【摘要】：在大多數(shù)細(xì)胞中,線(xiàn)粒體外膜的通透可誘發(fā)細(xì)胞凋亡,該途徑主要由Bcl-2家族蛋白調(diào)控(因此也稱(chēng)為Bcl-2凋亡機(jī)制)。該家族蛋白具有不同的生物活性,可分為四類(lèi):效應(yīng)者,保護(hù)者(也稱(chēng)抑制者),激活者和致敏者。雖然目前對(duì)于Bcl-2蛋白質(zhì)家族成員之間復(fù)雜的相互作用已有大量研究,但關(guān)于它們?nèi)绾握{(diào)控線(xiàn)粒體外膜通透的統(tǒng)一機(jī)制仍然存有爭(zhēng)議。由于雙穩(wěn)行為常常被用來(lái)解釋細(xì)胞凋亡“全或無(wú)”的決定,在該研究中,我們比較了由生物學(xué)家提出的三種不同的相互作用模式(直接激活模式、間接激活模式、統(tǒng)一模式)的雙穩(wěn)性來(lái)揭示最優(yōu)的調(diào)控模式。采用數(shù)學(xué)分析和數(shù)值模擬相結(jié)合的方法,我們發(fā)現(xiàn)只有統(tǒng)一模式在考慮蛋白質(zhì)的生成和降解的情形下才會(huì)出現(xiàn)雙穩(wěn),從而認(rèn)為統(tǒng)一模式是最優(yōu)的Bcl-2蛋白質(zhì)家族調(diào)控細(xì)胞凋亡的機(jī)制。進(jìn)一步對(duì)統(tǒng)一模式進(jìn)行參數(shù)敏感性分析驗(yàn)證了這一結(jié)果。此外,在統(tǒng)一模式的基礎(chǔ)上進(jìn)行了擴(kuò)展研究,分別增加了效應(yīng)者Bax的自激活機(jī)制和保護(hù)者Bcl-2可抑制非活化態(tài)的Bax這兩種機(jī)制,結(jié)果表明前者可增強(qiáng)系統(tǒng)的雙穩(wěn)性而后者抑制雙穩(wěn)性。最后,通過(guò)雙參數(shù)分岔分析發(fā)現(xiàn)致敏者不僅可降低Bax的激活閾值,而且對(duì)系統(tǒng)雙穩(wěn)性起抑制作用。我們的研究可能對(duì)病理細(xì)胞的Bcl-2分子機(jī)制以及對(duì)由異常凋亡引起的相關(guān)疾病的控制提供一些理論性的見(jiàn)解。第一章,首先介紹了細(xì)胞凋亡的重要意義,然后簡(jiǎn)單介紹了Bcl-2蛋白質(zhì)家族以及當(dāng)前關(guān)于細(xì)胞凋亡的研究近況,最后對(duì)本文的研究工作做了簡(jiǎn)單總結(jié),并補(bǔ)充了本文用到的系統(tǒng)生物學(xué)知識(shí)和數(shù)學(xué)相關(guān)知識(shí)。第二章,根據(jù)前人總結(jié)的三種機(jī)制構(gòu)建了模型,通過(guò)穩(wěn)態(tài)解存在性分析對(duì)三種相互作用模式的雙穩(wěn)性行為進(jìn)行了評(píng)估,并對(duì)結(jié)果進(jìn)行了直觀上的解釋。第三章,針對(duì)可產(chǎn)生雙穩(wěn)的統(tǒng)一模型進(jìn)行了擴(kuò)展研究。首先是參數(shù)敏感性分析,探討了各參數(shù)的變化對(duì)雙穩(wěn)區(qū)間及Bax激活閾值的影響,然后分別考慮了增加效應(yīng)者Bax的自激活機(jī)制以及Bcl-2可抑制未活化Bax兩種機(jī)制后對(duì)系統(tǒng)雙穩(wěn)性的影響,最后對(duì)模型進(jìn)行了雙參數(shù)分岔分析探討了致敏者(Bad)在雙穩(wěn)機(jī)制中所發(fā)揮的作用。
[Abstract]:In most cells, the permeability of mitochondrial outer membrane can induce apoptosis, and this pathway is mainly regulated by Bcl-2 family proteins (therefore also known as Bcl-2 apoptosis mechanism). The family proteins have different biological activities, and can be divided into four categories: effectors, protectors (also known as suppressors), activators and sensitizers. Although there has been a great deal of research on the complex interaction between Bcl-2 protein family members, there is still controversy about how they regulate the permeability of mitochondrial outer membrane. Since bistable behavior is often used to explain the "total or no" decision of apoptosis, we compared three different modes of interaction (direct activation mode, indirect activation mode) proposed by biologists in this study. The bistability of unified mode to reveal the optimal regulation model. With the combination of mathematical analysis and numerical simulation, we find that bistability occurs only when the uniform model takes into account the formation and degradation of proteins. It is concluded