Bcl-2蛋白質家族調控細胞凋亡最優(yōu)模式的研究
發(fā)布時間：2019-04-09 18:14
【摘要】：在大多數細胞中,線粒體外膜的通透可誘發(fā)細胞凋亡,該途徑主要由Bcl-2家族蛋白調控(因此也稱為Bcl-2凋亡機制)。該家族蛋白具有不同的生物活性,可分為四類:效應者,保護者(也稱抑制者),激活者和致敏者。雖然目前對于Bcl-2蛋白質家族成員之間復雜的相互作用已有大量研究,但關于它們如何調控線粒體外膜通透的統(tǒng)一機制仍然存有爭議。由于雙穩(wěn)行為常常被用來解釋細胞凋亡“全或無”的決定,在該研究中,我們比較了由生物學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)性來揭示最優(yōu)的調控模式。采用數學分析和數值模擬相結合的方法,我們發(fā)現只有統(tǒng)一模式在考慮蛋白質的生成和降解的情形下才會出現雙穩(wěn),從而認為統(tǒng)一模式是最優(yōu)的Bcl-2蛋白質家族調控細胞凋亡的機制。進一步對統(tǒng)一模式進行參數敏感性分析驗證了這一結果。此外,在統(tǒng)一模式的基礎上進行了擴展研究,分別增加了效應者Bax的自激活機制和保護者Bcl-2可抑制非活化態(tài)的Bax這兩種機制,結果表明前者可增強系統(tǒng)的雙穩(wěn)性而后者抑制雙穩(wěn)性。最后,通過雙參數分岔分析發(fā)現致敏者不僅可降低Bax的激活閾值,而且對系統(tǒng)雙穩(wěn)性起抑制作用。我們的研究可能對病理細胞的Bcl-2分子機制以及對由異常凋亡引起的相關疾病的控制提供一些理論性的見解。第一章,首先介紹了細胞凋亡的重要意義,然后簡單介紹了Bcl-2蛋白質家族以及當前關于細胞凋亡的研究近況,最后對本文的研究工作做了簡單總結,并補充了本文用到的系統(tǒng)生物學知識和數學相關知識。第二章,根據前人總結的三種機制構建了模型,通過穩(wěn)態(tài)解存在性分析對三種相互作用模式的雙穩(wěn)性行為進行了評估,并對結果進行了直觀上的解釋。第三章,針對可產生雙穩(wěn)的統(tǒng)一模型進行了擴展研究。首先是參數敏感性分析,探討了各參數的變化對雙穩(wěn)區(qū)間及Bax激活閾值的影響,然后分別考慮了增加效應者Bax的自激活機制以及Bcl-2可抑制未活化Bax兩種機制后對系統(tǒng)雙穩(wěn)性的影響,最后對模型進行了雙參數分岔分析探討了致敏者(Bad)在雙穩(wěn)機制中所發(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.
【學位授予單位】：中北大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：Q255
本文編號：2455417
[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.
【學位授予單位】：中北大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：Q255
【參考文獻】
相關期刊論文 前5條
1 周建平;;癌癥的系統(tǒng)生物學模型研究進展[J];信陽師范學院學報(自然科學版);2014年04期
2 徐麗麗;高世勇;季宇彬;;細胞凋亡相關蛋白的研究進展[J];齊齊哈爾醫(yī)學院學報;2008年11期
3 李捷萌;陳彥青;劉榮國;;線粒體凋亡途徑與Bcl-2家族蛋白研究進展[J];醫(yī)學綜述;2008年04期
4 孟祥東,嚴云勤;BCL-2家族與線粒體對細胞凋亡的調控[J];細胞與分子免疫學雜志;2005年S1期
5 卿晨,丁健;Bcl-2基因家族在調節(jié)細胞凋亡中的作用[J];國外醫(yī)學(分子生物學分冊);2000年01期
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