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Mitochondrial Medicine: developing treatments of OXPHOS-defects in recombinant mammalian models

Objective

Mitochondria are the major source of ATP, synthesized by the mitochondrial respiratory chain (MRC) through the process of oxidative phosphorylation. ATP deficiency leads to cellular dysfunction and ultimately death. In mammals, 13 mitochondrial DNA (mtDNA)-encoded subunits interact with over 70 nuclear-encoded subunits to form four of the five MRC complexes. Many additional factors are essential for the regulation of MRC activity, and the maintenance and expression of mtDNA. As a result, genetic defects affecting either genome can compromise ATP synthesis and cause human disease. There is no effective treatment for mitochondrial disorders. Major hurdles to this achievement include (i) the still incomplete molecular definition of mitochondrial disease; (ii) the poorly understood function of many disease gene products, (iii) the difficulty to rationally manipulate the complex biochemical and genetic systems underpinning mitochondrial bioenergetics.
The ultimate scope of MitCare is to develop effective therapy in mitochondrial medicine. MitCare will implement three Workpackages (WP). WP1 will test the effects of pharmacological stimulation of mitochondrial biogenesis in mouse disease models. WP2 will test the effects of Adeno-Associated Viral (AAV)- and lentiviral-mediated delivery of therapeutic genes, in mouse models and human mutant cells, respectively. Since the clinical features of human disorders often fail to be faithfully replicated in mice, WP3 will implement the creation of a mitochondrial disease model in the pig, whose proximity to humans is much closer than mice. The Surf1 gene, encoding an assembly factor of complex IV, will be disrupted by zincfinger nuclease technology in swine fibroblasts, which will then serve to clone a Surf1 knockout pig by somatic cell nuclear transfer. “Mitopigs” will be used to test the direct transferability of experimental treatments from suitable mammalian models to the clinics.

Field of science

  • /natural sciences/biological sciences/zoology/mammalogy
  • /natural sciences/biological sciences/genetics and heredity/genome

Call for proposal

ERC-2012-ADG_20120314
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Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

MEDICAL RESEARCH COUNCIL
Address
North Star Avenue Polaris House 2 Floor David Phillips Building
SN2 1FL Swindon
United Kingdom
Activity type
Research Organisations
EU contribution
€ 2 004 200
Principal investigator
Massimo Zeviani (Prof.)
Administrative Contact
Irina James (Mrs.)

Beneficiaries (3)

MEDICAL RESEARCH COUNCIL
United Kingdom
EU contribution
€ 2 004 200
Address
North Star Avenue Polaris House 2 Floor David Phillips Building
SN2 1FL Swindon
Activity type
Research Organisations
Principal investigator
Massimo Zeviani (Prof.)
Administrative Contact
Irina James (Mrs.)
AVANTEA srl
Italy
EU contribution
€ 401 000
Address
Via Cabrini 12
26100 Cremona
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Giovanna Lazzari (Dr.)
FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA
Italy
EU contribution
€ 94 800
Address
Via Giovanni Celoria 11
20133 Milano
Activity type
Research Organisations
Administrative Contact
Alberto Guglielmo (Mr.)