that the unified model is the optimal mechanism of Bcl-2 protein family regulating cell apoptosis. This result is verified by parameter sensitivity analysis of the unified model. In addition, on the basis of the unified model, the self-activation mechanism of effector Bax and the protector Bcl-2 can inhibit the inactivated Bax mechanism are added, and the two mechanisms are added, respectively, which are the self-activation mechanism of effector Bax and the protector Bax mechanism. The results show that the former can enhance the bistability of the system while the latter can suppress the bistability of the system. Finally, the biparametric bifurcation analysis shows that the sensitizer can not only reduce the activation threshold of Bax, but also inhibit the bistability of the system. Our study may provide some theoretical insights into the molecular mechanism of Bcl-2 in pathological cells and the control of diseases associated with abnormal apoptosis. In the first chapter, we first introduce the significance of apoptosis, then briefly introduce the Bcl-2 protein family and the current research on apoptosis. Finally, we make a brief summary of the research work in this paper. The system biology knowledge and mathematics related knowledge used in this paper are supplemented. In the second chapter, according to the three mechanisms summarized by predecessors, the bistability behavior of the three interaction modes is evaluated by the analysis of the existence of steady-state solutions, and the results are explained intuitively. In chapter 3, we extend the unified model which can produce bistability. First of all, the parameter sensitivity analysis is used to discuss the influence of each parameter change on the bistable interval and the activation threshold of Bax. Then the effects of the self-activation mechanism of the increased effector Bax and the inhibition of unactivated Bax by Bcl-2 on the bistability of the system are considered respectively. Finally, the role of sensitizer (Bad) in bistable mechanism is discussed by means of two-parameter bifurcation analysis.
【學(xué)位授予單位】：中北大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：Q255

【參考文獻(xiàn)】

相關(guān)期刊論文 前5條

1 周建平;;癌癥的系統(tǒng)生物學(xué)模型研究進(jìn)展[J];信陽(yáng)師范學(xué)院學(xué)報(bào)(自然科學(xué)版);2014年04期

2 徐麗麗;高世勇;季宇彬;;細(xì)胞凋亡相關(guān)蛋白的研究進(jìn)展[J];齊齊哈爾醫(yī)學(xué)院學(xué)報(bào);2008年11期

3 李捷萌;陳彥青;劉榮國(guó);;線(xiàn)粒體凋亡途徑與Bcl-2家族蛋白研究進(jìn)展[J];醫(yī)學(xué)綜述;2008年04期

4 孟祥東,嚴(yán)云勤;BCL-2家族與線(xiàn)粒體對(duì)細(xì)胞凋亡的調(diào)控[J];細(xì)胞與分子免疫學(xué)雜志;2005年S1期

5 卿晨,丁健;Bcl-2基因家族在調(diào)節(jié)細(xì)胞凋亡中的作用[J];國(guó)外醫(yī)學(xué)(分子生物學(xué)分冊(cè));2000年01期

，

本文編號(hào)：2455417