中文摘要
本课题以抗心肌纤维化具有确切作用的芪参颗粒为研究对象,深入研究温阳益气活血解毒法防治心肌纤维化的分子网络调控机制。采用基于RNA-SEQ测序,基于共表达分析、网络融合等生物信息学技术,构建中药干预心肌纤维化的mRNA-miRNA-lncRNA多层面药效实体网络;利用基于ADME/t和WES的大规模直接靶标预测技术,结合实体语法系统的网络推理与实证技术,预测芪参颗粒的直接药靶;以已知效应蛋白为探针,构建抗心肌纤维化mRNA-miRNA-lncRNA-蛋白多维度药效分子调控网络,并以网络拓扑结构为基础进行功能模块化分析与关键节点筛选;最终通过功能获得/缺失实验验证主要有效成分与主要靶标,进而揭示温阳益气活血解毒法防治心肌纤维化的分子网络调控机制和效应物质基础,为提高中医抗心肌纤维化的临床疗效建立新策略、新治法、新手段提供科学依据。
英文摘要
Qishenkeli has definite therapeutic effects on reversing cardiac fibrosis. This research is to systematically explore the underlying molecular network regulatory mechanism of the efficacy and how the principles of warming yang, tonifying qi, promoting blood circulation and detoxication work on cardiac fibrosis. Integrated bioinformatics techniques such as RNA-SEQ, co-expression analysis, network fusion et al. are applied to build a multilevel molecular network of anti-cardiac fibrosis of herbs,, which contains different dimensions of “gene-transcription (mRNA、miRNA、lncRNA)-protein” levels. And then, a forecast of qishenkeli’s direct drug targets will be predicted based on large-scale direct target prediction technology ADME/T, integrating with entity grammar system network and demonstration technology. Then multidimensional efficacy molecular regulation networks of anti-myocardial fibrosis were established from mRNA-miRNA-lncRNA to protein levels by using known effective proteins as probes, and critical node modular were screening based on network topology and mode functional analysis. After that, the main active ingredients and potential targets are validated by get/lose molecular biology experiments both in vivo and in vitro. And finally revealing the molecular network regulatory mechanism and substantial base of qishenkeli, on reversing cardiac fibrosis by the method of warming yang, tonifying qi, promoting blood circulation and detoxication, thus to provide scientific evidence for setting up novel strategies, therapeutic principles and methods to improve the clinical anti-cardiac fibrosis efficacy for Chinese medicine.
