基于数学模型的血流，药物以及细胞内外信号传输特性的定量分析
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摘要
人体内各个系统,小至细胞,大至器官,都在通过不断地自我调节以缓冲外界扰动对内平衡的影响。当这种自我调节机制减弱时,就无法维持生命系统的正常功能,从而导致疾病的产生。因此,对生物系统调节机制的研究有助于我们深入地理解各种生理现象,从而推动新型疾病诊断技术和治疗方式的发展,改善人们的生活质量。
由于生物系统的复杂性以及检测技术的局限性等原因,实验手段通常只能考察系统中部分因素的关系。为了能够系统深入地揭示生物系统的调节机理,本博士论文运用多孔介质内的传热分析,基于优化方法的医疗图像分析及复杂生物网络的系统建模方法对生物组织内的血流调节、药物输运和细胞内外信号传导等问题进行了定量分析,以期为优化心血管疾病诊断、靶向药物输运以及新药筛选技术提供理论依据。主要研究内容包括以下几个方面：
1.基于手部传热分析的血流动态变化评价。
首先从断层医学图像序列出发,提出了三维有限元网格模型的重构方法,构建了具有真实外形的手部三维有限元网格模型。然后,基于Darcy定律和Pennes生物传热理论构建了血流传热模型,用于考察反应性充血过程中指尖温度响应的定量特性。结果表明,指尖温度在无过载充血的情况下需要超过200秒才能恢复到稳定水平,而在强过载充血的情况下,仅需50秒。同时,强弱反应性充血中温度峰值相差0.3℃,足以通过民用红外热像仪分辨出来。因此,结合温度反弹量,恢复时间以及其他诸如稳定温度等基准量,就能有效地衡量血管壁调节能力,从而对心血管疾病做出风险预测。
2.脉冲高强度聚焦超声照射下药物输运特性的定量分析。
通过核磁共振成像技术记录了不同脉冲高强度聚焦超声(p-HIFU)照射前后新西兰大白兔大腿肌肉组织内药物浓度的动态变化。基于这些实验数据和Toft&Kermode模型,发展了优化算法得到了肌肉组织内的药物渗透率,药物清除率以及细胞外空隙分数。通过对这些组织药物输运参数的统计分析,定量地考察了不同p-HIFU能量沉积对药物传输特性的影响和作用机理。结果显示,p-HIFU引起的肌肉组织内的初期水肿与后期药物输运能力的增强存在着紧密的联系。更重要的是,p-HIFU在引起组织内药物渗透性增强的同时还能有效地扩大细胞外空隙和降低药物的清除率,这种综合作用能够为药物与组织提供充分的接触作用,使得组织累计接触的药物量可以增加到3-4倍。通过合理地控制p-HIFU照射,最终能够达到在减少组织烧伤的情况下最大化组织内药物输运增强的效果。
3.免疫系统细胞间相互作用网络的数学建模。
根据SOD1基因突变引起的肌萎缩性脊髓侧索硬化症(ALS)中免疫系统的作用,建立了ALS中免疫细胞与运动神经元相互作用的系统模型。该模型采用常微分方程来描述各个细胞通过调节因子相互作用所引起的动态变化。进一步,基于SOD1转基因小鼠的载体实验数据,采用优化算法确定了数学模型中的待定参数。优化后的数学模型能够恰当地再现疾病发展过程中的初始期、稳定期和恶化期。然后,通过对几种潜在治疗方案的测试发现,抑制1型辅助性T细胞能够有效地减缓疾病的发展,从而改善患者的生活质量。这揭示了1型辅助性T细胞的快速增长在疾病后期快速恶化过程中的主导作用。
4.细胞内蛋白质信号通路模型的数学建模。
提出了系统考察致活酶抑制剂综合效果(对癌细胞的抑制作用和肝细胞的副作用)的算法。基于该算法,我们根据在线共享的实验数据建立了PC9癌细胞和人类原代肝细胞内的蛋白质信号通路模型,描述了作为细胞内信号传递载体的各蛋白质磷酸化水平对外部干扰的动态响应。然后通过该模型对27种致活酶抑制剂综合治疗效果的测试,筛选出克里唑蒂尼作为抑制PC9癌细胞而且避免损伤肝细胞的最佳药物。进一步,基于该算法开发了在线的致活酶抑制剂综合治疗效果预测工具KIEP,以便于研究人员使用该工具预测药效。
Human body is a very complex self-regulating system. Each componet at different levels, such as cells or organs, is involved in achieving homeostasis to allow survival and functioning of biological system against challenges from varying conditions. Decline of this self-regulating capability will induce many diseases. Investigation of the regulatory mechanisms of biological systems can give us a deep insight into different physiological phenomena, which will benefit for the development of new disease diagnostic techniques and treatment methods to improve people's quality of life and health.
