Cell-specific roles of ephrin-B2 signaling in neurovascular repair and regeneration after ischemic injury of the brain

• Applicant: Professor Dr. Peter Vajkoczy
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology ; Molecular and Cellular Neurology and Neuropathology
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269353708

A major complication after stroke is the disruption of the blood-brain barrier and development of malignant brain swelling. The brain is capable of repairing its neurovascular unit after stroke; however, often too slow and insufficient. We aim at a better understanding of the underlying mechanisms/therapeutic optimization of this repair. In the 1st funding period, we have revealed that ephrin-B2 is cell-specifically involved in diverse repair processes and that ephrin-B2 activation enhances regeneration of the neurovascular unit after stroke. In the 2nd funding period, we will further strengthen our knowledge on the role of ephrin-B2 in ischemic stroke. To this end, we will more realistically model the clinical scenario, with aged animals and animals with comorbidity phenotypes. We will test whether the relevance of endothelial ephrin-B2 in mediating vascular integrity and BBB repair after stroke is conserved in these animals. Second, we will elucidate the ephrin-B2 dependent signaling pathways and their influence on neurovascular repair and regeneration after stroke, using our genetic models with cell-specific deletion of Efnb2. We will apply RNA-seq technologies and validate the results on the RNA, protein, and functional level. Third, we will unravel the role of neuronal ephrin-B2 in spine biology under normal and ischemic conditions. For this, we will take ex vivo (organotypic slice cultures) and in vivo (2P-LSCM) approaches to visualize changes in spine morphology/number after neuron-specific deletion of Efnb2. Forth, we will apply our knowledge in intravital imaging of the ischemic brain, using 2P-LSCM and cell specific in vivo labeling techniques, to understand the role of cell-specific ephrin-B2 for cell interactions during the anatomical and functional re-assembly of the neurovascular unit. Taken together, this proposal will significantly contribute to our understanding of the endogenous repair mechanisms of the neurovascular unit and the functional/therapeutic role of ephrin-B2 in this context after stroke.

• DFG Programme: Research Units
• Subproject of: FOR 2325: Interactions at the Neurovascular Interface