Aim 1: Define circadian mechanisms in the neurovascular unit, and immune, cardiovascular and metabolic systems in experimental stroke models.
We will perform collaborative cell and in vivo experiments in Boston and Madrid. Molecular pathways will be connected to metabolic responses in collaboration with Oxford. Synergy will be obtained by combining expertise in the neurovascular unit (Boston), immune mechanisms (Madrid) and physiology (Oxford). Rigor will be obtained by establishing standards for circadian parameters and replicating key experiments in different models across all three sites.
Aim 2: Confirm and extend cell and animal model findings with genetic, imaging, outcome, and biomarker analyses in stroke patients.
We will perform collaborative analyses on shared data and samples from Los Angeles, Stanford and Munich. New insights will be obtained by combining expertise in clinical trials (Los Angeles), imaging (Stanford) and biomarkers (Munich). Rigor (and a paradigm shift) will be obtained by establishing new standards for circadian parameters in patients. We will replicate key findings in independent databases across all 3 sites. We will also initiate bench-to-bedside and bedside back-to-bench analyses to connect clinical data with cell and animal model data.
Aim 3: Identify novel targets for stroke therapy based on circadian biology.
Based on cell, animal model, and human data collected in Aims 1 and 2, we will define how circadian rhythms modulate mechanisms for ischemic stroke and thereby remap the landscape of diagnostic markers and therapeutic targets.