Due to complexity of biological systems and limitations of current experimental techniques, experimental methods can only focus on limited factors of the biological system. In order to understand regulatory mechanisms of biological systems systematically and deeply, this doctoral thesis used heat transfer analysis, optimization methods and bio-system modelling to investigate blood flow regulation, drug delivery and intra/extracellular signal transmission, which was expected to benefit for the improvement of cardiovascular disease diagnostic, targeted drug delivery and drug screening. The main contents are listed as following:
1. Analysis of heat transfer in hand for evaluation of blood flow dynamics.
First, an algorithm for3D mesh model reconstruction based on medical image sequences to generate the finite element mesh of a hand with real shape was presented. Then, based on Darcy's law and Pennes bio-heat transfer theory, a mathematical model of blood perfusion and heat transfer in biolgical tissue was established to investigate quantitative features of fingertip temperature response to reactive hyperemia. The results indicate that, for fingertip temperature recovery, it took more than200s without overload of blood reperfusion while only50s with high overload of blood reperfusion. Meanwhile, the difference between the peak temperature with low and high overload of blood perfusion is about0.3℃, which is signaficant enough for thermal infrared imager to distinguish. As a result, comprehensive assessment of time lapse to reach peak temperature, peak temperature and other datum quantity, such as steady state temperature, can reflect the regulatory ability of the vessel wall more effectively, which will finally generate the accurate prediction of cardiovascular disease risk.
2. Quantitative assessment of pulsed high intensity focused ultrasound influence on drug delivery in muscle.
Dynamic contrast-enhanced T1-weighted magnetic resonance imaging was used to record the dynamics of contrast concentration in the rabbits thigh muscle before and after different levels of pulsed high intensity focused ultrasound (p-HIFU) irradiation. According to these data, Toft&Kermode pharmacokinetic model was optimized to obtain the tissue permeability, drug clearance and extracellular volume fraction. Based on statistical analysis of these tissue parameters, we quantitatively investigated the influence and mechanism of p-HIFU on drug delivery. The results indicate that irradiation induced edema is highly related to the later stage enhancement of drug delivery in muscle. And p-HIFU induced permeability enhancement always accompanies with decreased drug clearance rate and increased extracellular volume. Such kind of comprehensive effects can provide sufficient contact between with tissue and drug, which increases the cumulative exposure amount of tissue to drug3-4times. By adjusting irradiation parameters of p-HIFU, an optimal therapeutic effect, which maximizes drug delivery enhancement while burns the tissue less, can be achieved.
3. Mathematical modeling of cell-cell interactions network in immune system.
A mathematical model of interactions between immune cells and motorneurons in SOD1mutation induced amyotrophic lateral sclerosis (ALS) was developed. Dynamics of various cells and regulatory factors in this model was described by ordinary differential equations. Experimental data of transgenic mice were used for training the mathematical model to determine the unknown parameters. The optimized model can felicitously represent three typical stages in ALS:initialization, stabilization and deterioration. Then several potential therapies was tested and the results reveal that suppression of T helper1cells can improve the life quality of patients effectively, which demonstrates the dominant role of T helper1cell in exacerbating the disease at the later stage.
4. Intracellular signaling pathway model based assesment of pharmacodynamic effects.
We proposed an algorithm to systematically investigate the study the comprehensive effects of kinase inhibitors (supressive effect on cancer cells and side effect on liver cells). Based on this algorithm, online shared experimental data were used to establish a mathematical model intergrating the signaling pathways of PC9cells and human primary hepatocytes, which described phosphorylation levels of different intracellular signaling protein response to perturbations were described by ordinary differential equations. Then comprehensive effects of27kinase inhibiors were predicted and crizotinib was finally screened out with an optimal concentration which can suppress PC9cancer cell expansion effectively while avoiding severe damage to primary human hepatocytes. Furthermore, based on our algorithm, an online tool with user friendly interface called KIEP was developed for researchers to predict the comprehensive effects of a kinase inhibitor.
