Project: Restoring function in stroke via GPR17, a new receptor involved in adult brain self-repair
Ischemia-induced loss of oligodendrocytes, the myelin forming cells enwrapping neuronal axons and ensuring impulse transmission, contributes to stroke-associated deficits to a higher extent than previously believed. Recent data also indicate that re-myelination contributes to amelioration of spontaneous post-stroke recovery. In line with these findings, oligodendrocyte precursor cells (OPCs) able to generate mature myelinating cells are still present in the adult brain, and react to injuries by resuming proliferation and differentiation. However, more basic data are needed to validate remyelination as a novel target for new rehabilitation approaches to stroke. RENEW IT aims at filling this gap by exploiting the previous cutting-edge unique and complementary expertises of the 4 participating Partners (P) in: (i) animal stroke models and visualization of brain ischemia evolution by non invasive Magnetic Resonance Imaging (MRI) (P1); (ii) the assessment of higher brain functions in alert animals (P3); (iii) the physiology and pathology of adult neural precursor cells (P1, P2, P4), and, (iv) the discovery and characterization of a new key player of oligodendrogenesis, the GPR17 receptor, for which a conditional fluorescent reporter mouse for fate mapping studies has been recently generated (P1, P2). In proof-of-principle experiments, myelin reconstruction after stroke will be monitored longitudinally via MRI coupled to assessment of integrated behavioral functions in alert animals. To challenge the hypothesis that implementation of endogenous oligodendrogenesis indeed results in increased post-stroke recovery, RENEW IT will also exploit previous innovative technology set up by P4 in rodents to (i) transiently expand the brain's endogenous OPC pool by viral, transgenic and pharmacological approaches, and then (ii) instruct generated cells to differentiate to myelinating oligodendrocytes via GPR17-based strategies. The availability of the new fluorescent GPR17 mouse will allow to ultimately correlate the fate of GPR17-expressing OPCs in vivo with increased myelination and functional recovery after stroke. The achievement of these aims will be possible only thanks to the complementary and synergistic integration of the expertises of all 4 Partners. Globally, RENEW IT will provide new information on the extent and modalities of brain self-repair through white matter reconstruction, and also help developing new strategies to stimulate remodelling of neuronal circuitries after stroke. Finally, RENEW IT will also allow the application and validation of non-invasive MRI techniques for the visualization of white matter alterations and reorganization after ischemia, with immediate translation of MRI protocols to humans, a decisive goal of great diagnostic and prognostic value.
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