title: Analysis of Post-Traumatic Brain Injury Gene Expression Signature Reveals Tubulins, Nfe2l2, Nfkb, Cd44, and S100a4 as Treatment Targets.
abstract: We aimed to define the chronically altered gene expression signature of traumatic brain injury (TBI-sig) to discover novel treatments to reverse pathologic gene expression or reinforce the expression of recovery-related genes. Genome-wide RNA-sequencing was performed at 3 months post-TBI induced by lateral fluid-percussion injury in rats. We found 4964 regulated genes in the perilesional cortex and 1966 in the thalamus (FDR < 0.05). TBI-sig was used for a LINCS analysis which identified 11 compounds that showed a strong connectivity with the TBI-sig in neuronal cell lines. Of these, celecoxib and sirolimus were recently reported to have a disease-modifying effect in in vivo animal models of epilepsy. Other compounds revealed by the analysis were BRD-K91844626, BRD-A11009626, NO-ASA, BRD-K55260239, SDZ-NKT-343, STK-661558, BRD-K75971499, ionomycin, and desmethylclomipramine. Network analysis of overlapping genes revealed the effects on tubulins (Tubb2a, Tubb3, Tubb4b), Nfe2l2, S100a4, Cd44, and Nfkb2, all of which are linked to TBI-relevant outcomes, including epileptogenesis and tissue repair. Desmethylclomipramine modulated most of the gene targets considered favorable for TBI outcome. Our data demonstrate long-lasting transcriptomics changes after TBI. LINCS analysis predicted that these changes could be modulated by various compounds, some of which are already in clinical use but never tested in TBI.
authors.affiliation: Epilepsy Research Laboratory, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: Anssi
authors.initials: A
authors.lastname: Lipponen
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Finland.|University of Eastern Finland Bioinformatics Center, University of Eastern Finland, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Paananen
authors.affiliation: Epilepsy Research Laboratory, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: Noora
authors.initials: N
authors.lastname: Puhakka
authors.affiliation: Epilepsy Research Laboratory, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: Asla
authors.initials: A
authors.lastname: Pitkänen
mesh_terms: D001921:Brain / Q000378:metabolism; D000070642:Brain Injuries, Traumatic / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics / Q000473:pathology; D015870:Gene Expression; D053263:Gene Regulatory Networks; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics*; D000071999:S100 Calcium-Binding Protein A4 / Q000235:genetics*; D059467:Transcriptome; D014404:Tubulin / Q000235:genetics*
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D000071999:S100 Calcium-Binding Protein A4; D014404:Tubulin; C077591:S100A4 protein, human