Project description
Determining the causes of atherosclerosis
Atherosclerosis is a disease of the larger arteries that leads to patchy development of fibrofatty lesions which may cause heart attacks and stroke. Recruited macrophages are important triggers of disease activity, while the functional role of local smooth muscle cells (SMCs) remains sparsely explored. Research using lineage tracking techniques in mice uncovered a large population of SMC-derived cells in plaques. They also identified that they derive from only a few founder SMCs that undergo massive clonal expansion and phenotypic modulation during lesion formation. The EU-funded EXPLOSIA project will conduct a comparative analysis of SMC-derived cells in mouse, pig and human atherosclerosis and explore the causal roles of SMC-derived cells in plaque progression.
Objective
Atherosclerosis is considered an inflammatory disease caused by the accumulation, modification and immune cell recognition of low-density lipoproteins in the arterial wall. Plaque macrophages are held to be the main drivers of disease activity, whereas smooth muscle cells (SMCs) have traditionally been considered protective by forming fibrous tissue that stabilises plaques from undergoing rupture and causing thrombosis.
In the present project, we challenge this dichotomous view of cellular villains and heroes in atherosclerosis. Using lineage tracking techniques in mice, we and others have uncovered a large population of SMCs in plaques, which has escaped detection because the cells completely lose conventional SMC phenotype. Strikingly, we have found that the entire plaque SMC population derives from only few founder SMCs that undergo massive clonal expansion and phenotypic modulation during lesion formation. We hypothesise that the balance between the different modulated SMC subtypes and the functions they carry are central to lesion progression.
In EXPLOSIA we will address this hypothesis in 3 steps. First, we will conduct a comparative analysis of clonal structure in mice, minipigs, and humans. Second, we will determine links between SMC subtypes, their gene expression programs, and atherosclerotic disease activity by combining single-cell transcriptomics with novel techniques to alter atherosclerotic disease activity in gene-modified mice and minipigs. Third, we will develop techniques for manipulating genes in modulated plaque SMCs and test the causal role of perturbing SMC subtypes and function for lesion progression.
The aim of the project is to answer the following key questions for a deeper understanding of atherosclerosis:
- What is the clonal architecture of SMCs in human atherosclerosis?
- What is the SMC gene expression signature of atherosclerotic disease activity?
- Can interventions targeting SMCs prevent dangerous lesion development?
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.
- medical and health sciences clinical medicine angiology vascular diseases
- medical and health sciences clinical medicine cardiology cardiovascular diseases arteriosclerosis
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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-COG - Consolidator 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-2019-COG
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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.
8000 Aarhus C
Denmark
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.