| 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. |
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