基于“方剂-靶标网络-病证”关联模式的异病同证机制研究

Treating different diseases with the same syndrome embodies the essential theory of TCM clinical practice, however, due to the ambiguity and uncertainty of syndrome, it is hard to reveal the mechanism of “different diseases with the same syndrome” if only focus on syndrome research itself. Therefore, “syndrome differentiation through formula effect assessment” theory, chemical genetics strategy will be adopted, with formula taken as a “probe”, to disclose the relevance between “formulae-targets network-disease and syndrome”, which is a possible pathway for the research. Then the project takes ischemic stroke and coronary heart  disease as example, using Danhong injection as a “probe” which could cure disease with syndrome of blood stasis, applying  complex network and data mining method, to acquire the targets network of ischemic stroke, coronary heart  disease, syndrome of blood stasis and Danhong injection, which based on relevance of “formulae-targets network-syndrome”. And based on that, chemical genetics strategy will be adopted to do directional regulation and control research on the effector cell molecular network of Danhong injection and to verify it. And meanwhile, via research on the intervention of Danhong injection on animal models of ischemic stroke and coronary  heart  disease, the result will be further verified. Then, specific medicine targets, metabolic biomarkers of those two different diseases but of the same syndrome- blood stasis, could be obtained. The project puts forward a new strategy for “different diseases with the same syndrome”, which combines original thinking of TCM and modern technology successfully. It will not only enrich the understanding of the process of diseases, but also provide a powerful evidence for the clinical application.

异病同证是体现中医核心诊疗理念的内容之一，由于证候的模糊性、不确定性，单纯从证候切入，难以揭示异病同证的机制。遵循“以方测证”的思路，采用化学遗传学的研究策略，以方剂为“探针”，揭示“方剂-靶标网络-病证”之间的关联性，是进行异病同证机制研究的可行路径。本项目以脑卒中、冠心病为范例，采用临床上广泛应用的治疗血瘀证的丹红注射液为“探针”，基于“方剂-靶标网络-病证”关联模式，运用复杂网络和数据挖掘技术和方法，获得脑卒中和冠心病、血瘀证、丹红注射液的网络靶标。在此基础上，应用化学遗传学的策略与方法，开展丹红注射液对效应细胞分子网络的定向调控研究与验证；同时通过丹红注射液干预脑卒中、冠心病的动物模型研究，进一步验证和确认；获得脑卒中、冠心病血瘀证的特定靶标网络、代谢标志物等。本项目为异病同证机制研究提出了新策略，将中医原创思维与现代科学有机结合，丰富对疾病过程的认识，指导方剂临床科学应用。

异病同证是体现中医核心诊疗理念的内容之一，由于证候的诊断模糊性、动物模型缺失，单纯从证候切入，难以揭示异病同证的机制。本项目遵循“以方测证”的思路，以治疗血瘀证的代表方剂丹红注射液为“探针”，针对脑卒中、冠心病，按照“方剂-靶标网络-病证”关联模式，通过细胞、整体等多层次的研究，揭示丹红注射液治疗脑卒中、冠心病的关键靶标及对分子网络的调控，以揭示异病同证的生物基础及方剂干预作用。.本项目主要取得以下4方面的科研成果：1、构建数据驱动的“方剂-靶标网络-病证”异质网络分析方法，解析异病同治（脑心同治）的生物学基础；2、脑心同治的关键靶标筛选与验证，发现丹红注射液抗心肌肥大的直接作用靶点为内皮素B受体（ETBR）和血管紧张素II 1型受体（AT1R）；3、采用转录组、蛋白质组、代谢组等多组学，揭示丹红注射液抗心脑血管疾病网络靶标；发现丹红注射液抗氧化应激的关键转录因子（Apex1、Mef2d和Pbx3等）；抗脑缺血的关键转录因子（PBX1、ATF1、NFYC 等）；揭示脂质代谢、细胞凋亡、氧化应激、DNA损伤修复、细胞骨架、以及血管生成等共性环节；4、构建整合药理学计算平台、分子靶向及细胞功能表型分析平台，支撑异病同证/同治的基础研究。本项目揭示丹红注射液干预脑卒中、冠心病急性缺血的共同网络靶标及关键病理环节，深化了脑卒中、冠心病血瘀证生物学基础的认识，构建多组学整合研究策略，为中药方剂复杂体系解析提供技术方法，并在多个中药方剂中得到应用。.本项目发表论文25篇，其中SCI论文16篇，1篇IF＞10，2篇IF＞5；获得专利或软件著作权5项；毕业博士研究生5名，硕士研究生25名，出站博士后4名；卫计委有突出贡献的中青年专家1名、中国青年科技奖1名、中国科协求是杰出青年成果转化奖1人。