The role of DNA damage response signaling in chronic kidney disease. Nephronophthisis (NPHP) is an autosomal recessive chronic kidney disease (CKD), characterized by tubulointerstitial fibrosis, tubular basement membrane disruption and kidney cysts. Renal fibrosis is the primary determinant of end-stage kidney disease, with no effective therapy available today. Recent work has identified NPHP as a ?ciliopathy?, caused by mutations in genes, whose proteins localize to the centrosome and/or primary cilium, and has generated a unifying pathogenic concept for NPHP-related ciliopathies (NPHP-RC). Despite the identification of mutations in more than 30 genes as causative of NPHP-RC, little is known about the molecular mechanisms underlying the disease. Recently, by whole exome resequencing I was involved in the identification of 3 novel genes ? CEP164, FAN1 and SDCCAG8 as causing NPHP-RC with renal degeneration/fibrosis when mutated. Surprisingly, the centrosomal proteins CEP164 and SDCCAG8 were also localized at cell nuclei, and their inactivation led to impaired DNA damage response (DDR) signaling accompanied by cell cycle defects. Hence, together with FAN1, which is a known DNA damage repair protein, CEP164 and SDCCAG8 implicate defective DDR signaling as a novel pathomechanism of NPHP-RC. I hypothesize that renal degeneration/fibrosis in NPHP-RC is caused by defects in DNA damage response pathways. To test this hypothesis, I will (1) examine the role of ?ciliopathy proteins? in regulating the DNA damage response pathway using the Cep164 and Sdccag8 mouse models of renal fibrosis; (2) perform a high-throughput screen for small molecules that influence and counteract the NPHP-RC pathogenesis; (3) characterize the functions and regulation of trafficking of CEP164 and SDCCAG8 between their dual localizations at centrosomes and in nuclei. Accomplishment of the proposed research will provide (1) new insights into the pathomechanisms of ciliopathies; (2) new chemical compounds that can lead to therapies for NPHP-RC and renal fibrosis; (3) new animal models for studying DDR-related diseases. The objective of this K99/R00 application is to utilize the newly generated animal models for the study of molecular mechanisms of NPHP-RC. This will facilitate the transition of my research career towards an independent investigator position. The training (K99) phase of this award will be mentored by Dr. Friedhelm Hildebrandt, who is an investigator of Howard Hughes Medical Institute and internationally recognized leader in the fields of human genetics and of pediatric kidney diseases. In March 2013 I will move to the Boston Children's Hospital (BCH)/Harvard Medical School (HMS) with Dr. Hildebrandt's laboratory. My long-term career goal is to establish myself as an independent investigator in the field of kidney research, focusing on animal models of kidney diseases. The BCH/HMS has several collaborative research groups working on kidney development and diseases providing an ideal environment for my training and career development.

Public Health Relevance

Nephronophthisis-related ciliopathies (NPHP-RC), caused by functional defects of the cilium, are considered disease models `par excellence' for chronic renal fibrosis. Recently, gene identification has linked the pathogenesis of NPHP-RC to defective DNA damage response (DDR) signaling, resulting in genome instability and cell cycle defects. Generation of new animal models of NPHP-RC will allow to examine the role of DDR in kidney degeneration/fibrosis and search for novel therapy for this currently untreatable pathology.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Transition Award (R00)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Rasooly, Rebekah S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Vermeren, Matthieu; Lyraki, Rodanthi; Wani, Sachin et al. (2017) Osteoclast stimulation factor 1 (Ostf1) KNOCKOUT increases trabecular bone mass in mice. Mamm Genome 28:498-514
Airik, Rannar; Schueler, Markus; Airik, Merlin et al. (2016) SDCCAG8 Interacts with RAB Effector Proteins RABEP2 and ERC1 and Is Required for Hedgehog Signaling. PLoS One 11:e0156081
Braun, Daniela A; Schueler, Markus; Halbritter, Jan et al. (2016) Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity. Kidney Int 89:468-475
Airik, Rannar; Schueler, Markus; Airik, Merlin et al. (2016) A FANCD2/FANCI-Associated Nuclease 1-Knockout Model Develops Karyomegalic Interstitial Nephritis. J Am Soc Nephrol 27:3552-3559
Schueler, Markus; Braun, Daniela A; Chandrasekar, Gayathri et al. (2015) DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling. Am J Hum Genet 96:81-92
Airik, Rannar; Slaats, Gisela G; Guo, Zhi et al. (2014) Renal-retinal ciliopathy gene Sdccag8 regulates DNA damage response signaling. J Am Soc Nephrol 25:2573-83
Insolera, Ryan; Shao, Wei; Airik, Rannar et al. (2014) SDCCAG8 regulates pericentriolar material recruitment and neuronal migration in the developing cortex. Neuron 83:805-22