Research On The Optimal Mode Of Apoptotic Switch Regulated By Bcl-2 Family Proteins

In most cell types,apoptosis occurs by the mitochondrial outer membrane permeability(MOMP)-mediated pathway,which is controlled by Bcl-2 family proteins(referred to as Bcl-2 apoptotic switch).These family proteins show distinct bioactivities,and can be divided into four types: effectors,guardians(or inhibitors),activators and sensitizers.Even though the complicated interactions among Bcl-2 family members have been studied extensively,the exact molecular mechanism about which they regulate MOMP remains elusive.As bistable behaviors are frequently used to illustrate the all-or-none decisions of apoptosis,in this paper,we revealed the optimal interaction mode by comparing the bistable responses of three different modes(direct activation,indirect activation,and unified mode)proposed by biologists.Applying the method that combines mathematical analysis and numerical simulation,we discovered that only the unified mode with proteins synthesis and degradation is identified as a bistable system,which is in favor of it as an optimal regulation mode of Bcl-2 apoptotic switch.The further parameter sensitivity analysis for the unified mode was performed and consolidated this perspective.Furthermore,we extended the unified mode by adding the Bax auto-activation and the non-activated form of Bax sequestered by Bcl-2,respectively.The results demonstrated that the former enforces the robustness of the bistability,while the latter deteriorates the robustness.Moreover,two-parameter bifurcation analysis suggested that the sensitizers lower the threshold of activation of Bax,but have a negative influence on the width of the bistability region.Our study may provide theoretical foundation for the molecular mechanisms of pathological cells and the manipulation of diseases associated with abnormal apoptosis.In chapter 1,we firstly introduced the significance of apoptosis,then gave a brief introduction on Bcl-2 family proteins and the recent development of studies on apoptosis.Finally,we primitively summarized the main work of this paper based on the previous work.Moreover,system biology background and mathematical knowledge this paper involved were supplemented in this chapter.In chapter 2,we constucted models based on the three apoptotic switches summerized by biologists,then assessed the bistable behaviors of the three interaction modes via analyzing the existence of steady state solutions.Finally,we gave the intuitive explanation for the results.In chapter 3,the extension research based on unified mode which can exhibit bistable behavior was implemented.Firstly,the parameter sensitivity analysis was performed,then we studied the influences on bistability by adding the Bax auto-activation and the non-activated form of Bax inhibited by Bcl-2,respectively.Finally,in order to discuss the functional role of sensitizers(refered to Bad in text)in the bistable unified mechanism,two-parameter bifurcation analysis was performed.