AUTHOR=Wang Pengqian , Yu Yanan , Liu Jun , Li Bing , Zhang Yingying , Li Dongfeng , Xu Wenjuan , Liu Qiong , Wang Zhong 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.637253

DOI=10.3389/fphar.2021.637253

ISSN=1663-9812

ABSTRACT=Stroke is a complex disease featured by multiple common genetic variations and 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 bio-systematical variation of multiple-target drugs. Here, a quantitative approach for inter-module coordination and its transition, named as IMCC, was developed. Applying IMCC to mouse cerebral ischemia-related genes micro-array, we globally investigated modular map and its rewiring from ischemic stroke to drugs (BA, JA, UA) perturbation states, and locally identified the cooperative pathological module pair (PMP) 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, 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, chemokine signaling activation. The core protein, genes, and interaction in PMP 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 bring 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 and inevitable choice for network-based drug discovery.