TFEB activity is tightly controlled by PTM-mediated nuclear translocation and signaling. Numerous studies have demonstrated beneficial effects of heterologous TFEB expression in rodent models of neurodegenerative disease, however, the role of TFEB in mammalian aging has not been investigated. This project pioneers the exploration of TFEB signaling from the signaling from lysosome to the nucleus through PTM modulation and epigenomic modification to direct transcriptional programs governing lysosomal status.
The hypothesis is that TFEB serves as a signal integrator to promote cell health by modulating specific transcriptional programs and that TFEB signaling needed for cellular homeostasis is deteriorated by aging.
- Determine age- and TFEB-driven changes in lysosomal content and systemic metabolic changes throughout the mouse lifespan.
- Identify age-dependent post-translational modifications of TFEB that link unique TFEB proteoforms with distinct targetomes.
- Identify age- and TFEB-dependent changes in histone PTMs and their mediating enzymes.