Integrated in vivo multiomics analysis identifies p21-activated kinase signaling as a driver of colitis.
Integrated in vivo multiomics analysis identifies p21-activated kinase signaling as a driver of colitis.
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DOI：
10.1126/scisignal.aan3580
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发表时间：
2018-02-27
影响因子：
7.3
通讯作者：
Haigis KM
中科院分区：
文献类型：
--
作者：
Lyons J;Brubaker DK;Ghazi PC;Baldwin KR;Edwards A;Boukhali M;Strasser SD;Suarez-Lopez L;Lin YJ;Yajnik V;Kissil JL;Haas W;Lauffenburger DA;Haigis KM
炎症性肠病（IBD）是一种慢性胃肠道疾病。 IBD 的分子机制尚不明确，治疗选择也有限。为了深入了解慢性结肠炎症（结肠炎）的发病机制，我们进行了一项多组学分析，该分析整合了来自该疾病小鼠模型的 RNA 微阵列、总蛋白质谱 (MS) 和磷蛋白 MS 测量。因为我们从单个样本中收集了所有三种类型的数据，所以我们可以跟踪从 RNA 到蛋白质再到磷蛋白的信息流，以识别协调或不一致调节的信号分子。有了这些信息，我们确定了具有复杂体内调节的途径。例如，编码急性期蛋白的基因在肝脏中表达，但在炎症期间，MS 在结肠中检测到这些蛋白。我们还使用多维数据集来确定哪些类型的数据最能描述慢性炎症的特定方面。利用基因集富集分析和跨组学共表达网络分析，我们发现每个数据集都提供了关于结肠炎分子发病机制的独特观点。将人类转录组数据与小鼠多组学数据相结合，表明 p21 激活激酶 (Pak) 信号传导增强是结肠炎的驱动因素，而 FRAX597 对 Pak1 和 Pak2 的化学抑制可抑制小鼠的活动性结肠炎。这些研究提供了对结肠炎机制的转化见解，并将 Pak 确定为 IBD 的治疗靶点。转录组学、蛋白质组学和磷酸蛋白质组学揭示了结肠炎的治疗靶点。
Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal tract. The molecular mechanisms underlying IBD are poorly characterized and treatment options are limited. To gain insight into the pathogenesis of chronic colonic inflammation (colitis), we performed a multi-omic analysis that integrates RNA microarray, total protein mass spectrometry (MS), and phosphoprotein MS measurements from a mouse model of the disease. Because we collected all three types of data from individual samples, we could track information flow from RNA to protein to phosphoprotein to identify signaling molecules that were coordinately or discordantly regulated. With this information, we identified pathways that had complex in vivo regulation. For example, the genes encoding acute phase proteins were expressed in the liver, but the proteins were detected by MS in colons during inflammation. We also used the multi-dimensional dataset to ascertain which types of data best described particular facets of chronic inflammation. Using gene set enrichment analysis and trans-omic co-expression network analysis, we found that each data set provides a unique viewpoint on the molecular pathogenesis of colitis. Combining human transcriptomic data with the mouse multi-omic data implicated increased p21-activated kinase (Pak) signaling as a driver of colitis and chemical inhibition of Pak1 and Pak2 with FRAX597 suppressed active colitis in mice. These studies provide translational insights into the mechanisms contributing to colitis and identify Pak as a therapeutic target in IBD. Transcriptomics, proteomics, and phospho-proteomics reveals therapeutic targets in colitis.
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影响因子：
64.5
作者：
Huttlin EL;Jedrychowski MP;Elias JE;Goswami T;Rad R;Beausoleil SA;Villén J;Haas W;Sowa ME;Gygi SP
通讯作者：
Gygi SP
DOI：
10.1186/1745-7580-4-5
发表时间：
2008-04-29
期刊：
Immunome research
影响因子：
--
作者：
Lattin JE;Schroder K;Su AI;Walker JR;Zhang J;Wiltshire T;Saijo K;Glass CK;Hume DA;Kellie S;Sweet MJ
通讯作者：
Sweet MJ
影响因子：
3.7
作者：
Itakura A;Aslan JE;Kusanto BT;Phillips KG;Porter JE;Newton PK;Nan X;Insall RH;Chernoff J;McCarty OJ
通讯作者：
McCarty OJ
影响因子：
3.7
作者：
Laubitz D;Harrison CA;Midura-Kiela MT;Ramalingam R;Larmonier CB;Chase JH;Caporaso JG;Besselsen DG;Ghishan FK;Kiela PR
通讯作者：
Kiela PR
影响因子：
15.9
作者：
D'Alessio, Silvia;Correale, Carmen;Danese, Silvio
通讯作者：
Danese, Silvio