由于生物系统的复杂性以及检测技术的局限性等原因,实验手段通常只能考察系统中部分因素的关系。为了能够系统深入地揭示生物系统的调节机理,本博士论文运用多孔介质内的传热分析,基于优化方法的医疗图像分析及复杂生物网络的系统建模方法对生物组织内的血流调节、药物输运和细胞内外信号传导等问题进行了定量分析,以期为优化心血管疾病诊断、靶向药物输运以及新药筛选技术提供理论依据。主要研究内容包括以下几个方面：
1.基于手部传热分析的血流动态变化评价。
首先从断层医学图像序列出发,提出了三维有限元网格模型的重构方法,构建了具有真实外形的手部三维有限元网格模型。然后,基于Darcy定律和Pennes生物传热理论构建了血流传热模型,用于考察反应性充血过程中指尖温度响应的定量特性。结果表明,指尖温度在无过载充血的情况下需要超过200秒才能恢复到稳定水平,而在强过载充血的情况下,仅需50秒。同时,强弱反应性充血中温度峰值相差0.3℃,足以通过民用红外热像仪分辨出来。因此,结合温度反弹量,恢复时间以及其他诸如稳定温度等基准量,就能有效地衡量血管壁调节能力,从而对心血管疾病做出风险预测。
2.脉冲高强度聚焦超声照射下药物输运特性的定量分析。
通过核磁共振成像技术记录了不同脉冲高强度聚焦超声(p-HIFU)照射前后新西兰大白兔大腿肌肉组织内药物浓度的动态变化。基于这些实验数据和Toft&Kermode模型,发展了优化算法得到了肌肉组织内的药物渗透率,药物清除率以及细胞外空隙分数。通过对这些组织药物输运参数的统计分析,定量地考察了不同p-HIFU能量沉积对药物传输特性的影响和作用机理。结果显示,p-HIFU引起的肌肉组织内的初期水肿与后期药物输运能力的增强存在着紧密的联系。更重要的是,p-HIFU在引起组织内药物渗透性增强的同时还能有效地扩大细胞外空隙和降低药物的清除率,这种综合作用能够为药物与组织提供充分的接触作用,使得组织累计接触的药物量可以增加到3-4倍。通过合理地控制p-HIFU照射,最终能够达到在减少组织烧伤的情况下最大化组织内药物输运增强的效果。
3.免疫系统细胞间相互作用网络的数学建模。
根据SOD1基因突变引起的肌萎缩性脊髓侧索硬化症(ALS)中免疫系统的作用,建立了ALS中免疫细胞与运动神经元相互作用的系统模型。该模型采用常微分方程来描述各个细胞通过调节因子相互作用所引起的动态变化。进一步,基于SOD1转基因小鼠的载体实验数据,采用优化算法确定了数学模型中的待定参数。优化后的数学模型能够恰当地再现疾病发展过程中的初始期、稳定期和恶化期。然后,通过对几种潜在治疗方案的测试发现,抑制1型辅助性T细胞能够有效地减缓疾病的发展,从而改善患者的生活质量。这揭示了1型辅助性T细胞的快速增长在疾病后期快速恶化过程中的主导作用。
4.细胞内蛋白质信号通路模型的数学建模。
提出了系统考察致活酶抑制剂综合效果(对癌细胞的抑制作用和肝细胞的副作用)的算法。基于该算法,我们根据在线共享的实验数据建立了PC9癌细胞和人类原代肝细胞内的蛋白质信号通路模型,描述了作为细胞内信号传递载体的各蛋白质磷酸化水平对外部干扰的动态响应。然后通过该模型对27种致活酶抑制剂综合治疗效果的测试,筛选出克里唑蒂尼作为抑制PC9癌细胞而且避免损伤肝细胞的最佳药物。进一步,基于该算法开发了在线的致活酶抑制剂综合治疗效果预测工具KIEP,以便于研究人员使用该工具预测药效。
Human body is a very complex self-regulating system. Each componet at different levels, such as cells or organs, is involved in achieving homeostasis to allow survival and functioning of biological system against challenges from varying conditions. Decline of this self-regulating capability will induce many diseases. Investigation of the regulatory mechanisms of biological systems can give us a deep insight into different physiological phenomena, which will benefit for the development of new disease diagnostic techniques and treatment methods to improve people's quality of life and health.
