Unknown,Transcriptomics,Genomics,Proteomics

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Mouse ischemic tolerance genomic analysis of the brain and blood.

ABSTRACT: Ischemic tolerance can be induced by numerous preconditioning stimuli, including various Toll-like receptor (TLR) ligands. We have shown previously that systemic administration of the TLR4 ligand, lipopolysaccharide (LPS) or the TLR9 ligand, unmethylated CpG ODNs prior to transient brain ischemia in mice confers substantial protection against ischemic damage. To elucidate the molecular mechanisms of preconditioning, we compared brain and blood genomic profiles in response to preconditioning with these TLR ligands and to preconditioning via exposure to brief ischemia. The experiment is a comparison of multiple treatment groups with sampling at multiple time points. The objective is to identify differentially regulated genes associated with preconditioning. Time points are examined both following preconditioning alone and following subsequent ischemic challenge (middle cerebral artery occlusion (MCAO)). Brain ipsilateral cortex tissue and blood were collected and processed from each animal. 6 experimental conditions: (n=3-4 mice/condition) LPS treated (i.p. 0.2mg/kg) + ischemic challenge (45min MCAO) CpG treated (i.p. 0.8mg/kg) + ischemic challenge (45min MCAO) Saline treated (i.p.) + ischemic challenge (45min MCAO) brief ischemia (12 min MCAO) + ischemic challenge (45min MCAO) Sham of brief ischemia (12 min) + ischemic challenge (45min MCAO) Non-treated + ischemic challenge (45min MCAO) Time points: Pre-ischemic challenge 3hr 24hr 72hr Post-ischemic challenge 3hr 24hr Unhandled (6 mice)-BASELINE

ORGANISM(S): Mus musculus

SUBMITTER: Susan Stevens

PROVIDER: E-GEOD-32529 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Astrogliosis is a hallmark of the response to brain ischemia, comprised of changes in gene expression and morphology. Hsp72 protects from cerebral ischemia, and although several mechanisms of protection have been investigated, effects on astrocyte activation are unknown. To identify potential mechanisms of protection, gene expression was assessed in mice subjected to middle cerebral artery (MCAO) or sham surgery, of either wildtype (WT) or Hsp72-overexpressing (Hsp72Tg) mice. After stroke, both genotypes exhibited genes related to cell death, stress response, and immune response. Furthermore, genes indicative of astrocyte activation, including cytoskeletal proteins and cytokines, were upregulated. To measure astrocyte activation after stroke, detailed histological and morphological analyses were performed in the cortical penumbra after stroke using unbiased stereology. Consistent with other reports, we observed a marked and persistent increase in glial fibrillary acidic protein (GFAP ) as soon as 3 hours after MCAO. In contrast, vimentin immunoreactivity appeared 12-24 hours after stroke, peaked at 72 hours, and returned to baseline after 30 days. Surprisingly, no change in overall astrocyte number was observed based on glutamine synthetase (GS) immunoreactivity. To determine if Hsp72Tg mice exhibited altered astrocyte activation compared to WT controls, morphological evaluation by fractal analysis was used. Overexpression of Hsp72 reduced astrocyte cell area, arbor area, and to a lesser extent fractal dimension, 72 hours following stroke. In conclusion, in vivo overexpression of Hsp72 alters gene expression following stroke, including genes involved in astrocyte activation, and decreases astrocyte activation acutely following MCAO. Thus, modulation of astrogliosis may be a neuroprotective mechanism exerted by Hsp72 after ischemia. A total of 10 samples were analyzed, with 5 of each genotype, wildtype (WT) and Hsp72-overexpressing (Hsp72Tg) mice. Of the 5 in each group, 3 received middle cerebral artery occlusion (MCAO) and 2 received a sham surgery. The sham samples serve as the controls for the MCAO samples in each genotype. All samples were taken from the ischemic or control hemisphere 24 hours after surgery.

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Mouse ischemic tolerance genomic analysis of the brain and blood.

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