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Cross species transcriptomic signatures predict response to MK2 inhibition in mouse models of chronic inflammation

ABSTRACT: Translating observations from preclinical models to patients is one of the most pressing challenges in biomedical research. Part of the challenge derives from the necessity of studying preclinical therapeutic responses in genetically and environmentally homogenous mouse models, which exhibit less variability than genetically and environmentally heterogeneous humans. This problem is especially relevant for inflammatory bowel diseases (IBD), which are genetically complex and exhibit significant inter-patient heterogeneity in disease presentation and therapeutic response. Here, we show that mouse models of IBD exhibit variable responses to inhibition a MK2, a pro-inflammatory serine/threonine kinase, and that MK2 inhibition suppresses inflammation by targeting inflammatory monocytes and neutrophils. Using a computational approach (TransComp-R) that allows for cross-species comparison of transcriptomic features, we identified an IBD patient subgroup that is predicted to respond to MK2 inhibition and an independent preclinical model of chronic intestinal inflammation predicted to be non-responsive, which we validated experimentally. Thus, cross-species mouse-human translation approaches can help to identify patient subpopulations in which to deploy new therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE164339 | GEO | 2021/01/08

REPOSITORIES: GEO

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