随机延迟协同对miR-17-92调控癌症网络中基因切换行为及物理机制研究

The miR-17-92 clusters have been found to be high expression in many tumors, showing as oncogene-induced tumors, but it also has been reported as a tumor suppressor gene, which inhibits the proliferation of certain types of tumor cells. So far, it is not fully understood that the overexpression of miR-17-92 clusters may exhibit the mechanism of oncogene or tumor suppressor.This project involved with the effects of miR-17-92 in the cancer network, considering the external environmental perturbations and multiple time delays in the process of biochemical reaction , and establishes an abstract model containing noise and delays. Based on the modified Gillespie stochastic simulation and delayed Langevin equation, calculating characteristic parameters of the gene switch behavior(gene switch time,etc), analyzing the effect mechanism of synergy of noise and time delay on the gene bidirectional switch behavior and early warning signal (intersection point of bidirectional switch time) in the regulation of miR-17-92 in cancer network, exploring cancer network for external perturbations exhibit multiple response behavior, revealling the biophysical mechanisms of gene switch.The implementation of this project utilizes the view of physical steady state.transition theory to understand the gene switch behavior and mechanism in the regulation of miR-17-92 in cancer network, and provides a theoretical guide to develop potential strategies of miR-17-92-based therapeutic targets.

miR-17-92基因簇被发现在许多恶性肿瘤中存在高表达，且显示为致癌基因诱发肿瘤，然而也有报道显示其亦可作为抑癌基因抑制某些种类肿瘤细胞的增殖。迄今为止，对miR-17-92基因簇的过度表达可能表现出致癌或抑癌的发生机制尚不完全清楚。本项目以miR-17-92涉及的癌症网络为研究对象，考虑外界环境随机干扰及生化反应过程中多种延迟的作用，建立含有噪声和延迟的理论模型。基于改进Gillespie随机模拟及延迟Langevin方程，计算表征基因开关切换行为的特征参量(切换时间等)，分析噪声和延迟协同对癌症网络中基因双向开关切换行为及早期预警信号的影响机制，探讨癌症网络对于外界干扰表现出多种响应行为，揭示其基因开关切换的生物物理机制。本项目的实施将从物理学稳态跃迁理论的角度理解miR-17-92调控癌症网络中基因切换行为及机制，为开发潜在基于miR-17-92的癌症治疗方案提供一定的理论指导。

本项目以miR-17-92研究对象，考虑噪声和延迟协同对癌症网络中基因双向开关切换行为及早期预警信号的影响机制，建立关于癌症网络的基因调控模型，从稳态跃迁理论的角度出发研究了miR-17-92调控癌症网络中基因切换行为机制，结合早期预警信号的理论深入研究了miR-17-92在癌症网络中引起的丰富的动力学行为。基于Gillespie随机模拟及延迟Langevin方程，通过计算各反应分子数在生化反应过程中随时间的变化以及反应分子数之间的变化关系，进一步探究噪声和延迟协同在癌症网络中引起的开关切换行为及早期预警信号的影响机制。主要研究结果表明：（1）噪声和延迟协同对miR-17-92癌症网络产生多种响应行为，诱导细胞状态在静默期、正常细胞周期、癌症区、凋亡区参与各项生化过程。（2）不同的噪声强度及时间延迟对miR-17-92调控E2F/Myc网络中基因双向开关切换行为具有不同的调节作用，二者之间的协同作用也会对系统中开关切换行为产生重要影响。（3）在miR-17-92调控E2F/Myc网络中基因双向开关切换行为的基础上，发现早期预警指标的影响机制。（4）相反方向开关切换时间的交点作为miR-17-92调控E2F/Myc网络中开关切换预警信号对于疾病的预防提供一定的理论参考。

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