Due to complexity of biological systems and limitations of current experimental techniques, experimental methods can only focus on limited factors of the biological system. In order to understand regulatory mechanisms of biological systems systematically and deeply, this doctoral thesis used heat transfer analysis, optimization methods and bio-system modelling to investigate blood flow regulation, drug delivery and intra/extracellular signal transmission, which was expected to benefit for the improvement of cardiovascular disease diagnostic, targeted drug delivery and drug screening. The main contents are listed as following:
1. Analysis of heat transfer in hand for evaluation of blood flow dynamics.
First, an algorithm for3D mesh model reconstruction based on medical image sequences to generate the finite element mesh of a hand with real shape was presented. Then, based on Darcy's law and Pennes bio-heat transfer theory, a mathematical model of blood perfusion and heat transfer in biolgical tissue was established to investigate quantitative features of fingertip temperature response to reactive hyperemia. The results indicate that, for fingertip temperature recovery, it took more than200s without overload of blood reperfusion while only50s with high overload of blood reperfusion. Meanwhile, the difference between the peak temperature with low and high overload of blood perfusion is about0.3℃, which is signaficant enough for thermal infrared imager to distinguish. As a result, comprehensive assessment of time lapse to reach peak temperature, peak temperature and other datum quantity, such as steady state temperature, can reflect the regulatory ability of the vessel wall more effectively, which will finally generate the accurate prediction of cardiovascular disease risk.
2. Quantitative assessment of pulsed high intensity focused ultrasound influence on drug delivery in muscle.
Dynamic contrast-enhanced T1-weighted magnetic resonance imaging was used to record the dynamics of contrast concentration in the rabbits thigh muscle before and after different levels of pulsed high intensity focused ultrasound (p-HIFU) irradiation. According to these data, Toft&Kermode pharmacokinetic model was optimized to obtain the tissue permeability, drug clearance and extracellular volume fraction. Based on statistical analysis of these tissue parameters, we quantitatively investigated the influence and mechanism of p-HIFU on drug delivery. The results indicate that irradiation induced edema is highly related to the later stage enhancement of drug delivery in muscle. And p-HIFU induced permeability enhancement always accompanies with decreased drug clearance rate and increased extracellular volume. Such kind of comprehensive effects can provide sufficient contact between with tissue and drug, which increases the cumulative exposure amount of tissue to drug3-4times. By adjusting irradiation parameters of p-HIFU, an optimal therapeutic effect, which maximizes drug delivery enhancement while burns the tissue less, can be achieved.
3. Mathematical modeling of cell-cell interactions network in immune system.
A mathematical model of interactions between immune cells and motorneurons in SOD1mutation induced amyotrophic lateral sclerosis (ALS) was developed. Dynamics of various cells and regulatory factors in this model was described by ordinary differential equations. Experimental data of transgenic mice were used for training the mathematical model to determine the unknown parameters. The optimized model can felicitously represent three typical stages in ALS:initialization, stabilization and deterioration. Then several potential therapies was tested and the results reveal that suppression of T helper1cells can improve the life quality of patients effectively, which demonstrates the dominant role of T helper1cell in exacerbating the disease at the later stage.
4. Intracellular signaling pathway model based assesment of pharmacodynamic effects.
We proposed an algorithm to systematically investigate the study the comprehensive effects of kinase inhibitors (supressive effect on cancer cells and side effect on liver cells). Based on this algorithm, online shared experimental data were used to establish a mathematical model intergrating the signaling pathways of PC9cells and human primary hepatocytes, which described phosphorylation levels of different intracellular signaling protein response to perturbations were described by ordinary differential equations. Then comprehensive effects of27kinase inhibiors were predicted and crizotinib was finally screened out with an optimal concentration which can suppress PC9cancer cell expansion effectively while avoiding severe damage to primary human hepatocytes. Furthermore, based on our algorithm, an online tool with user friendly interface called KIEP was developed for researchers to predict the comprehensive effects of a kinase inhibitor.
引文
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