The concept of the neurovascular unit states that the pathophysiology of stroke, brain injury, and degeneration cannot be investigated as a purely neuronal phenomenon. Instead, interactions between cells from all neuronal, glial, and vascular compartments must be considered. The first cycle of our P01 program was focused on dissecting acute mechansims of disease in the neurovascular unit. In this renewal, we now propose to look at how the neurovascular unit undergoes repair and recovery. Project 1 (Lo/Xing: Gliovascular regulation of the microglial switch) examines how endothelium and astrocytes differentially regulate the activation of microglia. Microglia can span the range from good to bad. We will test the hypothesis that signaling at the gliovascular interface regulates the microglial switch as the neurovascular unit transitions from initial injury into repair. Project 2 (Arai/Huang: Mechanisms of recovery after white matter injury) examines how oligovascular signaling between brain endothelium and oligodendrocyte precursor cells mediate remodeling in diseased white matter. This allows us to extend the neurovascular unit concept for understanding how white matter recovers and reconnects. Project 3 (Ayata/van Leyen: Targeting ROCK for neurovascular recovery after stroke) will ask how the rho-kinase system may be a central signaling system for specific neuronal and vascular recovery endpoints during stroke recovery. This project is also our attempt at translation since it provides a potential therapeutic target for promoting neurovascular unit repair. Direct collaborations exist between all projects. All studies are supported by three cores. Core A (Boas/Sakadzic) provides powerful tools for in vivo and cellular imaging. Core B (Whalen) supports neuro-behavioral assays for assessing recovery in animal models across all projects. Core C (Lo) is our program coordination core that provides infrastructure for all collaborations We are excited about this next phase of our highly integrated P01 that dissects new mechanisms of cell-cell signaling in endothelial, glial and neuronal systems as the neurovascular unit transitions from initial injury into recovery after stroke, brain injury and degeneration.

Public Health Relevance

Mechanisms of remodeling and repair studied here should allow us to find ways to promote recovery after stroke. Our overall goal fits with the NINDS Stroke Progress Review which identified remodeling in the neurovascular unit as a high priority area. Importantly, the mechanisms dissected here have relevance not just for stroke but more broadly for brain injury and neurodegeneration as well.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Bosetti, Francesca
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Massachusetts General Hospital
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