1. Research Background:
Chronic kidney disease (CKD) is affecting a steadily increasing proportion of the aging population in the industrial world with more than 10% of the population suffering from CKD.
Recent evidence indicates that CKD does not only result in end-stage renal failure ultimately requiring dialysis or kidney transplantation: CKD has been identified as a major cardiovascular risk factor and is among the most important non-neoplastic disorders that affect overall survival.
The causes of CKD and age-related renal pathologies are poorly understood but genetic as well as environmental factors clearly play a role. Our lab studies the molecular principles underlying kidney disorders ranging from proteinuric kidney diseases to cystic and fibrotic renal disease with a strong focus on age-related renal pathologies using genetic disorders as a model.
We aim to unravel molecular principles of kidney disorders, particularly age-related kidney diseases. Two major topics relevant for the proposed project are adumbrated below.
2. Research questions addresses by the group:
- Over the past several years, we and others have shown that cilia-derived signaling is required for maintaining kidney tissue integrity and function. Mutations in genes encoding for proteins localized to renal cilia are a major cause of polycystic kidney disease and a variety of degenerative renal disorders in humans, summarized under the term ciliopathies. Interestingly, kidney degeneration in ciliopathies shares many common features with chronic kidney disease in renal aging. Very recently, we have identified actin binding proteins as novel components of the ciliary membrane-associated proteome (Kohli et al., EMBO Rep 2017). Currently we are aiming to unravel the detailed function of actin and actin binders within primary cilia and we are investigating the role of ciliary signaling defects in age-related renal pathologies.
- Moreover, recent studies revealed the pivotal role of the hippo signaling effectors YAP/TAZ in maintaining glomerular integrity and preventing the death of specialized cells at the kidney filter called podocytes. We could demonstrate that mechanosensory stimuli control YAP/TAZ activity in podocytes. Moreover we found that both knockout and transgenic expression of YAP in podocytes results in podocyte damage and proteinuria. Now we aim to unravel the mechanisms how YAP/TAZ alterations contribute to podocyte survival and influence renal aging.
3. Possible projects:
Possible projects include, but are not limited to the following topics:
- The role of Hippo/YAP/TAZ Signaling in the pathogenesis of FSGS and of age-related glomerular disease (based on: Rinschen et al, Sci Sign 2017)
- Understanding the exact nature of podocyte cell death in renal aging and disease
- The role of actin binding proteins in primary cilia: their impact on ciliary dynamics and signaling and there role in the pathogenesis of renal fibrosis and cystic kidney disease
(based on Kohli et al., EMBO Rep 2017)
- Genetic and pharmacologic interventions to prevent acute kidney injury and renal fibrosis
4. Applied Methods and model organisms:
- Model organisms:
mouse, C. elegans, human and murine cell lines, primary cells, stem cells, organoids
- Methods (selection):
molecular cloning; 2D/3D cell culture; genome engineering primarily based on CRISPR/Cas9 in mice, cultured human cells and worms; lenti-/retroviral gene transfer; FACS; recombineering; genomics (RNAseq, ChIPseq, …); RBP analysis; proteomics; confocal imaging; super resolution microscopy (STED/GSD); 2P-in-vivo-imaging of the kidney; hybridoma techniques; lncRNA analysis; ...
5. Desirable skills and qualifications:
We are searching for highly motivated young scientists with great enthusiasm for biomedical research and with qualities of great team-players.
- Rinschen, M.M., F. Grahammer, A.K. Hoppe, P. Kohli, H. Hagmann, O. Kretz, S. Bertsch, M. Hohne, H. Gobel, M.P. Bartram, R.K. Gandhirajan, M. Kruger, P.T. Brinkkoetter, T.B. Huber, M. Kann, S.A. Wickstrom, T. Benzing, and B. Schermer (2017) YAP-mediated mechanotransduction determines the podocyte's response to damage. Sci Signal, 10(474).
- Kohli, P., M. Hohne, C. Jungst, S. Bertsch, L.K. Ebert, A.C. Schauss, T. Benzing, M.M. Rinschen, and B. Schermer (2017) The ciliary membrane-associated proteome reveals actin-binding proteins as key components of cilia. EMBO Rep, 18(9): 1521-1535.