Integrated in vivo multiomics analysis identifies p21-activated kinase signaling as a driver of colitis
Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal tract that has limited treatment options. To gain insight into the pathogenesis of chronic colonic inflammation (colitis), we performed a multiomics analysis that integrated RNA microarray, total protein mass spectrometry...
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| 语言: | en_US |
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American Association for the Advancement of Science (AAAS)
2018
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| 在线阅读: | http://hdl.handle.net/1721.1/118787 https://orcid.org/0000-0002-9272-4094 https://orcid.org/0000-0003-4115-5001 https://orcid.org/0000-0002-3719-0536 https://orcid.org/0000-0002-0050-989X |
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| author | Ghazi, Phaedra C. Baldwin, Katherine R. Edwards, Amanda Boukhali, Myriam Lin, Yi-Jang Yajnik, Vijay Kissil, Joseph L. Haas, Wilhelm Haigis, Kevin M. Lyons, Jesse Stolberg Brubaker, Douglas Strasser, Samantha Dale Suarez Lopez, Lucia Lauffenburger, Douglas A |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Ghazi, Phaedra C. Baldwin, Katherine R. Edwards, Amanda Boukhali, Myriam Lin, Yi-Jang Yajnik, Vijay Kissil, Joseph L. Haas, Wilhelm Haigis, Kevin M. Lyons, Jesse Stolberg Brubaker, Douglas Strasser, Samantha Dale Suarez Lopez, Lucia Lauffenburger, Douglas A |
| author_sort | Ghazi, Phaedra C. |
| collection | MIT |
| description | Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal tract that has limited treatment options. To gain insight into the pathogenesis of chronic colonic inflammation (colitis), we performed a multiomics analysis that integrated 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 tracked information flow from RNA to protein to phosphoprotein and identified signaling molecules that were coordinately or discordantly regulated and pathways that had complex regulation in vivo. For example, the genes encoding acute-phase proteins were expressed in the liver, but the proteins were detected by MS in the colon during inflammation. We also ascertained the types of data that best described particular facets of chronic inflammation. Using gene set enrichment analysis and trans-omics coexpression network analysis, we found that each data set provided a distinct viewpoint on the molecular pathogenesis of colitis. Combining human transcriptomic data with the mouse multiomics data implicated increased p21-activated kinase (Pak) signaling as a driver of colitis. 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 potential therapeutic target in IBD. |
| first_indexed | 2024-09-23T13:28:55Z |
| format | Article |
| id | mit-1721.1/118787 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:28:55Z |
| publishDate | 2018 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1187872022-09-28T14:32:26Z Integrated in vivo multiomics analysis identifies p21-activated kinase signaling as a driver of colitis Ghazi, Phaedra C. Baldwin, Katherine R. Edwards, Amanda Boukhali, Myriam Lin, Yi-Jang Yajnik, Vijay Kissil, Joseph L. Haas, Wilhelm Haigis, Kevin M. Lyons, Jesse Stolberg Brubaker, Douglas Strasser, Samantha Dale Suarez Lopez, Lucia Lauffenburger, Douglas A Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Koch Institute for Integrative Cancer Research at MIT Lyons, Jesse Stolberg Brubaker, Douglas Strasser, Samantha Dale Suarez Lopez, Lucia Lauffenburger, Douglas A Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal tract that has limited treatment options. To gain insight into the pathogenesis of chronic colonic inflammation (colitis), we performed a multiomics analysis that integrated 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 tracked information flow from RNA to protein to phosphoprotein and identified signaling molecules that were coordinately or discordantly regulated and pathways that had complex regulation in vivo. For example, the genes encoding acute-phase proteins were expressed in the liver, but the proteins were detected by MS in the colon during inflammation. We also ascertained the types of data that best described particular facets of chronic inflammation. Using gene set enrichment analysis and trans-omics coexpression network analysis, we found that each data set provided a distinct viewpoint on the molecular pathogenesis of colitis. Combining human transcriptomic data with the mouse multiomics data implicated increased p21-activated kinase (Pak) signaling as a driver of colitis. 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 potential therapeutic target in IBD. Crohn's and Colitis Foundation of America (Research Fellowship) National Science Foundation (U.S.). Graduate Research Fellowship Program (Grant 1122374) Institute for Collaborative Biotechnologies (W911NF-09-0001) 2018-10-25T19:49:59Z 2018-10-25T19:49:59Z 2018-02 Article http://purl.org/eprint/type/JournalArticle 1945-0877 1937-9145 http://hdl.handle.net/1721.1/118787 Lyons, Jesse, et al. “Integrated in Vivo Multiomics Analysis Identifies P21-Activated Kinase Signaling as a Driver of Colitis.” Science Signaling, vol. 11, no. 519, Feb. 2018, p. eaan3580. https://orcid.org/0000-0002-9272-4094 https://orcid.org/0000-0003-4115-5001 https://orcid.org/0000-0002-3719-0536 https://orcid.org/0000-0002-0050-989X en_US https://doi.org/10.1126/scisignal.aan3580 Science Signaling Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science (AAAS) Prof. Lauffenburger via Howard Silver |
| spellingShingle | Ghazi, Phaedra C. Baldwin, Katherine R. Edwards, Amanda Boukhali, Myriam Lin, Yi-Jang Yajnik, Vijay Kissil, Joseph L. Haas, Wilhelm Haigis, Kevin M. Lyons, Jesse Stolberg Brubaker, Douglas Strasser, Samantha Dale Suarez Lopez, Lucia Lauffenburger, Douglas A Integrated in vivo multiomics analysis identifies p21-activated kinase signaling as a driver of colitis |
| title | Integrated in vivo multiomics analysis identifies p21-activated kinase signaling as a driver of colitis |
| title_full | Integrated in vivo multiomics analysis identifies p21-activated kinase signaling as a driver of colitis |
| title_fullStr | Integrated in vivo multiomics analysis identifies p21-activated kinase signaling as a driver of colitis |
| title_full_unstemmed | Integrated in vivo multiomics analysis identifies p21-activated kinase signaling as a driver of colitis |
| title_short | Integrated in vivo multiomics analysis identifies p21-activated kinase signaling as a driver of colitis |
| title_sort | integrated in vivo multiomics analysis identifies p21 activated kinase signaling as a driver of colitis |
| url | http://hdl.handle.net/1721.1/118787 https://orcid.org/0000-0002-9272-4094 https://orcid.org/0000-0003-4115-5001 https://orcid.org/0000-0002-3719-0536 https://orcid.org/0000-0002-0050-989X |
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