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Integrated in vivo multiomics analysis identifies p21-activated kinase signaling as a driver of colitis

ABSTRACT: Background and aims: 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, and phospho-protein measurements from a mouse model. We used this multi-dimensional dataset to track information flow from RNA to protein to phospho-protein and to ascertain which facets of inflammation are described by each data stream. Using trans-omic co-expression network analysis, we find that there are distinct modes of regulation present in the conserved and divergent correlation structures of the three data streams. As a result, each data stream provides a unique viewpoint on the molecular pathogenesis of colitis. Nevertheless, multiple independent computational analyses identified increased signaling through p21-activated kinase (Pak) during colitis, and chemical inhibition of Pak1/2 suppressed inflammation in mice. These studies provide a comprehensive view of the state of signaling in the context of colitis and identify Pak as a therapeutic target. We used microarrays to examine changes in global gene expression patterns associated with chronic inflammation induced by the T cell transfer model of Inflammatory Bowel Disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE95705 | GEO | 2017/06/16

SECONDARY ACCESSION(S): PRJNA378174

REPOSITORIES: GEO

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Project description:The goal of this study was to use global gene expression as a diagnostic tool to compare hepatic gene expression patterns in both male and female FHM in streams with the lowest and highest reproductive success, and potentially identify a suite of mRNA transcripts indicative of reproduction in a population The goal of this study was to compare differences in hepatic mRNA expression between gender at high and low egg-producing streams, not differences between individual streams. A k-means cluster analysis was performed using eggs/pair/day on the original 17 streams to delineate 3 clusters: high, medium and low. From that analysis, FHM from 6 of the original 17-streams used in Crago et al. (2010) were chosen for the microarray experiment (Fig. 1, Table 1). In this study the experimental condition is reproductive success; High versus Low reproductive success. The streams grouped into High Reproductive Success were Oak Creek-2007 (2313 eggs), Point Creek (1277 eggs), Meeme Creek (1164 eggs) and Baird Creek (967 eggs). The streams grouped into Low Reproductive Success were: Ashwaubenon Creek (0 eggs), Devils Creek (541 eggs) and Oak Creek-2006 (642 eggs). Multiple regression analysis using the 22 sediment and water quality characteristics measured in the 6 streams with the highest (n = 4 and lowest (n = 3) streams demonstrated that there were no differences amongst the streams in regards to measure sediment and water variables. .5 One array was run for each gender from each stream. So that Males from Point Creek were pooled and run on one array, males from Ashwaubenon Creek were run on a separate array, and so forth. There were 14 arrays used in this study, 7 for males, 7 for females from individual rivers. So that Males from Point Creek were pooled and run on one array, males from Ashwaubenon Creek were run on a separate array, and so forth. In the case of Oak Creek, which was sampled in both years, there was a large difference in egg production between two years. Therefore separate arrays were run for Oak Creek 2006 and Oak Creek 2007. All streams chosen had overall survival rates of at least 80% through the 21-day sampling period, except Devils River. The survival rate for Devils River was at 100% until four days prior to the end of the experiment when six fish died or escaped.

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Integrated in vivo multiomics analysis identifies p21-activated kinase signaling as a driver of colitis

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