系统辐射生物学的初步探索研究

发布时间：2018-06-19 00:18

本文选题：辐射生物学 + 系统生物学　；参考：《中国科学院研究生院（近代物理研究所）》2015年博士论文

【摘要】：辐射生物学是一门有着悠久历史的学科,主要研究各种电离辐照和非电离辐照的生物学效应,对于临床的放射治疗、空间辐照效应等等领域有着指导性意义。近十多年来,在生命科学领域,在已有的各种组学的研究基础上,许多顶尖的生命科学家又提出了系统生物学这一新概念,迅速得到了整个生命科学界的关注重视。系统生物学主要指对于复杂生命系统的整体建模工作,是一个囊括了各种组学、信息学和系统学的综合学科。它打破了生命科学中传统的还原论的思想,将基因组、蛋白组和代谢组等等不同层面的组学信息综合利用,提倡在系统的水平理解生命系统中存在的各种机理。本论文试图用系统生物学的一些方法手段来研究辐照细胞的特性和机理,对于如何结合辐射生物学和系统生物学做了初步的研究。通过细胞水平解释了电离辐照后92-1细胞的周期动力学的变化,通过分子水平的建模解释了电离辐照后细胞命运与关键的p53-p21通路之间的关系。从这些工作中,初步确认了系统辐射生物学建立的可能性。全文的内容安排如下:第一章介绍了系统辐射生物学的相关背景,具体包括1)系统生物学的一些基本内容和组成部分,各种组学研究的最新进展的介绍和总结;2)辐射生物学的简单介绍,先前有一些学者提出了系统辐射生物学的概念,但相应的研究并未全面展开;3)数学建模,特别是动力学建模的一些简单概念。第二章介绍了在分子水平上,利用简单的唯象模型对于电离辐照后92-1细胞的周期动力学进行了计算机模拟研究。该模型考虑了辐照后92-1细胞在细胞周期G1期和G2期周期检验点可能受到的阻滞,得到了电离辐照后92-1细胞的各周期细胞比例的变化,能较好地符合实验结果。电离辐照造成的基因组各种损伤的修复时间的定量关系一直是个悬而未决的问题,我们的模拟结果支持在辐照剂量较大时,辐照受损的细胞总的修复时间和辐照剂量呈正比关系。模拟结果同时暗示了相比于G2期检验点,G1期检验点更为严格,这使得细胞即使修复后能通过G2期检验点也大多会被阻滞在G1期,这和前人的推论是吻合的。相比于前人对于周期动力学的数学建模,我们的唯象模型更为直观,并且可扩展性强。第三章介绍了在细胞水平上,关于电离辐照后细胞命运的数学建模工作。电离辐照后的细胞命运在中期分为1)修复完成通过周期检验点进入正常细胞周期;2)长时间周期阻滞;3)有丝分裂灾变。电离辐照后细胞的最终命运则包括细胞衰老、细胞凋亡、细胞自噬,等等。基于我们课题组已有的实验,并通过大量的文献调研,我们发现电离辐照后细胞的中期命运和p53-p21信号通路有着密切的关系,我们建立的数学模型能很好地重现电离辐照后p53和hdm2等关键蛋白表达量随时间的震荡行为,并能定性解释p53-p21信号通路的缺失与否是如何影响细胞走向周期阻滞或者有丝分裂灾变的。结合实验和数学计算的结果,我们将结论定为:细胞中p53-p21信号通路的状态决定了细胞的中期命运。对于最终命运则可表述为:经过长期周期阻滞的细胞的最终命运是细胞衰老,而经过有丝分裂灾变的细胞的最终命运既可能是细胞凋亡也可能是细胞衰老。第四章是对于系统生物学其他方面的初步探索。包括:1)研究辐照后mirco RNA-3928和Dicer蛋白表达量的变化关系。在细胞中mirco RNA-3928和Dicer蛋白组成一个负反馈的关系,Dicer蛋白是mirco RNA-3928成熟必不可少的帮手,而mirco RNA-3928的增多又会抑制Dicer蛋白在细胞中的表达量。在课题组已有的实验基础上,我们建立了一个数学模型,能很好地半定量描述辐照后mirco RNA-3928和Dicer蛋白表达量随时间出现的震荡关系。2)酵母中转录调控关系的拟合研究。在分析网络数据库中多组酵母时序基因芯片数据的基础上,我们对于转录调控网络中的转录因子和靶基因之间m RNA表达量的变化关系进行了非线性拟合研究。为了减少误差我们重点关注了那些只受到一个转录因子调控的靶基因,利用的转录调控公式考虑调控作用延时这一特征。拟合结果给出了部分转录调控关系的所需要的时间以及m RNA降解的平均时间。3)F型ATP聚合酶e亚基的分子进化。e亚基在ATP聚合酶的组装过程中起到稳定结构的作用,而在鸟类中存在另一个和它具有高度同源性的蛋白RBF,即黄体酮受体绑定蛋白,其细胞定位在细胞核中而非线粒体。我们考察了鸟类RBF和哺乳动物e亚基的序列信息,发现在鸟类RBF的前段序列中含有能进入细胞核的特征信号,在哺乳动物e亚基我们找到了一段特征信号,使得蛋白能顺利进入线粒体。这样我们便找到了为什么高度同源性的蛋白,在鸟类和哺乳动物中的细胞定位截然不同的原因。
[Abstract]:Radibiology is a subject with a long history. It mainly studies the biological effects of various ionizing and non ionizing radiation. It has a guiding significance in the field of clinical radiation therapy, space irradiation effect and so on. In the last more than 10 years, in the field of life science, on the basis of the research of various groups, many top students have been in the field of life science. The new concept of system biology, the new concept of system biology, has rapidly gained the attention of the whole life science community. System biology mainly refers to the overall modeling of complex life systems. It is a comprehensive discipline that covers all kinds of omics, informatics and systematics. It breaks the traditional reductionism thought in life science. This paper attempts to study the characteristics and mechanisms of irradiated cells and how to combine radiation biology and system biology with some methods of systematic biology. Preliminary studies. The changes in the periodic dynamics of 92-1 cells after ionizing irradiation are explained by the cell level. The relationship between cell fate and the key p53-p21 pathway after ionizing irradiation is explained by molecular level modeling. Chapter 1: the first chapter introduces the background of system radibibiology, including 1) some basic contents and components of system biology, introduction and summary of the latest progress in all kinds of omics research; 2) brief introduction of radiation biology, some previous scholars have put forward the concept of system radibibiology, but the corresponding research is not complete. 