本文選題：輻射生物學(xué) + 系統(tǒng)生物學(xué)��； 參考：《中國科學(xué)院研究生院（近代物理研究所）》2015年博士論文

【摘要】：輻射生物學(xué)是一門有著悠久歷史的學(xué)科,主要研究各種電離輻照和非電離輻照的生物學(xué)效應(yīng),對于臨床的放射治療、空間輻照效應(yīng)等等領(lǐng)域有著指導(dǎo)性意義。近十多年來,在生命科學(xué)領(lǐng)域,在已有的各種組學(xué)的研究基礎(chǔ)上,許多頂尖的生命科學(xué)家又提出了系統(tǒng)生物學(xué)這一新概念,迅速得到了整個生命科學(xué)界的關(guān)注重視。系統(tǒng)生物學(xué)主要指對于復(fù)雜生命系統(tǒng)的整體建模工作,是一個囊括了各種組學(xué)、信息學(xué)和系統(tǒng)學(xué)的綜合學(xué)科。它打破了生命科學(xué)中傳統(tǒng)的還原論的思想,將基因組、蛋白組和代謝組等等不同層面的組學(xué)信息綜合利用,提倡在系統(tǒng)的水平理解生命系統(tǒng)中存在的各種機(jī)理。本論文試圖用系統(tǒng)生物學(xué)的一些方法手段來研究輻照細(xì)胞的特性和機(jī)理,對于如何結(jié)合輻射生物學(xué)和系統(tǒng)生物學(xué)做了初步的研究。通過細(xì)胞水平解釋了電離輻照后92-1細(xì)胞的周期動力學(xué)的變化,通過分子水平的建模解釋了電離輻照后細(xì)胞命運(yùn)與關(guān)鍵的p53-p21通路之間的關(guān)系。從這些工作中,初步確認(rèn)了系統(tǒng)輻射生物學(xué)建立的可能性。全文的內(nèi)容安排如下:第一章介紹了系統(tǒng)輻射生物學(xué)的相關(guān)背景,具體包括1)系統(tǒng)生物學(xué)的一些基本內(nèi)容和組成部分,各種組學(xué)研究的最新進(jìn)展的介紹和總結(jié);2)輻射生物學(xué)的簡單介紹,先前有一些學(xué)者提出了系統(tǒng)輻射生物學(xué)的概念,但相應(yīng)的研究并未全面展開;3)數(shù)學(xué)建模,特別是動力學(xué)建模的一些簡單概念。第二章介紹了在分子水平上,利用簡單的唯象模型對于電離輻照后92-1細(xì)胞的周期動力學(xué)進(jìn)行了計算機(jī)模擬研究。該模型考慮了輻照后92-1細(xì)胞在細(xì)胞周期G1期和G2期周期檢驗(yàn)點(diǎn)可能受到的阻滯,得到了電離輻照后92-1細(xì)胞的各周期細(xì)胞比例的變化,能較好地符合實(shí)驗(yàn)結(jié)果。電離輻照造成的基因組各種損傷的修復(fù)時間的定量關(guān)系一直是個懸而未決的問題,我們的模擬結(jié)果支持在輻照劑量較大時,輻照受損的細(xì)胞總的修復(fù)時間和輻照劑量呈正比關(guān)系。模擬結(jié)果同時暗示了相比于G2期檢驗(yàn)點(diǎn),G1期檢驗(yàn)點(diǎn)更為嚴(yán)格,這使得細(xì)胞即使修復(fù)后能通過G2期檢驗(yàn)點(diǎn)也大多會被阻滯在G1期,這和前人的推論是吻合的。相比于前人對于周期動力學(xué)的數(shù)學(xué)建模,我們的唯象模型更為直觀,并且可擴(kuò)展性強(qiáng)。第三章介紹了在細(xì)胞水平上,關(guān)于電離輻照后細(xì)胞命運(yùn)的數(shù)學(xué)建模工作。電離輻照后的細(xì)胞命運(yùn)在中期分為1)修復(fù)完成通過周期檢驗(yàn)點(diǎn)進(jìn)入正常細(xì)胞周期;2)長時間周期阻滯;3)有絲分裂災(zāi)變。