Abstract
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.