复杂疾病的分子网络模型研究

The research on molecular network models of complex disease

复杂疾病是危害人类健康的主要杀手.不同于单基因缺陷性遗传病,复杂疾病的发生发展与多个基因之间、基因与环境之间的相互作用有关,致病机理复杂,其早期诊断及治疗困难是21世纪生物医学研究的重大挑战之一.随着生物知识的不断积累和多层次"组学"数据的井喷式涌现,复杂疾病研究迎来了新的"组学革命",研究模式从以往的只关注某个分子扩展到对分子之间相互形成的生物分子网络的系统分析.作为系统生物学核心概念,生物分子网络系统整合大量生物知识和高通量生物数据,是研究复杂疾病的强有力工具.本文以分子网络为主线,以数学建模为工具来研究复杂疾病,针对复杂疾病关系和复杂疾病的发生发展机制等复杂疾病研究的关键热点问题,分析和集成高通量多层次组学数据,构建并求解生物分子网络的数学模型,在若干复杂疾病相关系统生物学问题中取得有生物学意义的结果.本文提出若干生物网络建模、分析及应用的方法并提供若干应用软件,为从系统层面理解复杂疾病提供重要参考;同时,网络模型在若干实例中的应用得到若干有生物学意义的结论,为揭示复杂疾病机理、推动疾病治疗与预防起到了一定的作用.

Complex diseases such as cardiovascular disease, cancer and diabetes are major killers of human health. Unlike single gene defect diseases, complex diseases are usually believed to be associated with the interactions among genes and the interactions among genes and environmental factors. The underlying complex pathogeneses make both the early diagnosis and treatment difficult. Therefore the research of complex diseases is one of the major challenges of biomedical research in this century. Recently, the rapid accumulation of biological knowledge and multi-level high-throughput omics data, revolutionarily changed the research paradigm on complex disease. Instead of only focusing on single molecular, researchers are gradually extending their research to systematically analyzing genome-wide biomolecular interactions, i.e., biomolecular networks. In this context, bio-molecular network, which is a powerful tool to study complex diseases, enables systematically integration of high throughput biological data and plenty of biological knowledge. Recently, a large number of biological networks have been constructed, including protein interaction network, transcriptional regulation network, signal transduction network, metabolic network and so on. These studies have played a significant role in revealing the pathogeneses of complex diseases and promoting treatment or prevention of diseases. However, the biomolecular network research on complex diseases is still in its infancy. Due to the complexity of mechanisms and disease-related biological data, many challenges remain to be further explored and resolved. In this thesis, we use mathematical models of biomolecular networks to address some main challenges in the research of complex diseases. Specifically, we study molecular networks step by step from static, node dynamic, edge dynamic, to module dynamic of network construction and network analysis, and build several mathematical models to deepen the complex disease study by biomolecular networks concept.