電離輻照后細(xì)胞的最終命運(yùn)則包括細(xì)胞衰老、細(xì)胞凋亡、細(xì)胞自噬,等等�；谖覀冋n題組已有的實(shí)驗(yàn),并通過大量的文獻(xiàn)調(diào)研,我們發(fā)現(xiàn)電離輻照后細(xì)胞的中期命運(yùn)和p53-p21信號通路有著密切的關(guān)系,我們建立的數(shù)學(xué)模型能很好地重現(xiàn)電離輻照后p53和hdm2等關(guān)鍵蛋白表達(dá)量隨時間的震蕩行為,并能定性解釋p53-p21信號通路的缺失與否是如何影響細(xì)胞走向周期阻滯或者有絲分裂災(zāi)變的。結(jié)合實(shí)驗(yàn)和數(shù)學(xué)計算的結(jié)果,我們將結(jié)論定為:細(xì)胞中p53-p21信號通路的狀態(tài)決定了細(xì)胞的中期命運(yùn)。對于最終命運(yùn)則可表述為:經(jīng)過長期周期阻滯的細(xì)胞的最終命運(yùn)是細(xì)胞衰老,而經(jīng)過有絲分裂災(zāi)變的細(xì)胞的最終命運(yùn)既可能是細(xì)胞凋亡也可能是細(xì)胞衰老。第四章是對于系統(tǒng)生物學(xué)其他方面的初步探索。包括:1)研究輻照后mirco RNA-3928和Dicer蛋白表達(dá)量的變化關(guān)系。在細(xì)胞中mirco RNA-3928和Dicer蛋白組成一個負(fù)反饋的關(guān)系,Dicer蛋白是mirco RNA-3928成熟必不可少的幫手,而mirco RNA-3928的增多又會抑制Dicer蛋白在細(xì)胞中的表達(dá)量。在課題組已有的實(shí)驗(yàn)基礎(chǔ)上,我們建立了一個數(shù)學(xué)模型,能很好地半定量描述輻照后mirco RNA-3928和Dicer蛋白表達(dá)量隨時間出現(xiàn)的震蕩關(guān)系。2)酵母中轉(zhuǎn)錄調(diào)控關(guān)系的擬合研究。在分析網(wǎng)絡(luò)數(shù)據(jù)庫中多組酵母時序基因芯片數(shù)據(jù)的基礎(chǔ)上,我們對于轉(zhuǎn)錄調(diào)控網(wǎng)絡(luò)中的轉(zhuǎn)錄因子和靶基因之間m RNA表達(dá)量的變化關(guān)系進(jìn)行了非線性擬合研究。為了減少誤差我們重點(diǎn)關(guān)注了那些只受到一個轉(zhuǎn)錄因子調(diào)控的靶基因,利用的轉(zhuǎn)錄調(diào)控公式考慮調(diào)控作用延時這一特征。擬合結(jié)果給出了部分轉(zhuǎn)錄調(diào)控關(guān)系的所需要的時間以及m RNA降解的平均時間。3)F型ATP聚合酶e亞基的分子進(jìn)化。e亞基在ATP聚合酶的組裝過程中起到穩(wěn)定結(jié)構(gòu)的作用,而在鳥類中存在另一個和它具有高度同源性的蛋白RBF,即黃體酮受體綁定蛋白,其細(xì)胞定位在細(xì)胞核中而非線粒體。我們考察了鳥類RBF和哺乳動物e亞基的序列信息,發(fā)現(xiàn)在鳥類RBF的前段序列中含有能進(jìn)入細(xì)胞核的特征信號,在哺乳動物e亞基我們找到了一段特征信號,使得蛋白能順利進(jìn)入線粒體。這樣我們便找到了為什么高度同源性的蛋白,在鳥類和哺乳動物中的細(xì)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.
【學(xué)位授予單位】：中國科學(xué)院研究生院（近代物理研究所）
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：Q691

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