Bcl-2蛋白质家族调控细胞凋亡最优模式的研究
发布时间：2019-04-09 18:14
【摘要】：在大多数细胞中,线粒体外膜的通透可诱发细胞凋亡,该途径主要由Bcl-2家族蛋白调控(因此也称为Bcl-2凋亡机制)。该家族蛋白具有不同的生物活性,可分为四类:效应者,保护者(也称抑制者),激活者和致敏者。虽然目前对于Bcl-2蛋白质家族成员之间复杂的相互作用已有大量研究,但关于它们如何调控线粒体外膜通透的统一机制仍然存有争议。由于双稳行为常常被用来解释细胞凋亡“全或无”的决定,在该研究中,我们比较了由生物学家提出的三种不同的相互作用模式(直接激活模式、间接激活模式、统一模式)的双稳性来揭示最优的调控模式。采用数学分析和数值模拟相结合的方法,我们发现只有统一模式在考虑蛋白质的生成和降解的情形下才会出现双稳,从而认为统一模式是最优的Bcl-2蛋白质家族调控细胞凋亡的机制。进一步对统一模式进行参数敏感性分析验证了这一结果。此外,在统一模式的基础上进行了扩展研究,分别增加了效应者Bax的自激活机制和保护者Bcl-2可抑制非活化态的Bax这两种机制,结果表明前者可增强系统的双稳性而后者抑制双稳性。最后,通过双参数分岔分析发现致敏者不仅可降低Bax的激活阈值,而且对系统双稳性起抑制作用。我们的研究可能对病理细胞的Bcl-2分子机制以及对由异常凋亡引起的相关疾病的控制提供一些理论性的见解。第一章,首先介绍了细胞凋亡的重要意义,然后简单介绍了Bcl-2蛋白质家族以及当前关于细胞凋亡的研究近况,最后对本文的研究工作做了简单总结,并补充了本文用到的系统生物学知识和数学相关知识。第二章,根据前人总结的三种机制构建了模型,通过稳态解存在性分析对三种相互作用模式的双稳性行为进行了评估,并对结果进行了直观上的解释。第三章,针对可产生双稳的统一模型进行了扩展研究。首先是参数敏感性分析,探讨了各参数的变化对双稳区间及Bax激活阈值的影响,然后分别考虑了增加效应者Bax的自激活机制以及Bcl-2可抑制未活化Bax两种机制后对系统双稳性的影响,最后对模型进行了双参数分岔分析探讨了致敏者(Bad)在双稳机制中所发挥的作用。
[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.
【学位授予单位】：中北大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：Q255
本文编号：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.
【学位授予单位】：中北大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：Q255
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