Genetic Screen In Mouse Embryonic Stem Cells For Abnormal Mitochondrial Phenotypes
The mitochondrion is an important compartment of the cell that is critical to many fundamental cellular functions, including the generation of chemical energy through the burning of food fuels. Mitochondrial disease often manifests itself as an encephalomyopathy with mental retardation and developmental disabilities as prominent features with few therapeutic options available. The objective of this project is to perform genetic screens in mouse embryonic stem (ES) cells for abnormal mitochondrial phenotypes to identify and characterize genes that are important for mitochondrial function, that are possible etiological candidates for mitochondrial disorders, and that are potential novel therapeutic targets. The sentinel components of this strategy include gene-trap mutagenesis of ES cells followed by screening for alterations of fluorescent markers for mitochondrial mass and mitochondrial membrane potential (MMP) by fluorescence-activated cell sorting (FACS).
In a pilot screen, we have already identified a clone with a gene trap event in Sucla2, a recently recognized mitochondrial disease gene. We have successfully injected this clone into blastocysts to establish a mouse line and are currently breeding for homozygotes to develop a new mouse model for mitochondrial encephalomyopathy.
Relevance of the project to IDDRC mission:
Mitochondrial encephalopathies are associated with mental retardation and severe developmental disabilities in children with no effective therapies available.