Systems biology of interstitial lung diseases: integration of mRNA and microRNA expression changes.
Systems biology of interstitial lung diseases: integration of mRNA and microRNA expression changes.
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DOI：
10.1186/1755-8794-4-8
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发表时间：
2011-01-17
影响因子：
2.7
通讯作者：
Galas D
中科院分区：
文献类型：
--
作者：
Cho JH;Gelinas R;Wang K;Etheridge A;Piper MG;Batte K;Dakhallah D;Price J;Bornman D;Zhang S;Marsh C;Galas D
间质性肺疾病（ILD）的分子通路知之甚少。系统生物学方法，与全球表达数据集，被用来确定扰动的基因网络，以获得一些了解的潜在机制，并制定具体的假设，这些慢性肺部疾病。从肺组织研究联盟获得来自患有不同类型ILD的患者的肺组织样品，并分离总细胞RNA。通过基于杂交和扩增的方法分析全局mRNA和microRNA。差异表达的基因被编译并用于鉴定关键信号通路和潜在的生物标志物。鉴定了形成调控网络的基因模块，并对体外培养的细胞进行研究，以与体内结果进行比较。通过分析mRNA和microRNA（miRNA）表达水平，我们发现了差异表达基因的子集，这些基因将ILD患者与对照区分开来，并与ILD的不同疾病阶段和亚型相关。基于通路数据库的网络分析揭示了几种疾病相关的基因模块，涉及TGF-β、Wnt、粘着斑和平滑肌肌动蛋白通路的基因，这些基因与纤维化进展（ILD的关键病理过程）有关。一个更全面的方法也被调整，以构建一个假定的全球基因调控网络的基础上扰动的关键调控元件，转录因子和microRNA。我们的数据强调了TGF-β信号传导的重要性和含肌动蛋白的平滑肌成纤维细胞在这些疾病中的持久性。我们提出的证据表明，在TGF-β信号传导的下游，miR-23 a簇和转录因子Zeb 1的microRNA可能在介导上皮向间充质转化（EMT）和这些疾病中间充质细胞的持续存在中发挥作用。我们提出了一个全面的概述的分子网络干扰ILD，讨论了几个潜在的关键分子调控电路，并确定microRNA物种，可能发挥核心作用，促进ILD的进展。这些发现推进了我们在分子水平上对这些疾病的理解，为定义疾病的具体特征提供了新的分子特征，提出了新的假设，并揭示了治疗干预的新的潜在靶点。
The molecular pathways involved in the interstitial lung diseases (ILDs) are poorly understood. Systems biology approaches, with global expression data sets, were used to identify perturbed gene networks, to gain some understanding of the underlying mechanisms, and to develop specific hypotheses relevant to these chronic lung diseases. Lung tissue samples from patients with different types of ILD were obtained from the Lung Tissue Research Consortium and total cell RNA was isolated. Global mRNA and microRNA were profiled by hybridization and amplification-based methods. Differentially expressed genes were compiled and used to identify critical signaling pathways and potential biomarkers. Modules of genes were identified that formed a regulatory network, and studies were performed on cultured cells in vitro for comparison with the in vivo results. By profiling mRNA and microRNA (miRNA) expression levels, we found subsets of differentially expressed genes that distinguished patients with ILDs from controls and that correlated with different disease stages and subtypes of ILDs. Network analysis, based on pathway databases, revealed several disease-associated gene modules, involving genes from the TGF-β, Wnt, focal adhesion, and smooth muscle actin pathways that are implicated in advancing fibrosis, a critical pathological process in ILDs. A more comprehensive approach was also adapted to construct a putative global gene regulatory network based on the perturbation of key regulatory elements, transcription factors and microRNAs. Our data underscores the importance of TGF-β signaling and the persistence of smooth muscle actin-containing fibroblasts in these diseases. We present evidence that, downstream of TGF-β signaling, microRNAs of the miR-23a cluster and the transcription factor Zeb1 could have roles in mediating an epithelial to mesenchymal transition (EMT) and the resultant persistence of mesenchymal cells in these diseases. We present a comprehensive overview of the molecular networks perturbed in ILDs, discuss several potential key molecular regulatory circuits, and identify microRNA species that may play central roles in facilitating the progression of ILDs. These findings advance our understanding of these diseases at the molecular level, provide new molecular signatures in defining the specific characteristics of the diseases, suggest new hypotheses, and reveal new potential targets for therapeutic intervention.
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影响因子：
4.3
作者：
Hart, Christopher E.;Mjolsness, Eric;Wold, Barbara J.
通讯作者：
Wold, Barbara J.
影响因子：
2
作者：
Dekel, E;Mangan, S;Alon, U
通讯作者：
Alon, U
影响因子：
4.1
作者：
Kuratomi, G;Komuro, A;Imamura, T
通讯作者：
Imamura, T
影响因子：
6
作者：
Chilosi, M;Poletti, V;Doglioni, C
通讯作者：
Doglioni, C
影响因子：
9.5
作者：
Burrage, Kevin;Hood, Lindsay;Ragan, Mark A.
通讯作者：
Ragan, Mark A.