WP1 – Preclinical and translational studies
Rick Dijkhuizen (UMCU) & Ed van Bavel (AUMC)
Our hypothesis is that identifying causes and consequences of secondary vascular events following recanalization, and testing the beneficial effects of candidate neuroprotective drugs, will provide new leads for therapeutic interventions.
WP1 focuses on the causes and consequences of vascular dysregulation after recanalization, using rodent models of acute ischemic stroke (AIS) with serial imaging over typically a week. If additional funding is acquired, we will also assess chronic (patho)physiological changes that affect long-term outcome. We will include studies of oxygen metabolism, collateral function, and their effects on tissue progression upon recanalization. While our studies target the vasculature, progression of all cell types in the neurovascular unit will be studied. In addition, the effect of two promising neuroprotective agents, 2-IB and ghrelin, on prolonged perilesional tissue salvageability will be addressed.
A major concern of previous animal work is the focus on young healthy male animals, while clear sex differences have been identified and while stroke incidence and outcome clearly depend on age and comorbidities. We will therefore include both sexes as well as aged and hypertensive animals in our studies. If additional funding is acquired, we will also assess the effects of intracerebral hemorrhage (ICH) and subsequent surgical intervention on perihematomal tissue in a large animal ICH model.
- To identify the characteristics of futile recanalization from the relationship between macro- and microvascular hemodynamics, energy metabolism and lesion outcome in different ischemic stroke subtypes.
- To identify vascular factors that explain post-recanalization perfusion deficit in hypertensive stroke subjects.
- To identify critical factors that determine progress of post-AIS perilesional tissue towards recovery versus infarction in the week following recanalization.
- To determine the efficacy and mode of action of 2-IB and ghrelin combined with recanalization after AIS.
- To determine the efficacy and mode of action of minimally invasive hematoma removal after intracerebral hemorrhage (ICH) (pending funding).
- To identify biomarkers that predict long-term functional outcome after recanalization (pending funding).