datasheet1_IMCC: A Novel Quantitative Approach Revealing Variation of Global Modular Map and Local Inter-Module Coordination Among Differential Drug’s Targeted Cerebral Ischemic Networks.zip

Stroke is a common disease characterized by multiple genetic dysfunctions. In this complex disease, detecting the strength of inter-module coordination (genetic community interaction) and subsequent modular rewiring is essential to characterize the reactive biosystematic variation (biosystematic perturbation) brought by multiple-target drugs, whose effects are achieved by hitting on a series of targets (target profile) jointly. Here, a quantitative approach for inter-module coordination and its transition, named as IMCC, was developed. Applying IMCC to mouse cerebral ischemia–related gene microarray, we investigated a holistic view of modular map and its rewiring from ischemic stroke to drugs (baicalin, BA; ursodeoxycholic acid, UA; and jasminoidin, JA) perturbation states and locally identified the cooperative pathological module pair and its dissection. Our result suggested the global modular map in cerebral ischemia exhibited a characteristic “core–periphery” architecture, and this architecture was rewired by the effective drugs heterogeneously: BA and UA converged modules into an intensively connected integrity, whereas JA diverged partial modules and widened the remaining inter-module paths. Locally, the PMP dissociation brought by drugs contributed to the reversion of the pathological condition: the focus of the cellular function shift from survival after nervous system injury into development and repair, including neurotrophin regulation, hormone releasing, and chemokine signaling activation. The core targets and mechanisms were validated by in vivo experiments. Overall, our result highlights the holistic inter-module coordination rearrangement rather than a target or a single module that brings phenotype alteration. This strategy may lead to systematically explore detailed variation of inter-module pharmacological action mode of multiple-target drugs, which is the principal problem of module pharmacology for network-based drug discovery.

脑卒中（Stroke）是一类以多种遗传功能异常为特征的常见疾病。在这一复杂疾病中，检测模块间协调（inter-module coordination）的强度与后续的模块重连（modular rewiring），对于表征多靶点药物引发的反应性生物系统变异（biosystematic perturbation）至关重要——此类药物的作用通过共同靶向一系列靶点（target profile）来实现。本研究开发了一种用于分析模块间协调及其动态转变的定量方法，命名为IMCC（IMCC）。将IMCC应用于小鼠脑缺血相关基因芯片（gene microarray）数据，我们解析了缺血性脑卒中（ischemic stroke）向药物干预状态转变的全维度模块图谱及其重连模式：所涉药物包括黄芩苷（baicalin, BA）、熊去氧胆酸（ursodeoxycholic acid, UA）与栀子苷（jasminoidin, JA），并在局部层面识别出协同病理模块对（cooperative pathological module pair）及其解离机制。研究结果显示，脑缺血状态下的全局模块图谱呈现典型的“核心-外围”（core–periphery）结构，且该结构会被有效药物以异质性方式重连：BA与UA将模块整合为紧密连接的整体，而JA则使部分模块发生分散，并拓宽了剩余模块间的通路。局部层面，药物介导的协同病理模块对（PMP）解离有助于病理状态的逆转：细胞功能的核心焦点从神经系统损伤后的存活维持转向发育与修复过程，包括神经营养因子（neurotrophin）调控、激素释放以及趋化因子信号（chemokine signaling）激活。核心靶点与作用机制已通过体内实验（in vivo experiments）得到验证。总体而言，本研究结果表明，表型改变的核心驱动因素是全维度模块间协调重排，而非单一靶点或单个模块。该策略可为系统探索多靶点药物的模块间药理作用模式的细微变异提供研究思路，而这正是基于网络的药物发现（network-based drug discovery）领域中模块药理学（module pharmacology）的核心问题。