揭示病证结合的生物学基础，发现证候生物标志物，进而阐释证候标志物对疾病个体化诊疗的意义是病证结合研究的关键科学问题。如何实现病证宏观表型与微观分子信息的系统整合，发现病证表型与分子指标的演变规律是解决上述问题的关键方法学难点。本项目拟采用计算、临床与实验相交叉的策略，并以慢性胃炎寒热证为范例开展研究，建立基于“表型—分子”生物网络的病证结合研究方法体系。首先，基于多层次网络关联模型和临床检测，构建慢性胃炎寒热证“表型—分子”生物网络；然后以寒热证“能量代谢—免疫调节”网络失衡为切入点，分析慢性胃炎发展过程中病证表型与表观遗传等分子指标的演变规律，揭示慢性胃炎寒热证的网络生物学基础；进而，分别结合寒热中药干预的网络扰动实验、临床队列研究，发现网络中寒热证标志物对于慢性胃炎个体化治疗和恶性转化风险评价的意义。本项目将为病证结合的生物学基础研究以及发现源于证候的新型标志物提供重要方法学。

The key scientific question of “disease-ZHENG integration” is to study its biological mechanisms, discover ZHENG-based biomarkers and explain the clinical values of ZHENG-based biomarkers for personalized medicine. To resolve this question, novel methods should be developed to integrate phenotypes and molecular information, and then systematically examine their variation patterns under the disease-ZHENG integration. Based on a computational-clinical-experimental multidisciplinary strategy, we will use the chronic gastritis (CG) with Cold and/or Hot ZHENG as the example to establish a “phenotype-molecule” biological network based methodology for “disease-ZHENG integration”. Firstly, construct the phenotype-molecule biological network of CG with Cold / Hot ZHENG based on a multi-layer network association model and a following clinical investigation. Then, based on the previous observation of “metabolism-immune” network imbalance in Cold / Hot ZHENG patients, systematically analyze the variation patterns of phenotypes and molecular features (such as epigenetic and transcriptomic features) during CG progression and malignant transformation, and uncover the network-based biological mechanisms of CG with Cold / Hot ZHENG. Finally, implement network perturbation experiments with Cold / Hot herb treatment or clinical cohort study, to find Cold / Hot ZHENG based potential biomarkers for personalized medicine and/or CG malignant transformation risk evaluation. This study will provide an important methodological support to understand the biological basis of disease-ZHENG integration and discover ZHENG-based biomarkers.