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Integrated in vivo multiomics analysis identifies p21-activated kinase signaling as a driver of colitis
- Source :
- Prof. Lauffenburger via Howard Silver
- Publication Year :
- 2018
-
Abstract
- 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.<br />Crohn's and Colitis Foundation of America (Research Fellowship)<br />National Science Foundation (U.S.). Graduate Research Fellowship Program (Grant 1122374)<br />Institute for Collaborative Biotechnologies (W911NF-09-0001)
- Subjects :
- 0301 basic medicine
Proteomics
Cell signaling
Pyridones
Biology
Biochemistry
Inflammatory bowel disease
Article
Pathogenesis
Transcriptome
03 medical and health sciences
PAK1
medicine
Animals
Humans
Gene Regulatory Networks
Colitis
Molecular Biology
Cells, Cultured
Microarray analysis techniques
Gene Expression Profiling
Cell Biology
medicine.disease
3. Good health
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
Pyrimidines
p21-Activated Kinases
Phosphoprotein
Cancer research
Signal Transduction
Subjects
Details
- ISSN :
- 19379145
- Volume :
- 11
- Issue :
- 519
- Database :
- OpenAIRE
- Journal :
- Science signaling
- Accession number :
- edsair.doi.dedup.....aff36b977c78388e604a0cf6dfbcd291