Chu Hongwei, Sun Pin, Yin Jiahui, Liu Guangming, Wang Yiwei, Zhao Pengyao, Zhu Yizhun, Yang Xiaohan, Zheng Tiezheng, Zhou Xuezhong, Jin Weilin, Sun Changkai
Department of Biomedical Engineering, Faculty of Electronic Information and Electrical Engineering, Dalian University of Technology, Dalian, China.
Liaoning Provincial Key Laboratory of Cerebral Diseases, Institute for Brain Disorders, Dalian Medical University, Dalian, China.
PLoS One. 2017 Apr 7;12(4):e0174964. doi: 10.1371/journal.pone.0174964. eCollection 2017.
Epilepsy is a complex neurological disorder and a significant health problem. The pathogenesis of epilepsy remains obscure in a significant number of patients and the current treatment options are not adequate in about a third of individuals which were known as refractory epilepsies (RE). Network medicine provides an effective approach for studying the molecular mechanisms underlying complex diseases. Here we integrated 1876 disease-gene associations of RE and located those genes to human protein-protein interaction (PPI) network to obtain 42 significant RE-associated disease modules. The functional analysis of these disease modules showed novel molecular pathological mechanisms of RE, such as the novel enriched pathways (e.g., "presynaptic nicotinic acetylcholine receptors", "signaling by insulin receptor"). Further analysis on the relationships between current drug targets and the RE-related disease genes showed the rational mechanisms of most antiepileptic drugs. In addition, we detected ten potential novel drug targets (e.g., KCNA1, KCNA4-6, KCNC3, KCND2, KCNMA1, CAMK2G, CACNB4 and GRM1) located in three RE related disease modules, which might provide novel insights into the new drug discovery for RE therapy.
癫痫是一种复杂的神经系统疾病，也是一个重大的健康问题。在相当数量的患者中，癫痫的发病机制仍不清楚，目前的治疗方案对约三分之一的患者（即难治性癫痫，RE）并不足够。网络医学为研究复杂疾病背后的分子机制提供了一种有效方法。在此，我们整合了1876个难治性癫痫的疾病-基因关联，并将这些基因定位到人类蛋白质-蛋白质相互作用（PPI）网络中，以获得42个与难治性癫痫显著相关的疾病模块。对这些疾病模块的功能分析揭示了难治性癫痫新的分子病理机制，如新型富集通路（如“突触前烟碱型乙酰胆碱受体”、“胰岛素受体信号传导”）。对当前药物靶点与难治性癫痫相关疾病基因之间关系的进一步分析显示了大多数抗癫痫药物的合理作用机制。此外，我们在三个与难治性癫痫相关的疾病模块中检测到十个潜在的新型药物靶点（如KCNA1、KCNA4 - 6、KCNC3、KCND2、KCNMA1、CAMK2G、CACNB4和GRM1），这可能为难治性癫痫治疗的新药发现提供新的见解。
