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mtDNA-CURE SIGNED

Treating mitochondrial disease caused by pathogenic mtDNA mutations

Total Cost €

EC-Contrib. €

Partnership

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mtDNA-CURE project word cloud

Explore the words cloud of the mtDNA-CURE project. It provides you a very rough idea of what is the project "mtDNA-CURE" about.

integration switch heteroplasmy genetic hypothesis provides mice human experimental single relatives sub recessive observations vivo maternal wild fundamental counteract trna mitochondrial biochemistry proteomics describe genetics series mutated small mixture successful remained fly will acting threshold screening chance elucidate biology stimulators replication describes levels insights genes translation corollary mechanistic hundred mammalian harbouring impair obtain abortive fair mouse experiments mutations patients treatment decades close mutation function circumstance healthy mechanisms molecular displacement innovative vitro unknown convinced strategies completely length genome validated unsolved loop congruent mtdna disease feel pathogenic whereas powerful

Project "mtDNA-CURE" data sheet

The following table provides information about the project.

Coordinator	KAROLINSKA INSTITUTET Organization address address: Nobels Vag 5 city: STOCKHOLM postcode: 17177 website: www.ki.se contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.
Coordinator Country	Sweden [SE]
Total cost	2˙500˙000 €
EC max contribution	2˙500˙000 € (100%)
Programme	1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
Code Call	ERC-2016-ADG
Funding Scheme	ERC-ADG
Starting year	2018
Duration (year-month-day)	from 2018-01-01 to 2022-12-31

Partnership

Take a look of project's partnership.

#	participants	country	role	EC contrib. [€]
1	KAROLINSKA INSTITUTET KAROLINSKA INSTITUTET Organization address address: Nobels Vag 5 city: STOCKHOLM postcode: 17177 website: www.ki.se contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.	SE (STOCKHOLM)	coordinator	2˙500˙000.00
2	MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Organization address address: HOFGARTENSTRASSE 8 city: Munich postcode: 80539 website: www.mpg.de contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.	DE (Munich)	participant	0.00

Map

Project 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.

Publications

List of publications.
year	authors and title	journal	last update
2019	R. Filograna, C. Koolmeister, M. Upadhyay, A. Pajak, P. Clemente, R. Wibom, M. L. Simard, A. Wredenberg, C. Freyer, J. B. Stewart, N. G. Larsson Modulation of mtDNA copy number ameliorates the pathological consequences of a heteroplasmic mtDNA mutation in the mouse published pages: eaav9824, ISSN: 2375-2548, DOI: 10.1126/sciadv.aav9824	Science Advances 5/4	2019-11-22

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