Research projects in progress
Creation of an animal model
Creation of a knockin mouse for a mutation in the GFM1 gene as a study model of hepatic encephalopathy caused by dysfunction of the mitochondrial elongation factor G1.
Duration
3 años
Budget
259.200 €
Financiador
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Objetivo
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Resultados
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“Proyect driven by the Bank Fundation “la Caixa” and and done within a collaboration with the MENCÍA Fundatión”.
Mitochondrial diseases result from failures of the mitochondria, specialized energy-creating compartments present in almost every cell of the body. This causes an energy deficit that affects one or more of the organism’s systems. Nearly all mitochondrial diseases are of genetic origin and can be transmitted by maternal inheritance through the mitochondrial DNA, or by Mendelian inheritance, through the nuclear genome. The latter group includes hepatic encephalopathy owing to a deficiency in the mitochondrial elongation factor G1 (which participates in the mitochondrial synthesis of proteins), caused by mutations in the GFM1 gene.
The disease appears soon after birth, affecting mainly the liver and the brain and develops rapidly causing patients to die in the first few months of life, although there are rare cases of survival beyond the age of 6.
The aim of our project is to generate and characterize a genetically-modified mouse with the same mutation in the GFM1 gene as the one detected in patients with less serious clinical profiles. The creation of this mouse will provide a biological model of the disease for the use of the whole scientific community.
- First we will check how the altered protein expresses itself in the mouse and then we will study its capacity to synthesize proteins and how its mitochondria function.
- We will also conduct studies to detect possible failures in organs that have proved to be affected in patients.
- This biological model will be used additionally to study other factors that play a part in the synthesis of mitochondrial proteins that may compensate for the deficit of EFG1 in other tissues.
- Finally, access to a biological model will provide us with a highly useful tool for pre-clinical trials of possible treatments for the disease.
This project will not just prove to be a valuable instrument for the development and validation of therapeutic approaches for the treatment of patients with hepatic encephalopathy caused by GFM1 mutations, but will also enable us to gain a better understanding of the pathophysiological mechanisms of other similar diseases, in other words, those that also affect the mitochondrial synthesis of proteins, owing to mutations in other genes. These diseases include neonatal lactic acidosis caused by mutations in MRPS16, MRPS22 or RMND1, spastic paraplegia owing to mutations in SPG7, or other equally serious diseases due to mutations in the genes PUS1, TUFM, TSFM, C12orf65,TRMU, DARS2 or TACO1.
Although in the majority of these cases the prevalence data for these diseases indicates that their frequency is very low, it is also true that more than half of the patients have been identified in the last 5 years. This is probably due to a greater knowledge of these pathologies and the use of advanced genetic diagnosis techniques by mass sequencing. When we publish the results obtained from our project and make our generated mouse available to others we will be aiding a better understanding of these diseases. This in turn will contribute to creating synergies capable of benefitting, in the medium and long-term, patients with diseases belonging to this group, all of which are serious and effectively incurable at present.
Execution: 
75%
