本文選題：細胞命運 + 多尺度動力學模擬��； 參考：《西北農(nóng)林科技大學》2015年博士論文

【摘要】：多細胞生物可以通過調(diào)節(jié)細胞增殖和細胞凋亡的平衡來維持生物機體內(nèi)的穩(wěn)定,即通過調(diào)控細胞內(nèi)分子代謝的平衡以及細胞組織的結(jié)構(gòu)和功能來保證生理功能的正常進行。當細胞內(nèi)的穩(wěn)態(tài)遭到破壞的時候,細胞會出現(xiàn)生存困難甚至死亡,因此在許多復雜疾病的發(fā)病機理中,細胞內(nèi)分子間調(diào)控的失調(diào)均起著重要的作用。在決定細胞命運的復雜機理探究中,生物實驗方法和數(shù)學建模方法已成為兩種常用方法。此外,細胞命運的決定是由細胞的內(nèi)在因素和外在因素相互作用共同決定的。盡管我們已經(jīng)發(fā)現(xiàn)了許多與細胞凋亡有密切關(guān)系的蛋白質(zhì),但對于細胞死亡的機制并不了解。因此通過對決定細胞命運的生物學機制探究,進而尋求預防疾病、控制疾病的方法就成為當務之急。無論是單細胞水平還是多細胞水平的研究均表明,p53蛋白在細胞命運的決定中起著重要的作用。分子水平的天然振蕩器p53-Mdm2的動力學行為表明,p53蛋白在經(jīng)由一定IR處理后的細胞信號響應過程中起到重要作用,與細胞命運的決定呈現(xiàn)重要關(guān)聯(lián)。但是,我們認不清楚p53蛋白調(diào)控網(wǎng)絡(luò)(PTEN,p21,ARF,etc.)的下游重要調(diào)控靶點的相關(guān)作用機理。其中值得注意的一點是,microRNAs的加入為由p53蛋白介導的決定細胞命運的研究提供了新的著眼點,同時也有助于我們對生命機理的深入認知,從而為藥理學和病理學的研究提供新的理論依據(jù)。由于實驗數(shù)據(jù)的龐雜及實驗手段的限制,運用數(shù)學模型去模擬單個細胞或一個細胞群的p53蛋白動力學變化,成為了一種不可或缺的手段�，F(xiàn)在對蛋白網(wǎng)絡(luò)的模擬大部分是由常微分方程組成的確定性模型。這些動力學數(shù)學模型可使我們通過對信號系統(tǒng)的動態(tài)分析來刻畫細胞是存活還是死亡。但是,現(xiàn)有的模擬并沒有同時從內(nèi)外部應激信號這兩個方面入手,對細胞命運的決定原理進行解析,因此目前也沒有成功的模型來刻畫在同等條件下同一細胞群體中各個個體的特異性命運決策。在本研究中,我們基于系統(tǒng)藥理學的理念,模擬了依賴于p53蛋白的信號調(diào)控網(wǎng)絡(luò)模型,該模型包括三個模塊:DNA損傷修復模塊,即刺激信號信號響應模塊;ATM活化模塊,即信號轉(zhuǎn)導中介模塊和p53及相關(guān)蛋白和microRNA的生化分子網(wǎng)絡(luò)。通過體系中生化分子的含量變化來刻畫和探究細胞命運決定過程中p53網(wǎng)絡(luò)對內(nèi)外部應激信號的響應情況。主要的結(jié)果如下:1.首先我們在三個子模塊(DSB損傷修復模塊,ATM激活模塊,p53蛋白調(diào)控網(wǎng)絡(luò)模塊)的基礎(chǔ)上成功構(gòu)建了p53蛋白調(diào)控網(wǎng)絡(luò)的系統(tǒng)動力學數(shù)學模型,該模型可以較準確地模擬真實細胞的生物學行為,其模擬結(jié)果與實驗觀察所得的結(jié)果高度吻合;2.通過對多種內(nèi)應系統(tǒng)(三個大類區(qū)域,七小類區(qū)域)進行持續(xù)和短期外部應激信號刺激的動力學結(jié)果比較,發(fā)現(xiàn)單個的miRNA-145對整個蛋白網(wǎng)絡(luò)具有微弱的調(diào)控作用,揭示了在生命活動中,microRNA作為守護者的作用;3.在p53蛋白調(diào)控網(wǎng)絡(luò)的模擬基礎(chǔ)上,提出了雙因素的細胞命運決定模型,該模型能夠較全面的刻畫細胞凋亡的概率與蛋白水平,及其信號強度之間的關(guān)系;4.運用細胞生物學中的多尺度理念,將p53蛋白生化分子網(wǎng)絡(luò)的動力學模擬與細胞行為的多尺度相耦合,實現(xiàn)了從分子水平到細胞水平的數(shù)學建模。最終將生化分子-細胞行為-細胞命運的決定相關(guān)聯(lián),發(fā)現(xiàn)細胞可以通過網(wǎng)絡(luò)式的蛋白調(diào)控方式提高細胞本身的生存概率。綜上所述,本文從多蛋白,單個miRNA參與的p53蛋白動力學模型的構(gòu)建,到細胞命運的雙因素模型的提出,最終將這些模型與細胞多尺度的模型耦合起來,構(gòu)建了由內(nèi)外部應激信號共同參與的p53蛋白調(diào)控網(wǎng)絡(luò)的動力學響應模型,并通過計算模擬直接反映網(wǎng)絡(luò)式的調(diào)控模式對細胞命運的作用。本文將系統(tǒng)的研究蛋白網(wǎng)絡(luò)的動力學特性和細胞多尺度研究相耦合的研究框架可作為后期類似研究的范例,同時也可為后期的藥理學病理學提供研究理論基礎(chǔ)和可視化仿真模擬。此外,為保證模擬網(wǎng)絡(luò)通路的完整性,我們還以p53調(diào)控蛋白網(wǎng)絡(luò)的下游蛋白TNF-α為例,通過CoMFA法和CoMSIA法的分析預測,研究了構(gòu)效關(guān)系中的咪唑基化合物對TNF-α的釋放的抑制作用,從而為設(shè)計潛在的咪唑類TNF-α釋放抑制劑提供新的理論依據(jù)。
[Abstract]:Multicellular organisms can maintain the stability of the organism by regulating the balance of cell proliferation and apoptosis, that is, the normal progress of physiological function is guaranteed by regulating the balance of intracellular metabolism and the structure and function of cell tissue. In the pathogenesis of many complex diseases, the imbalance between intracellular molecules plays an important role. In determining the complex mechanism of cell fate, the biological experiment method and mathematical modeling method have become two common methods. In addition, the cell fate is determined by the internal and external factors of the cell. Interaction is decided. Although we have found many proteins that are closely related to apoptosis, we do not understand the mechanism of cell death. Therefore, it is urgent to seek the prevention and control of the disease by exploring the biological mechanism that determines the fate of the cells. Multicellular level studies have shown that p53 protein plays an important role in the determination of cell fate. The kinetic behavior of the molecular level natural oscillator p53-Mdm2 indicates that the p53 protein plays an important role in the cellular signal response process after a certain IR treatment, and has an important association with the determination of the cell fate. But, we It is not clear that the p53 protein regulatory network (PTEN, p21, ARF, etc.) is the related mechanism of the downstream important regulatory targets. One of the noteworthy points is that the addition of microRNAs provides a new eye for the study of cell fate mediated by p53 protein, and also helps us to understand the mechanism of life, and thus for pharmacology. It provides a new theoretical basis for the study of pathology. Because