TP6 - SASKit

Senescence-related biomarkers and signaling pathways in blood and brain of stroke models

Stroke is the most common cause of dependency worldwide, usually due to cognitive impairment. Stroke is linked to senescence, and metabolic factors such as hyperlipidemia and defective glucose metabolism account for its second largest risk factor. Both for gauging prognostic outcome and theranostic interventions, senescence/apoptosis markers emerge as promising candidates. Little is known on how these markers, usually obtained from blood, correspond to markers in the brain, and how in turn both relate to cognitive dysfunction.
We identified biomarker candidates on a pathomechanistic basis using brain hypoxia/ischemia in vitro models of both normal mice, and of a metabolically perturbed mouse strain with defective metabolism (UCP2-/- mouse). For this purpose, vital frontal somatosensory cortex slices of mice were subjected to hypoxia/hypoglycemia to mimic ischemic stroke conditions. In our experiments we monitor evoked field potentials (and degree of recovery), as well as latency to anoxic negativity in electrophysiological recordings to quantify ischemia tolerance. After slice extraction, using histological techniques we quantify apoptosis/senescence and match these data to expression data, and custom protein expression analytics with particular attention to expression of senescence/apoptosis and related pathways. These data sets are used to  test mathematical models and are currently employed to evaluate modeling predictions.
Furthermore,we translated these findings to the in vivo setting by quantifying markers in a mouse stroke model (middle cerebral artery occlusion, MCAO), in healthy and UCP2-/- mice. To discern age-related effects, we studied groups of young and old (6 vs. 12-18 months) mice. To compare effects for tissue vs. blood, we performed measurements for both. Specifically, we provided samples for transcriptomics analyses. Further, to allow for correlation to functional outcome (and corresponding to the clinical data in subproject 5), we assessed stroke-dependent dysfunctions via sensorimotor tests in these mice, and also tested for synaptic plasticity. All data were fed to subproject 1 and 2 .

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