动脉粥样硬化发生发展过程中关键节点和调控网络的系统生物学研究

Atherosclerosis is one of the major factors causing cardiovascular diseases including myocardial infarction. The onset and progression of atherosclerosis resulted from dysregulation of the blood vessel homeostasis involve complicated dynamic regulations among biomolecular networks. This project aims to develop a mathematical model to describe the critical events that lead to the onset and progression of atherosclerosis, based on both theoretical analysis and biological experiment, and further establish a theoretical method for early prediction of the dysregulation of blood vessel homeostasis and atherosclerotic lesion formation based on bifurcation theory of nonlinear dynamical system from the viewpoint of systems biology. Specifically, (1) infer regulatory networks of arteriosclerotic vascular disease by integrating heterogeneous high throughput data, e.g., data of genomics, proteomics and metabolomics, at different stages; (2) identify functional modules, active pathways, and further dynamical network biomarkers to characterize the critical transition from normal vessel to atherosclerotic lesion, by comparing and analyzing the biomolecular networks on various conditions; (3) develop a prediction model to identify the early signal of the critical transition in atherosclerosis by using a few or even a single sample, and further validate the theoretical results with biological experiments using animal models.

动脉粥样硬化是心脑血管疾病的主要原因之一，其发生发展不仅是一个非线性的稳态失衡过程，而且涉及到复杂分子网络的动态调控。本项目由理论计算和实验验证相结合的系统生物学研究模式，建立动脉血管稳态失衡从而导致粥样硬化的数学模型，开发基于系统科学和动力系统理论等的粥样硬化早期诊断方法，近一步确定稳态失衡的关键节点和关键分子网络。(1)通过整合生物医学大数据，基于双聚类算法和矩阵分解模型，推断动脉血管稳态失衡过程中的基因、蛋白质、代谢分子间的调控关系，建立动脉粥样硬化过程的分子调控网络。(2)通过整合基因、蛋白质、代谢等多层次网络，确定刻画稳态失衡过程的动态网络标记物及其活性分子群，得到疾病发生发展过程的关键节点和关键网络，从网络层次解析脂质代谢紊乱和炎症导致动脉粥样硬化的致病机理。(3) 建立动脉粥样硬化的发病前兆检测方法和基于单样本采样的发病前兆预测模型，由动物模型实验验证所得到的计算和理论结果。

动脉粥样硬化是心脑血管疾病的主要原因之一，其发生发展不仅是一个非线性的稳态失衡过程，而且涉及到复杂分子网络的动态调控。本项目由理论计算和实验验证相结合的系统生物学研究模式，建立了动脉血管稳态失衡从而导致粥样硬化的数学模型，开发基于系统科学和动力系统理论等的粥样硬化检测方法，确定了稳态失衡的关键节点和关键分子网络。特别是，(1)通过整合生物数据，推断动脉血管稳态失衡过程中的基因、蛋白质、代谢分子间的调控关系，建立动脉粥样硬化过程的分子调控网络；(2)通过整合基因、代谢等多层次网络，确定刻画稳态失衡过程的动态网络标记物及分子群，得到疾病发生发展过程的关键节点和关键网络，从网络层次解析脂质代谢紊乱和炎症导致动脉粥样硬化的致病机理；(3) 建立动脉粥样硬化的检测方法，由动物模型实验验证了理论结果。