Objective
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences genetics mutation
- engineering and technology electrical engineering, electronic engineering, information engineering electronic engineering sensors
- medical and health sciences basic medicine neurology stroke
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
MAIN PROGRAMME
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
ERC-ADG - Advanced Grant
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2017-ADG
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
CB2 1TN CAMBRIDGE
United Kingdom
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.