DNA damage response pathways in podocytes: novel targets to treat focal segmental glomerulosclerosis

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Accumulating DNA damage and alterations in DNA damage response signaling play fundamental roles in the aging process and contribute to a wide range of aging-associated diseases. For terminally differentiated glomerular podocytes functional maintenance including the continuous repair of their genome is of great importance for cellular survival. Accordingly, we recently identified the progeria-associated gene Ercc1, coding for a key enzyme in DNA nucleotide excision repair (NER), to counteract glomerular aging. Genome-wide transcriptome analyses revealed the signature of aged glomeruli in 14 week-old compound heterozygous mice harboring a loss-of-function and a hypomorphic allele of Ercc1 (Ercc1-/Δ). Subsequently, we have generated a podocyte-specific Ercc1 knockout mouse model (Ercc1pko). These mice display severe podocyte dysfunction and histologic evidence of focal segmental glomerulosclerosis (FSGS). Based on our previous data we hypothesize that accumulation of DNA damage in podocytes plays a fundamental role in the development of FSGS in the elderly. The overarching goal of this proposal is to understand the mechanisms how DNA damage response (DDR) signaling affects podocyte homeostasis and survival and how alterations of this network lead to FSGS. Specifically, we aim (1) at delineating the crosstalk between DNA damage signaling and known pathways crucial for podocyte homeostasis using mouse models and C. elegans, (2) at unraveling the impact of DDR signaling and DDR preconditioning in experimental mouse models of FSGS, and (3) at investigating the role of mTOR inhibition, caloric restriction and cellular senescence in DDR-related FSGS. We expect that this project will significantly enhance the understanding of age-related FSGS and lead to the identification of novel targets potentially amenable to pharmacological interventions.