LncRNA在肌萎缩侧索硬化中的作用及机制研究

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that mainly affects motor neurons. Patients suffering from ALS can simultaneously have both upper and lower motor neuron manifestations and usually die of respiratory failure within 3-5 years after onset. ALS is a progressive and incurable disease, which has significant impact on the patients' quality of life, and brings great burdens on their families as well as the society. However, the pathogenesis of ALS has not been fully understood so far. Our previous research project found that aberrant miRNA down-expression was involved in the pathogenesis of ALS. However, the mechanism of miRNA down-expression remains unclear. Recent studies have suggested that long non-coding RNA (lncRNA) may regulate the abnormal expression of miRNA. Therefore, dysregulation of lncRNA has emerged as a new mechanism involved in ALS pathogenesis. Our preliminary research using lncRNA expression microarray analysis showed aberrant lncRNA expression in the leukocytes derived from ALS patients. Furthermore, competing endogenous RNA(ceRNA) analysis revealed lncRNA ACHE as a ceRNA sponge absorbing miR-193b-3p and miR-3935-5p, which were found to be aberrantly expressed in ALS patients in our previous research project. In the present project, we plan to fully explore the aberrant lncRNA expression profiles in ALS patients based on the samples from ALS patients and animal models. By detecting the specific lncRNA disease-related changes in the plasma from different stages of ALS patients, we hope to get the fingerprint of ALS progression and provide novel tools for the early diagnosis of ALS. Furthermore, we will analyze the lncRNA expression profiles in the plasma and in the lumber part of spinal cord of transgenic ALS mice overexpressing the human mutant SOD1G93A. By comparing the two sets of lncRNA expression profiles, we can get the specific lncRNA expression profiles in ALS. We will also localize the differential expressed lncRNA in specific cell types using RNA-FISH. Furthermore, overexpression or supression of specific lncRNA in cultured primary spinal-cord motor neurons and transgenic mice models will be carried out to reveal the function and pathways of the lncRNA involved in ALS and explore new therapeutic targets for ALS. Overall, the results of the present project will propose a possible scenario that certain lncRNAs aberration is involved in the pathogenesis of ALS, and provide new insights into the early diagnosis and treatment for ALS.

肌萎缩侧索硬化（ALS）是一种致死性神经变性疾病，目前该病发病机制不清。近期研究表明lncRNA调节异常在神经变性疾病中发挥重要作用。申请者前期研究发现ALS患者外周血中存在lncRNA差异性表达；竞争性内源RNA关联分析发现某些差异表达的lncRNA参与miRNA的调节，而这些miRNA在申请者前一自然基金中被发现在ALS患者中异常表达。本项目拟进一步探索lncRNA在ALS发病中的作用及机制：检测患者、SOD1G93A小鼠外周血及腰段脊髓lncRNA表达，获得ALS疾病相关的生物标记物；运用RNA-FISH技术，明确差异lncRNA在不同神经细胞中的分布；体外培养模型小鼠脊髓运动神经元，干扰差异lncRNA的表达，明确其可能的调控机制；进一步在小鼠模型研究上述相关分子通路，寻找疾病可能的治疗靶点。本项目对阐明lncRNA在ALS发病中的作用及探索ALS的早期诊断和治疗策略具有重要意义。

肌萎缩侧索硬化（ALS）是一种致死性神经变性疾病，目前该病发病机制不清。近期研究表明lncRNA调节异常在神经变性疾病中发挥重要作用。我们从ALS患者外周血白细胞中，筛选出30个有表达差异的lncRNAs，并进一步进行了验证。我们发现lnc-DYRYK2-7:1、lnc-ABCA12-3:1、lnc-POTEM-4:7、lnc-CNTN4-2:1和lnc-NR3C2-8:1的表达在SALS患者中均是下降的。而lnc-XIST只在男性SALS患者中减少，在女性SALS患者中没有减少。我们对lnc-NR3C2-8、lnc-ABCA12-3及lnc-HIBADH-4进行了深入的机制研究。Ln-NR3C2-8通过结合miR-129-5p，从而解除miR-129-5p对USP10的抑制作用，进而导致p53的蛋白水平增强。Lnc-ABCA12-3被证实通过调控UBQLN1影响细胞泛素化水平、细胞自噬水平及mTOR信号通路。Lnc-HIBADH-4通过结合并调节miR-326表达并调节下游CTSD基因及蛋白功能变化，进而影响自噬-溶酶体信号通路变化。我们的研究对阐明lncRNA在ALS发病中的作用及探索ALS的早期诊断和治疗策略具有重要意义。

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