3) mathematical modeling, especially some simple concepts of dynamic modeling. The second chapter introduces a computer simulation study on the periodic dynamics of 92-1 cells after ionizing radiation at the molecular level. The model takes into account the period test points of the cell cycle G1 and G2 phase of the irradiated cells after irradiation. The change in the proportion of cells in each cycle of 92-1 cells after ionizing irradiation can well accord with the experimental results. The quantitative relationship between the repair time of various damage of the genome caused by ionizing irradiation is always an unresolved problem. Our simulation results are supported by irradiated cells when the radiation dose is large. The total repair time is proportional to the irradiation dose. The simulation results also suggest that the G1 phase test points are more strict compared to the G2 phase test points, which makes the cells most likely to be blocked at the G1 stage even after the repair of the G2 phase, which is consistent with the predecessors' inference. The phenomenological models are more intuitive and extensible. The third chapter introduces the mathematical modeling of cell fate at the cellular level. The fate of the cells after ionizing irradiation is divided into 1 in the medium term. The repair completes through the periodic checkpoint into the normal cell cycle; 2) long period period block; 3) mitotic catastrophe. The ultimate fate of cells after irradiation includes cell senescence, cell apoptosis, cell autophagy, etc. based on the experiments in our group, and through a lot of literature research, we found that the medium-term fate of the cells after ionizing irradiation is closely related to the p53-p21 signaling pathway, and the mathematical model established by us can reproduce the ionization well. After irradiation, the expression of key proteins such as p53 and HDM2 can oscillate with time, and can explain how the absence of p53-p21 signaling pathway affects cell cycle arrest or mitotic catastrophe. Combining the results of experimental and mathematical calculations, we conclude that the state of p53-p21 signaling pathway in the cell determines the cell The final fate for the final fate can be expressed as: the ultimate fate of cells after a long period of period is cell senescence, and the ultimate fate of cells through the mitotic catastrophe may be both cell apoptosis and cell senescence. The fourth chapter is a preliminary exploration of his aspects of system biology. Including: 1) after the study of irradiation The relationship between the changes in the expression of mirco RNA-3928 and Dicer protein. The relationship between mirco RNA-3928 and Dicer protein in the cell is a negative feedback. Dicer protein is an essential helper for RNA-3928 maturation of mirco, and the increase of mirco RNA-3928 will inhibit the expression of Dicer protein in cells. On the basis of the existing experiments in the group, we A mathematical model is established to describe the relationship between the transcription regulation of mirco RNA-3928 and the expression of Dicer protein after irradiation in.2). On the basis of the analysis of the data of the sequential gene chip of the multi group yeast in the network database, the transcriptional factors in the transcriptional regulation network are analyzed. In order to reduce the error, we focus on the target genes which are regulated only by one transcription factor and take into account the characteristics of the time delay of regulation and regulation in order to reduce the error. The fitting results give the necessary time for some transcriptional regulation. The molecular evolution of the F type ATP polymerase e subunit of the ATP polymerase e subunit of the ATP polymerase e subunit of the ATP polymerase plays a stable structure in the assembly process of ATP polymerase, and there is another highly homologous protein RBF, that is, the progesterone receptor binding protein in the birds, and the cells are located in the nucleus rather than in the mitochondria in the birds. The sequence information of the bird RBF and the mammalian e subunit was investigated. It was found that in the sequence of the bird's RBF, the characteristic signal that could enter the nucleus was contained. In the mammalian e subunit we found a characteristic signal that could make the protein enter the mitochondria smoothly, so that we found the highly homologous protein, in birds and in feeding. The location of cells in dairy animals is very different.
【学位授予单位】：中国科学院研究生院（近代物理研究所）
【学位级别】：博士
【学位授予年份】：2015
【分类号】：Q691

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