseases. Existing evidences show that editing of miRNAs are more frequent in central nervous systems. However, it is still largely unknown whether the editing and mutations in miRNAs have involved in the initiation and/or progression of PD/AD. This research will use self-developed bioinformatics algorithm to identify editing and mutations in miRNAs from the small RNA high-throughput sequencing profiles of PD/AD clinical samples and PD/AD primate model animals. By integrating the analysis of corresponding genome sequencing or mutation data, the study will also try to develop methods for differentiating the editing and mutations in miRNAs. By comparing the identified miRNA editing and mutations in samples of disease and control groups, the clinical and biological significances of these events will be investigated as well. We will also use molecular and/or cell biology experimental methods to investigate the functions of the identified editing and mutations in miRNAs in PD/AD. These results will provide new insights into the translational researches of PD/AD.

帕金森病（PD）和阿尔茨海默病（AD）是老龄人口中的高发病，其确切的致病机理还不清楚，也缺乏有效的疗法。随着我国迅速的进入老龄化，迫切需要开展针对PD/AD的基础研究。MicroRNA（miRNA）是一种内源性分家族的具有调控功能的非编码RNA。miRNA在PD/AD和各种生理过程中都有重要作用。miRNA的编辑和突变会引起严重的后果，并引发疾病。已有的研究表明miRNA的编辑事件主要发生在人类的中枢神经系统中。但目前还不清楚miRNA的编辑和突变是否参与了PD/AD的发生和发展。本研究利用自主开发的生物信息学方法，从PD/AD组织和PD/AD动物模型组织的小RNA高通量测序和基因组测序数据中发现并区分miRNA的编辑和突变。通过对比正常样品，考察这些事件和疾病的关系。并通过细胞和分子生物学实验，考察这些事件在PD/AD中的潜在功能，为PD/AD的转化医学研究提供新的视角。

帕金森病（PD）和阿尔茨海默病（AD）是老龄人口中的高发病，其确切的致病机理还不清楚，也缺乏有效的疗法。随着我国迅速的进入老龄化，迫切需要开展针对PD/AD的基础研究。MicroRNA（miRNA）是一种内源性分家族的具有调控功能的非编码RNA。miRNA在PD/AD和各种生理过程中都有重要作用。miRNA的编辑和突变会引起严重的后果，并引发疾病。已有的研究表明miRNA的编辑事件主要发生在人类的中枢神经系统中。但目前还不清楚miRNA的编辑和突变是否参与了PD/AD及其他疾病的发生和发展。.本研究利用自主开发的生物信息学方法，从PD/AD脑组织及其他疾病组织的小RNA高通量测序和基因组测序数据中全面识别了并区分miRNA的编辑和突变事件。通过对比正常样品，我们发现了一个位于miR-497-5p的A-to-I编辑位点（mir-497_25_A_g）的编辑水平在PD病人的前额叶中显著上升。我们通过细胞和分子生物学实验，验证了编辑后的miR-497-5p抑制了OPA1和VAPB。在PD病人的前额叶中OPA1和VAPB显著下调，这可能是mir-497_25_A_g的编辑水平在PD病人的前额叶中显著上调导致的。OPA1在PD病人的黑质中也显著下调，VAPB在PD病人的黑质中有下调趋势，但不显著。在正常人群中，mir-497_25_A_g的编辑水平和年龄显著正相关，而在PD病人中该相关性消失。同时，OPA1和VAPB的表达水平和正常人的年龄显著负相关。我们也通过进化分析发现，编辑后miR-497-5p位于OPA1和VAPB的结合位点只在部分灵长类动物中保守。我们也通过细胞和分子生物学实验，验证了编辑后的miR-497-5p抑制了食蟹猴OPA1和VAPB，而不能抑制小鼠的Opa1和Vapb。这些结果提示mir-497_25_A_g的编辑水平显著升高可能是PD的致病机理或之一。

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