A Rich-Club Organization in Brain Ischemia Protein Interaction Network.
A Rich-Club Organization in Brain Ischemia Protein Interaction Network.
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DOI：
10.1038/srep13513
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发表时间：
2015-08-27
影响因子：
4.6
通讯作者：
Zaraket FA
中科院分区：
文献类型：
--
作者：
Alawieh A;Sabra Z;Sabra M;Tomlinson S;Zaraket FA
缺血性卒中涉及多种病理生理机制，相互作用复杂。努力破译这些机制并了解脑损伤的演变是开发成功干预措施的关键。在一种创新的方法中，我们使用文献挖掘，自然语言处理和系统生物学工具来构建，注释和策划脑缺血相互作用组。策划的相互作用组包括人类和实验性中风脑缺血后失调的蛋白质。相互作用组的网络分析揭示了一个丰富的俱乐部组织，表明存在一个密集互连的枢纽结构的疾病发病机制的突出贡献者。相互作用组的功能注释揭示了突出的途径，并强调了补体和凝血级联反应在启动和放大损伤中的关键作用，该损伤始于富俱乐部的激活。我们进行了计算机屏幕上的假定干预，丰富的俱乐部组件有多效性的影响，我们确定雌激素作为一个突出的候选人。我们的研究结果表明，疾病相关相互作用组的复杂网络分析可能会导致更好地了解致病机制，并提供具有成本效益和基于机制的候选治疗方法的发现。
Ischemic stroke involves multiple pathophysiological mechanisms with complex interactions. Efforts to decipher those mechanisms and understand the evolution of cerebral injury is key for developing successful interventions. In an innovative approach, we use literature mining, natural language processing and systems biology tools to construct, annotate and curate a brain ischemia interactome. The curated interactome includes proteins that are deregulated after cerebral ischemia in human and experimental stroke. Network analysis of the interactome revealed a rich-club organization indicating the presence of a densely interconnected hub structure of prominent contributors to disease pathogenesis. Functional annotation of the interactome uncovered prominent pathways and highlighted the critical role of the complement and coagulation cascade in the initiation and amplification of injury starting by activation of the rich-club. We performed an in-silico screen for putative interventions that have pleiotropic effects on rich-club components and we identified estrogen as a prominent candidate. Our findings show that complex network analysis of disease related interactomes may lead to a better understanding of pathogenic mechanisms and provide cost-effective and mechanism-based discovery of candidate therapeutics.