Myel-IN-Crisis
Financiado
Myelin at the crossroads of Development and Disease
The oligodendrocyte, the largest cell in mammalian biology, greatly enables central nervous system (CNS) function through production of a single substance: myelin. Oligodendrocytes undergo a dramatic 1-2 day metamorphosis during m...
The oligodendrocyte, the largest cell in mammalian biology, greatly enables central nervous system (CNS) function through production of a single substance: myelin. Oligodendrocytes undergo a dramatic 1-2 day metamorphosis during myelination, increasing their cell surface area ~6500-fold with proteolipid extensions to nerve axons in the CNS white matter. How is this synthetic feat accomplished? We lack a comprehensive understanding of machinery that precisely coordinates transcription, translation, lipid synthesis and energy production. Moreover, how do these mechanisms become so intensively upregulated during myelination? Does this extraordinary transient state put the myelinating oligodendrocyte at risk of death in diseases of white matter? These questions underlie the Aims of the proposal Myel-IN-crisis.
I propose (Aim 1) testing whether an Integrated Synthetic Programme (ISP) controls oligodendrocyte differentiation, metabolic and synthetic requirements of developmental myelination. In Aim 2, I will investigate roles for smart sensor oxygen (HIF) and nutrient (mTOR) pathways in regulating initiation and termination of the ISP. During development, extrinsic white matter injury in preterm infants leads to cerebral palsy, while intrinsic defects in myelin protein PLP1 cause the fatal human leukodystrophy, Pelizaeus-Merzbacher disease (PMD). Preliminary studies indicate transcriptional and translational dysregulation in human PLP1-mutant oligodendrocytes, which become iron overloaded leading to apoptotic cell death. In Aim 3, I propose that either extrinsic (e.g., hypoxia) or intrinsic (e.g., PLP1 mutation) factors promote a Universal Stress Response (USR) in the pre-myelinating oligodendrocyte that leads to toxic dysregulation of the ISP. Finally, in Aim 4 we will identify the key pathways of the USR to generate strategies for rescue of myelination with potential translational impact in cerebral palsy and leukodystrophy, multiple sclerosis and stroke.
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Duración del proyecto: 79 meses
Fecha Inicio: 2018-08-08
Fecha Fin: 2025-03-31
Fecha Fin: 2025-03-31
Línea de financiación: concedida
El organismo H2020 notifico la concesión del proyecto el día 2018-08-08
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2017-ADG:
ERC Advanced Grant
Cerrada
hace 7 años
Presupuesto
El presupuesto total del proyecto asciende a
3M€
Líder del proyecto
THE CHANCELLOR MASTERS AND SCHOLARS OF THE UN...
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Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5
873.11K€ |
Participante