Project description
Insight into the epigenetic profile of motor neuron disorders
Motor neuron disorders (MND), comprising spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), are a group of devastating diseases mainly manifested by motor neuron degeneration. Emerging evidence suggests that disease severity is modulated through epigenetics in which DNA methylation plays a dominant role. The scope of the EU-funded MANTIS project is to uncover the epigenetic mechanism gone awry in MND. Leveraging cutting-edge techniques from next-generation sequencing to single-cell mass cytometry and patient-derived iPSCs, the scientists will explore the role of the ten-eleven translocation (TET) enzymes. In DNA methylation, TETs are responsible for balancing the hydroxymethylated cytosines (5hmC) to favor gene expression. The therapeutic potential of demethylation will also be explored to correct the epigenetic profile and restore the disrupted gene expression.
Objective
Motor neuron disorders (MND) are a spectrum of devastating diseases caused by motor neuron (MN) cell death. Recent findings revealed that DNA methylation is a hallmark of MN cell death. However, the cause and affected mechanisms leading to methylation increase remain mostly unknown, therefore limiting the design of therapeutic intervention. The discovery of a novel DNA modification has provided a paradigm shift in the understanding of DNA methylation and demethylation regulatory network. In fact, methylated cytosines (5mC) can be converted to hydroxymethylated cytosines (5hmC) by Ten-eleven-translocation (TET) enzyme family. 5hmC is found to be stably present in DNA and to influence gene expression as an epigenetic mark independent of 5mC. My preliminary experiments showed that MN death in a severe mouse model of Spinal Muscular Atrophy (SMA) is correlated to a genome-wide increase in 5mC levels and loss of 5hmC. This research proposal therefore aims to define the role of 5hmC and the TET family of enzymes in controlling MN pathophysiology. To address the common role of DNA demethylation loss in MND, I will investigate the methylation mechanism in SMA and another MND- Amyotrophic lateral sclerosis (ALS). The specific aims of this project are to (1) define the exact profile of 5mC and 5hmC in regulating gene expression in SMA and ALS via a genome-wide reduced representation sequencing; (2) test whether TETs interact with the Survival of Motor Neuron (SMN1) protein that is responsible for MNs cell death in SMA; (3) establish the therapeutic potential of a locus-specific demethylation in promoting restoration of the diseased epigenetic profile using the Crispr/Cas9 technology. These studies will greatly advance the understanding of the epigenetic regulation of MN cell death by 5hmC and TET proteins, and will set the stage for testing the therapeutic potential of these novel regulators in MNs disorders.
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: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
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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.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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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.
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)
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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) H2020-MSCA-IF-2019
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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.
75654 Paris
France
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.