Objective
This proposal describes a series of powerful experimental strategies to develop a completely novel treatment for mtDNA mutation disease based on identifying unknown mechanisms controlling mtDNA replication. Several hundred different mtDNA mutations affect tRNA genes and impair mitochondrial translation leading to human disease. There is typically heteroplasmy with a mixture of wild-type and mutated mtDNA, and the mutations are acting in a “recessive” (loss of function) way. Very high levels of mutated mtDNA are needed to cause disease in affected patients whereas maternal relatives with high, but sub-threshold levels of mutated mtDNA are completely healthy. The corollary of these observations is that even a small increase of wild-type mtDNA may efficiently counteract disease in affected patients. This hypothesis will be validated by a series of genetic experiments with mice harbouring single pathogenic mtDNA mutations. Furthermore, novel factors controlling mtDNA replication will be identified. In particular, we will elucidate the formation and function of the mammalian displacement (D) loop, which provides a switch between abortive and genome length mtDNA replication. This very fundamental problem in mammalian mitochondrial biology has remained unsolved for decades, but I feel that the innovative experimental strategies I present in this proposal are very powerful and should have a fair chance of being successful. In any circumstance, the project will provide important molecular insights into novel mechanisms relevant for mammalian mtDNA replication. Over the years I have been strongly convinced that congruent results from in vivo and in vitro studies are needed to obtain reliable mechanistic insights and this project is therefore based on the close integration of biochemistry, advanced proteomics and state-of-the-art mouse and fly genetics. Finally, I describe a powerful large-scale screening approach to develop small molecular stimulators of mtDNA replication.
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 proteomics
- natural sciences biological sciences genetics mutation
- natural sciences biological sciences genetics genomes
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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-2016-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.
171 77 STOCKHOLM
Sweden
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.