of the complexity of experimental data and the limitation of experimental means, it is an indispensable means to simulate the dynamic changes of p53 protein in a single cell or a cell group by using mathematical models. The simulation of protein network is now mostly determined by the determination of ordinary differential equations. These dynamic mathematical models enable us to describe the survival or death of cells by dynamic analysis of the signal system. However, the existing simulation does not start with the two aspects of the internal and external stress signals, and analyzes the principle of cell fate determination, because there is no successful model to describe it at the same time. In this study, based on the concept of systematic pharmacology, we simulated the signal control network model dependent on p53 protein, which includes three modules: the DNA damage repair module, the stimulus signal signal response module, the ATM activation module, the signal transduction mediator model. Biochemical molecular networks of blocks and p53 and related proteins and microRNA. The response of p53 networks to internal and external stress signals in the process of cell fate determination is described and explored by changes in the content of biochemical molecules in the system. The main results are as follows: 1. first we are in the three sub modules (DSB damage repair module, ATM activation module, p53 protein modulation) On the basis of the control network module, a systematic dynamic mathematical model of the p53 protein regulation network is successfully constructed. The model can accurately simulate the biological behavior of real cells. The simulation results are highly consistent with the results obtained from the experimental observation; 2. through the multiple internal response systems (three large classes, seven small areas), the model is consistent. Compared with the dynamic results of short-term external stress signal stimulation, it is found that a single miRNA-145 has a weak regulatory effect on the whole protein network, and reveals the role of microRNA as a guardian in life activities. 3. on the basis of the simulation of the p53 protein regulation network, a two factor cell fate determination model is proposed, which can be compared. A comprehensive characterization of the relationship between the probability of apoptosis and the protein level and its signal intensity; 4. by using the multi-scale concept in cell biology, the kinetic modeling of the biochemical molecular network of p53 protein and the multiscale of cell behavior are coupled to achieve the mathematical modeling from the molecular level to the cell level. Associated with the decision of behavior cell fate, it is found that cells can improve the survival probability of cells themselves through a network of protein regulation. In summary, this paper proposes the construction of a p53 protein kinetic model involving multiple proteins, single miRNA, and a dual factor model of cell fate. Coupled with the model, the dynamic response model of the p53 protein regulation network, which is involved in the internal and external stress signals, is constructed, and the effect of the network mode on the cell fate is directly reflected by the calculation simulation. The research framework of the dynamic characteristics of the protein network and the multi-scale study of the cell is systematically studied in this paper. As an example of later similar studies, it can also provide theoretical basis and visual simulation for later pharmacological pathology. In addition, in order to ensure the integrity of analog network pathways, we also study the structure effect relationship by the analysis and prediction of the downstream protein TNF- alpha of the p53 regulation protein network by the analysis and prediction of the CoMFA and CoMSIA methods. The inhibitory effect of imidazolyl compounds on the release of TNF- alpha, thus providing a new theoretical basis for the design of potential imidazole TNF- alpha release inhibitors.

【學位授予單位】：西北農(nóng)林科技大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R96

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