Satoh J I, Tabunoki H, Yamamura T
Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo, Japan; Department of Immunology, National Institute of Neuroscience, NCNP, Tokyo, Japan.
Mult Scler. 2009 May;15(5):531-41. doi: 10.1177/1352458508101943.
A recent proteomics study of multiple sclerosis (MS) lesion-specific proteome profiling clearly revealed a pivotal role of coagulation cascade proteins in chronic active demyelination. However, among thousands of proteins examined, nearly all of remaining proteins are yet to be characterized in terms of their implications in MS brain-lesion development.
By the systems biology approach using four different pathway analysis tools of bioinformatics, we studied molecular networks and pathways of the proteome dataset of acute plaques, chronic active plaques (CAP), and chronic plaques (CP).
The database search on Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein analysis through evolutionary relationships (PANTHER) indicated the relevance of extracellular matrix (ECM)-mediated focal adhesion and integrin signaling to CAP and CP proteome. KeyMolnet disclosed a central role of the complex interaction among diverse cytokine signaling pathways in brain-lesion development at all disease stages, as well as a role of integrin signaling in CAP and CP. Ingenuity pathway analysis (IPA) identified the network constructed with a wide range of ECM components, such as collagen, type I alpha1, type I alpha2, type VI alpha2, type VI alpha3, fibronectin 1, fibulin 2, laminin alpha1, vitronectin, and heparan sulfate proteoglycan, as one of the networks highly relevant to CAP proteome.
Although four distinct platforms produced diverse results, they commonly suggested a role of ECM and integrin signaling in development of chronic lesions of MS. These in silico observations indicate that the selective blockade of the interaction between ECM and integrins in brain lesions in situ would be a target for therapeutic intervention in MS.
最近一项针对多发性硬化症（MS）病变特异性蛋白质组分析的蛋白质组学研究清楚地揭示了凝血级联蛋白在慢性活动性脱髓鞘中的关键作用。然而，在检测的数千种蛋白质中，几乎所有其余蛋白质在MS脑损伤发展中的意义仍有待确定。
通过使用四种不同生物信息学通路分析工具的系统生物学方法，我们研究了急性斑块、慢性活动性斑块（CAP）和慢性斑块（CP）蛋白质组数据集的分子网络和通路。
对京都基因与基因组百科全书（KEGG）的数据库搜索以及通过进化关系进行的蛋白质分析（PANTHER）表明，细胞外基质（ECM）介导的粘着斑和整合素信号传导与CAP和CP蛋白质组相关。KeyMolnet揭示了不同细胞因子信号通路之间复杂相互作用在所有疾病阶段脑损伤发展中的核心作用，以及整合素信号传导在CAP和CP中的作用。 Ingenuity通路分析（IPA）确定了由多种ECM成分构建的网络，如I型α1胶原、I型α2胶原、VI型α2胶原、VI型α3胶原、纤连蛋白1、纤连蛋白2、层粘连蛋白α1、玻连蛋白和硫酸乙酰肝素蛋白聚糖，是与CAP蛋白质组高度相关的网络之一。
尽管四个不同的平台产生了不同的结果，但它们共同表明ECM和整合素信号传导在MS慢性病变发展中的作用。这些计算机模拟观察结果表明，原位选择性阻断脑损伤中ECM与整合素之间的相互作用将是MS治疗干预的一个靶点。
