The MitoMysh Project
Transgenic mice and the fight against aging
Mitomouse: SENS transgenic mouse project
Amutha Boominathan, lifespan.io
Translated by Ariel Finerman, Habr
Problem
Mitochondria generate energy in every human cell. Mutations in mitochondrial DNA inherited or acquired during life lead to metabolic, neurodegenerative and cardiovascular manifestations of aging.
The SENS Research Foundation has developed seven practical strategies for "repairing" the main factors of aging. While some of these strategies are currently being widely studied by the scientific community, MitoSENS' strategy to combat mitochondrial damage is one of the newest. Our theory is that with the help of "allotopic expression", that is, by placing functional copies of critical mitochondrial DNA (mtDNA) genes into the cell nucleus, defects arising from mutations in mtDNA can be eliminated.
When it was proposed, this unique and ambitious strategy was perhaps too "bold" for many laboratories and funding organizations. Thus, MitoSENS was an "internal" SENS project that would not have been possible without community support. So far, this community-funded approach has an excellent history leading to revolutionary discoveries.
In 2013, SENS organized its first crowdfunding campaign specifically for MitoSENS in partnership with LongeCity. This small initiative has generated considerable interest and paved the way for a larger fundraiser in 2015 on the site Lifespan.io . This was followed by breakthrough discoveries, and for the first time in human cells, scientists showed the fundamental work of the MitoSENS approach.
To bring its clinical application closer, SRF soon created a "maximally modifiable mouse model". This mouse has a unique modification in their nuclear genome that allows targeted insertion of new genes at a specific location. Using this mouse, we are ready to take the next step and continue mitochondrial gene therapy on an animal model.
Decision
Mice of the C57/BL6MT-FVB line (let's call them "Sick Mice") have a genetic defect (a mutation in the mitochondrial gene ATP8) and exhibit several age-related symptoms, including decreased fertility, arthritis, type II diabetes mellitus and neurological disorders. Since mitochondrial DNA is inherited only from the mother, crossing a female Sick Mouse with male mice from other lines will lead to the same mitochondrial dysfunction.
We will use the most variable mouse model to design a new transgenic mouse ("allotopic ATP8 transgenic mouse – MitoMysh"). This mouse will have the ATP8 gene, important for mitochondrial function, "hidden" in the cell nucleus and, therefore, able to be transmitted to offspring regardless of gender.
Our hypothesis is that both males and females in the offspring of a Sick Mouse and MitoMysh will show restored mitochondrial functions. This would mean the viability of the MitoSENS strategy by showing that functional backups of mitochondrial DNA genes in the nucleus can replace their mutated counterparts in living animals.
Finally, the mice will be evaluated for phenotypic improvements, such as behavioral, physiological, and biochemical changes. The success of the project will lay the foundation for successful gene therapy in humans.
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