基于分子网络模块探讨冠心病痰瘀互结证的分子机制

The molecular network module structure of biological systems was regarded to be one of the key factors for understanding complex biological systems, and it also provided a holistic and systematic perspective and tool for understanding the molecular mechanisms of Sydrome in Traditional Chinese Medicine. Intermingled phlegm and blood stasis syndrome(IPBSS) had become a common and important syndrome in patients with ischemic heart disease(IHD) in clinical, but the molecular mechanism of IPBSS with IHD had not yet been fully elucidated. The key difficulty of the complex relationship between macroscopic syndrome phenotype and microbiological indicators was not solved. For the first time, the project will apply the molecular network modules to the molecular mechanism research of IPBSS with IHD. In our privious work, we had discovered and preliminary verified two molecular network modules were closely related to the IPBSS with IHD by integrated modules analysis and clinical samples with RNA sequencing. In this project, the close relationship between the two molecular network modules and IPBSS with IHD will been further tested from the protein expression level in vivo putting rat model of IPBSS with IHD as experimental subjects. Furthermore, under the guideline of correspondence of formula and syndrome theory, DanLou Tablet will be used to observe the effect on the expression level of biomarker group proteins in the molecular network modules closely related to IPBSS with IHD to prove its molecular mechanism from the treatment perspective. The completion of this project will partly clarify the molecular mechanism of IPBSS with IHD based on the molecular network module perspective, and it will explore a new research perspective and approach for studying the nature of compound syndrome with complex disease.

分子网络模块结构被认为是理解生物复杂系统的关键因素之一，也为认识中医“证”分子机制提供了整体、系统的视角和工具。冠心病痰瘀互结证已成为临床常见的重要证型，但其分子机制尚未完全阐明，“宏观证候表型与微观生物学指标之间关系十分复杂”这一关键难点未能突破。本项目首次将分子网络模块应用于冠心病痰瘀互结证这一临床重大疑难病证的分子机制研究中，在前期分子网络模块的整合分析和临床样本RNA测序、发现并初步验证两个分子网络模块与冠心病痰瘀互结证密切相关的基础上，进一步以冠心病痰瘀互结证大鼠模型为实验对象，从蛋白表达水平验证这两个分子网络模块与冠心病痰瘀互结证的密切关系。进而以方测证，观察丹蒌片(化痰活血方)对冠心病痰瘀互结证分子网络模块生物标志物群蛋白表达水平的影响，反证其分子机制。本项目的完成，将基于分子网络模块视角，部分阐明冠心病痰瘀互结证的分子机制，并为复杂疾病复合证的本质研究探索新的视角和途径。

分子网络模块结构被认为是理解生物复杂系统的关键因素之一，也为认识中医“证”分子机制提供了整体、系统的视角和工具。冠心病痰瘀互结证已成为临床常见的重要证型，但其分子机制尚未完全阐明，“宏观证候表型与微观生物学指标之间关系十分复杂”这一关键难点未能突破。.本项目首次将分子网络模块应用于冠心病痰瘀互结证这一临床重大疑难病证的分子机制研究中。在前期分子网络模块的整合分析和临床样本RNA测序、发现并初步验证两个分子网络模块与冠心病痰瘀互结证密切相关的基础上，成功建立并评价冠心病痰瘀互结证大鼠模型，从蛋白表达水平验证这两个分子网络模块与冠心病痰瘀互结证的密切关系。进而以方测证，观察丹蒌片(化痰活血方)对冠心病痰瘀互结证分子网络模块生物标志物群蛋白表达水平的影响，反证其分子机制。.结果发现：从假手术组，到冠心病痰湿组和冠心病血瘀组，再发展到冠心病痰瘀互结组，12个生物网络标志物（IL-6、IL-1β、MMP-8、MMP-9、Resistin、MPO、ACE、NOD-2、E-selectin、LOX-1、CHI3L-1、GDF-15）呈规律性表达量升高趋势（P<0.05），丹蒌片可显著降低冠心病痰瘀互结证组中这12个生物网络标志物的水平（P<0.05）；2个生物网络标志物（TIMP-3和ACE-2）呈规律性表达量降低趋势（P<0.05），丹蒌片可显著升高冠心病痰瘀互结证组中这2个生物网络标志物的水平（P<0.05）。血清和心肌组织中蛋白表达趋势一致。.本项目的顺利完成，部分阐明了冠心病痰瘀互结证的分子机制，对冠心病痰瘀互结证精确诊断和精准治疗具有现实意义；为本项目立项之处提出的研究假说“分子网络模块能从系统、整体视角较好反映证的分子机制”提供了科学证据，为探讨复杂疾病复合证的本质探索新的研究视角和途径，具有良好的方法学示范意义。

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