BREPOCI
Financiado
The brain erythropoietin cycle as driver of adaptive neuroplasticity via functio...
The brain erythropoietin cycle as driver of adaptive neuroplasticity via functional hypoxia
Cognitive disability and decline play key roles in neuropsychiatric conditions but lack effective therapies. Erythropoietin (EPO) is a hypoxia-inducible growth factor, named after its original description in erythropoiesis. We dis...
Cognitive disability and decline play key roles in neuropsychiatric conditions but lack effective therapies. Erythropoietin (EPO) is a hypoxia-inducible growth factor, named after its original description in erythropoiesis. We discovered - by 'reverse approach' (human trials first) - that recombinant human (rh) EPO has potent procognitive effects, hematopoiesis-independent. Searching for mechanistic insight in mice, we saw that rhEPO markedly drives differentiation/maturation of pyramidal neurons and oligodendrocytes from non-dividing precursors in cornu ammonis, outside known neurogenesis areas. In parallel, rhEPO dampens microglia. This suggests that endogenous, brain-expressed EPO (bEPO), acting in auto/paracrine fashion, has fundamental, hitherto overlooked physiological significance.
BREPOCI will pursue the groundbreaking hypotheses that (I) 'functional hypoxia' is a physiological consequence of increased neuronal activity, inciting an integrated response of many brain cell types and (II) this activity-induced hypoxia stimulates bEPO expression to optimize multicellular brain plasticity, providing substantial 'hardware upgrade'. (III) Also, BREPOCI postulates diverse EPOR in brain and will study their nature and contribution to these pivotal processes upon normoxia, 'functional', and inspiratory hypoxia. (IV) rhEPO treatment of intellectual disability/autism caused by Tbr1 or Zbtb20 loss-of-function mutations will constitute a first mechanistic approach to specific brain pathologies, translatable to humans.
This ERC project can build on acquired novel genetic mouse tools (cell-type specific EPO/EPOR mutants, inducible hypoxia reporters, multiomic mice), sophisticated behavior tests, MRI/MRS, multiphoton imaging, NanoSIMS, sc/snRNA-seq, confocal/Lightsheet/electron microscopy, electrophysiology. BREPOCI will illuminate rhEPO/bEPO effects on physiological brain functions and explore how it limits developmental delay, intellectual disability, or neurodegeneration.
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Duración del proyecto: 64 meses
Fecha Inicio: 2022-04-29
Fecha Fin: 2027-08-31
Fecha Fin: 2027-08-31
Línea de financiación: concedida
El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2022-04-29
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2021-ADG:
ERC ADVANCED GRANTS
Cerrada
hace 3 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
Líder del proyecto
MAXPLANCKGESELLSCHAFT ZUR FORDERUNG DER WISSE...
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Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5