Triggering the selective removal of deleterious mtdna mutations from mammalian cells
Ended Project Grant Awarded Last action
- Award ID
- F31AG084238
- Recipient
-
University Of Southern California UEI G88KLJR3KYT5
- Awarding agency
-
National Institute on Aging
National Institutes of Health, Department of Health and Human Services
- Obligated
- $143,834
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date
- Place of performance
- Los Angeles, CA 90089, USA
Award details come from USAspending.gov.
Description
- Abstract
- As we age, mutations arise in the mitochondrial genome (mtdna) of stem cells, neurons, cardiomyocytes and muscle fibers. When these mutations expand, they compromise mitochondrial energy production and enhance the generation of reactive oxygen species. Together, these molecular changes accelerate the natural aging process and contribute to various age-related diseases, including cancer, sarcopenia, alzheimer's disease and parkinson's disease. In addition, mtdna mutations are responsible for a wide array of pediatric diseases that are characterized by epilepsy, muscle weakness and neuronal dysfunction. To this day though, no child has been cured of an mtdna disease, nor is there a treatment for the mtdna component of age-related diseases. The long-term goal of this proposal is to solve this problem. To identify treatments, we will use a variety of genetic and molecular biology tools, combined with state-of-the-art sequencing techniques, in an attempt to purge mammalian cells of mtdna molecules that carry deleterious mutations. To generate the most appropriate cell line for these experiments, we have created a cell line that carries an error-prone version of DNA polymerase gamma (polga), the enzyme that replicates the mitochondrial genome. This cell line also carries a genetic switch that allows the error-prone allele of polga to be replaced by a WT allele through CRE-recombination (POLGAD257AWT). Accordingly, we can control the mutation rate of the mitochondrial genome at will. In this application, we propose to use the POLGAD257AWT allele to create a population of cells that contain a broad and highly diverse spectrum of mtdna mutations, similar to aging humans. We will then replace the error-prone allele with the WT allele to prevent additional mutations from arising and track the existing mutations over time with madd-SEQ, a novel mutation detection assay that can detect millions of mutations at once. This assay will allow US to determine whether these mutations can be removed by manipulating mitochondrial dynamics. Finally, we will interrogate the mechanistic basis of this intervention by either enhancing or preventing mitophagy and monitoring mutation clearance under those conditions as well. Together, these experiments have the potential to transform our understanding of mitochondrial genetics in aging organisms and set the stage for the development of treatments aimed at preventing or ameliorating age-related and pediatric diseases associated with mtdna mutations.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | -$3,088 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $48,974 | |
| Amendment | $48,974 | |
| Original award | $48,974 |
Quick answers
Who received award F31AG084238?
F31AG084238 was awarded to University Of Southern California by National Institute on Aging (National Institutes of Health) on November 28, 2024.
How much is award F31AG084238 worth?
$143,834 has been obligated on F31AG084238.
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