Project description
Identifying the mechanisms of synapse loss caused by microglia in neurodegenerative diseases
Synapse loss plays a major role in cognitive impairment in many neurodegenerative diseases. Studies suggest that synapse loss might be caused by microglia, which mediate synaptic pruning during brain development. They also show that most risk genes linked to neurodegenerative disorders are highly expressed in microglia. However, not much is known about the causal mechanisms that link microglial risk variants to loss of synapses. The EU-funded REMIND project aims to identify the molecular mechanisms involved in microglia-mediated synapse loss. It will generate novel in vitro and ex vivo models of risk microglia to determine the role of genetic variants linked to neurodegeneration. Moreover, it will develop and validate novel in vivo approaches for effective targeting of pathological pruning.
Objective
Synapse loss is the major correlate of cognitive impairment in many neurodegenerative diseases. Recent literature suggests that microglia, which mediate synaptic pruning during brain development, can be responsible for synapse loss in neurodegeneration. Although the underlying mechanisms are poorly understood, growing evidence indicates that dysfunctional microglia affect synapses number and function in pathology. Genome-wide association studies reveal that the majority of risk genes associated with neurodegenerative disorders are highly expressed in microglia. While such studies clearly implicate these cells in the pathogenesis of the disease, little is known about the causal mechanisms that link microglial risk variants to loss of synapses.
We will identify the molecular mechanisms involved in microglia-mediated synapse loss. We will also generate novel in vitro and ex vivo models of ‘risk microglia’, by introducing genetic variants associated with cognitive impairment –alone or in combination- specifically in microglia, taking advantage of CRISPR/ Cas9 genome editing techniques. These goals will be achieved by combining cutting-edge transcriptomics and proteomics with mouse models of intense synaptic remodelling, to reveal the unique molecular signature of ‘shaper microglia’. A multidisciplinary approach will allow the extensive characterisation of risk models, by combining metabolic analysis, synaptic phagocytosis and degradation assays, with super-resolution microscopy, and novel genetically encoded labelling methods. With the knowledge generated here, we aim at developing and validating in vivo novel drugs- and nanobodies-based approaches for effective targeting of pathological pruning.
In summary, REMIND will focus on:
1) Identifying molecular players in microglial-mediated synapse loss
2) Generating ‘risk microglia’ models, to asses the role of genetic variants associated with neurodegeneration
3) Developing novel strategies for targeting prunining
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 neurobiology
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- natural sciences physical sciences optics microscopy super resolution microscopy
- medical and health sciences basic medicine pathology
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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)
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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-STG - Starting 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-2018-STG
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