Prof. Dr. med. Christine Kurschat
Department II of Internal Medicine
University Hospital Cologne
Kerpener Str. 62
50937 Cologne, Germany
+49 221 478-4480
Prof. Dr. rer. nat. Björn Schumacher
Institute for Genome Stability in Aging and Disease
University of Cologne
CECAD Research Center
Joseph-Stelzmann-Str. 26
50931 Cologne, Germany
+49 221 478-84202

Addresses of the institutions:

University Hospital of Cologne
Nephrolab Cologne &
Insitute for Genome Stability in Aging and Disease
Joseph-Stelzmann-Str. 26
50931 Cologne, Germany

Research project 4

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

Christine Kurschat and Björn Schumacher

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.