Podocytes are terminally differentiated cells with a limited ability of self-renewal. Functional maintenance including the continuous repair of their genome is of great importance for podocyte survival. Alterations in DNA damage response signaling occur in almost every cell during aging. These processes contribute to a wide range of aging-associated diseases. In podocytes, these pathways have not been elucidated so far. We hypothesize that accumulating DNA damage in podocytes will eventually lead to the development of focal segmental glomerulosclerosis (FSGS).
We recently identified the progeria-associated gene Ercc1, coding for a key enzyme in DNA nucleotide excision repair (NER), to slow glomerular aging. Genome-wide transcriptome analyses revealed premature aging in glomeruli of 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 FSGS.
Based on our previous data we will elucidate the mechanisms of DNA damage accumulation in podocytes and link this pathology to the development of FSGS in the elderly. The overarching goal of this proposal is to understand how DNA damage response (DDR) signaling affects podocyte homeostasis and survival and how alterations of this network lead to FSGS. Specifically, we will delineate the crosstalk between DNA damage signaling and known pathways crucial for podocyte homeostasis using mouse models and C. elegans. We will unravel the impact of DDR signaling and DDR preconditioning in experimental mouse models of FSGS, and investigate 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. Novel targets potentially amenable to pharmacological interventions will be identified.
PROJECT RELATED PUBLICATIONS
Wilson DMIII, Rieckher M, Williams AB, Schumacher B. Systematic analysis of DNA crosslink repair pathways during development and aging in Caenorhabditis elegans, Nucleic Acids Research. in press doi: 10.1093/nar/gkx660
Mueller M, Castells-Roca L, Babu V, Ermolaeva MA, Müller RU, Frommolt P, Williams AB, Greiss S, Schneider JI, Benzing T, Schermer B, Schumacher B. DAF-16/FoxO and EGL-27/GATA promote developmental growth in response to persistent somatic DNA damage. Nat Cell Biol. 2014 Nov 24:16(12):1168–1179.
Ermolaeva MA, Segref A, Dakhovnik A, Ou HL, Schneider JI, Utermöhlen O, Hoppe T, Schumacher B. DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature. 2013 Sep 19;501(7467):416-20.
Ising, C., Koehler, S., Braehler, S., Merkwirth, C., Höhne, M., Baris, O.R., Hagmann, H., Kann, M., Fabretti, F., Dafinger, C., Bloch, W., Schermer, B., Linkermann, A., Brüning, J.C., Kurschat, C., Müller, R.U., Wiesner, R., Langer, T., Benzing, T., Brinkkötter, P.T. Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure. Embo Mol Med 2015 7, 275-287.
Schermer B, Bartels V, Frommolt P, Habermann B, Braun F, Schultze JL, Roodbergen M, Hoeijmakers JH, Schumacher B, Nürnberg P, Dollé ME, Benzing T, Müller RU, Kurschat CE. Transcriptional profiling reveals progeroid Ercc1(-/Δ) mice as a model system for glomerular aging. BMC Genomics. 2013 Aug 16;14:559
Edifizi D, Schumacher B. Genome Instability in Development and Aging: Insights from Nucleotide Excision Repair in Humans, Mice, and Worms. Biomolecules. 2015 Aug 13;5(3):1855-69
