生物信息学在阿尔茨海默疾病研究中的应用
文献类型：学位论文
| 作者 | 陈舜梅 |
| 学位类别 | 博士 |
| 答辩日期 | 2014-04 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 黄京飞 |
| 关键词 | 淀粉样斑 物理化学特征 进化分析 分子动力学模拟 药物虚拟筛选 |
| 其他题名 | Bioinformatics applications in Alzheimer’s disease research |
| 学位专业 | 细胞生物学 |
| 中文摘要 | 由Aβ和tau蛋白淀粉样纤维聚集与阿尔茨海默疾病紧密相关。这些肽段一些较短的区域驱动了淀粉样斑聚集的发生。因此了解这些区域发生的聚集对治疗阿尔茨海默疾病是很重要的。通过构建数据库，并使用生物信息学工具进行数据挖掘是一探索疾病的方法。通过比较淀粉样斑聚集片段和非聚集片段能够揭示影响聚集形成的影响因素，如果能够把这些因素与阿尔茨海默疾病机制相结合，就为我们提供了预防和治疗阿尔茨海默疾病的策略和治疗手段，同时为治愈阿尔茨海默疾病提供理性药物设计的依据。 为了能够调研肽段对淀粉样纤维的形成的特性，我们构建了一个比较全的数据集，包括了聚集片段和非聚集片段的信息。通过对数据集的统计学分析，我们得到了以下的结论：从序列的角度，聚集片段和非聚集片段在氨基酸组成上几乎没有差异，对Aβ这种具有二元结构性的聚集片段，需要一个更加疏水的环境，暗示了疏水环境是形成淀粉样斑的一个因素。 我们也分析了聚集片段的其它物理化学特征，并与非聚集片段进行比较，得出聚集片段有着明显的区别于非聚集片段的物理化学特征。与非聚集片段相比，聚集片段具有低净电话，低静电势，溶剂可及表面积及B因子较小的特征，此外，它们有着丰富的疏水氨基酸，并倾向于形成氢键。对数据集的分子动力学模拟支持了聚集片段倾向刚性这一新特征的假说。更进一步的是，在disorder蛋白中出现聚集片段并不与聚集片段低柔性这一观察结果相矛盾。 从进化的角度研究发现，对聚集片段和非聚集片段在保守性上是几乎没有差异的。但是出乎意料的是，进化快的氨基酸对淀粉样斑的形成有贡献作用，此外，这些进化快的氨基酸并不是任意进化的，相反，它们都遵循相同的趋势，形成均一的物理学特征。我们的工作证明了在进化过程中的其中的一个趋势。 |
| 英文摘要 | Amyloid fibrillar aggregates of Aβ and tau are involved in Alzheimer disease. Short regions in these peptides trigger this aggregation. It is important to understand the basis of such short regions aggregation and amyloidosis for therapeutic intervention of Alzheimer disease. Set up datasets and use bioinformatics tool to data mining is an one way to explore diseases. Comparison of features of amyloidogenic segments with those of non-amyloidogenic segments could reveal factors that encode messages underlying the formation of amyloids aggregates. Such information combine with the mechanism of Alzheimer disease could be useful when designing a therapeutic regimen for prevent and treatment of Alzheimer diseases involving Aβ and tau aggregation, and provide basis for rational design of drugs for this neurodegenerative diseases. To investigate the properties of peptides and their effects on the amyloid fibril formation, we construct a comprehensive an amyloidogenic protein database, which include the information of the amyloidogenic segments and non-amyloidogenic segments. Based on a statistical study of this database, we arrived at the following conclusions. There is no significant difference in amino acid composition in sequence charcter, and for Aβ, such the discordants-containing amyloidogenic segments are observed with a more hydrophobic environment, which suggests that the hydrophobic environment might be one of the properties leading to the amyloid formation. We also analysis other specific physico-chemical properties of amyloidogenic segments and compare them with non-amyloidogenic segments. First, amyloidogenic segments are characterized by lower values for average net charge, electrostatic potential, solvent accessible surface area and B-factor when compared to the non-amyloidogenic segments of the same proteins. Second, they are enriched in hydrophobic residues and have a tendency to form hydrogen bonds. Thus, amyloidogenic segments have distinct physico-chemical properties that are different from those of non-amyloidogenic segments. Third, and quite unexpectedly, our dynamic simulation studies support the hypothesis that amyloidogenic segments have lower average flexibility than non-amyloidogenic segments. Furthermore, the presence of amyloidogenic segments in disordered proteins does not contradict the observation that amyloidogenic segments are less flexible. From evolustion study, there is almost no difference in evolutionary conservation between amyloidogenic segments and non-amyloidogenic segments. Beyond expec tation, rapidly evolving amino acid contribute to amyloid formation. In addition, the rapidly evolving amino acid is not evolve randomly, instead, they follow the same trend that with the uniform of physical characteristic. Our work demonstrated one aspect of such trend in evolution. |
| 语种 | 中文 |
| 公开日期 | 2014-07-14 |
| 源URL | [http://159.226.149.42:8088/handle/152453/7952]  |
| 专题 | 昆明动物研究所_结构生物信息学 |
| 推荐引用方式 GB/T 7714 | 陈舜梅. 生物信息学在阿尔茨海默疾病研究中的应用[D]. 北京. 中国科学院研究生院. 2014. |
入库方式： OAI收割
来源：昆明动物研究所
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