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题名 山黧豆神经性中毒的细胞信号途径及分子机理研究
姓名 谭瑞玥
院系 生命科学学院
专业 生态学
学位名称 理学硕士
外文题名 Cellular Signal Transduction Pathways and Molecular Mechanism of Neurolathyrism
第一导师姓名 熊友才
关键词 L-β-N-草酰-α,β-二氨基丙酸;神经性山黧豆中毒;神经退行性疾病;钙稳态失调;氧化胁迫;基因表达概况分析;细胞骨架;线粒体膜电位;细胞外基质与受体作用
外文关键词 L-β-ODAP;neurolathyrism’s disease;neurodegeneration disease;deregulation of [Ca2+]i homeostasis;oxidative stress;gene expression profiling;cytoskeletal;mitochondrial membrane polential;ECM-receptor interaction
学科 理学
摘要 山黧豆是优良的旱地作物,长期过量食用会导致人畜神经性山黧豆中毒,其在发展中国家时有发生,但机理尚不明确。本研究用离体培养的人神经胶质瘤M059K细胞系,以Glu为对照,用从山黧豆种子提取纯的β-ODAP处理细胞,通过分析细胞存活率与生长动态确定加药浓度,检测β-ODAP在细胞增殖率、细胞形态与细胞周期的变化、细胞死亡方式与DNA损伤动态、线粒体膜电位与细胞骨架方面、钙稳态调节状况和基因差异表达的动态及其表达的通路与网络方面对细胞的影响。结果表明,β-ODAP造成的细胞凋亡和坏死并不是其损伤神经元的主要方式,β-ODAP可以结合并异常激活神经细胞的AMPA受体,导致Ca2+产生细胞内流,使得β1整合蛋细胞表面表达量上升,进一步使黏着斑激酶磷酸化增加,FA蛋白单元在细胞微丝上大量聚集,诱使桩蛋白的表达量,影响细胞骨架的聚合,引起神经元营养障碍。此外大量Ca2+内流,导致钙稳态失调,细胞生存力下降,线粒体膜电位改变,ATP合成受阻,ROS生成增加,进而对生物膜造成损伤,以致神经元损伤而死亡。 此外,神经退行性疾病之间具有共同或相互关联的分子机制。本研究的成果不仅为神经性山黧豆中毒的细胞和分子机制的揭示奠定了良好的基础,也为其他神经退行性疾病的深入研究提供了新的信息。
外文摘要 Grass pea (Lathyrus sativas L.) has received great interest as an arid conditions adapted plant over the past several decades. Long-term excessive consumption of Lathyrus sativus seeds is considered as the cause of neurodegenerative disease neurolathyrism, which is a form of human and animal spastic paraparesis. Neurolathyrism often occurs in developing countries although the mechanism was unclear. In this study, human glioma cell line M059K were treated with β-ODAP, the glutamate was used as the control. The cell proliferation rate, changes of cell cycle, cell death manner, the dynamic on DNA damage, mitochondrial membrane potential, changes of cytoskeleton, calcium homeostasis and gene expression changes were investigated. The result indicated that the AMPA receptor might abnormally activated by β-ODAP, induced the influx of calcium, leaded to the over expression of integrinβ1, result in the FAK and tau hyperphosphorylation, over aggregation of FA unit on microfilament and over expression of paxillin, finally cause the disintegration of microfilament and microtubule. On the other hand, the over influx of calcium would lead to the disequilibrium of intracellular calcium homeostasis, further enhanced oxidative stress and causes mitochondria injury, induces damage or death of cells. In addition, by analyzed the results between ours and related studies on other neurodegeneration diseases, it showed that the molecular mechanisms of neurodegeneration diseases were correlated with each others. This study laid a good foundation for revealing the mechanisms of neurolathyrism in vitro, but it also provided the potential for further investigation of other neurodegeneration diseases.
研究领域 细胞生物学、分子生态学
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