Prof. Dr. Thomas Benzing & Prof. Dr. Bernhard Schermer

Research Area: Mechanisms of Aging-associated Chronic Kidney Disease (CKD)

Branches: Biomedical ResearchCell BiologyMolecular Biology

1. Research Background

Chronic kidney disease (CKD) affects a steadily increasing proportion of the aging population in the industrial world, with more than 13% of the population suffering from CKD. Recent findings underscore that CKD's ramifications go beyond the eventual need for dialysis or kidney transplantation due to end-stage renal failure. CKD has emerged as a primary cardiovascular risk factor and ranks among the most significant non-neoplastic conditions impacting overall longevity. While the origins of CKD and age-related renal pathologies remain incompletely elucidated, it is evident that both genetic and environmental factors contribute substantially. Within our laboratory, we delve into the molecular foundations of kidney disorders, with a particular emphasis on comprehending age-related renal pathologies.

2. Research questions addressed by the group:

A. Primary cilia and renal ciliopathies

In recent years, we and others have shown the essential role of primary cilia and ciliary signaling in preserving kidney architecture and ensuring proper function. Mutations in genes encoding for proteins localized to renal primary cilia are a significant cause of polycystic kidney diseases and of various degenerative renal disorders in humans. These conditions are collectively referred to as 'ciliopathies'. Notably, the kidney degeneration observed in ciliopathies exhibits striking parallels with chronic kidney disease stemming from natural renal aging.

Research questions (selection):

  • (1) What is the role of R-loop metabolism in ciliopathies and CKD?
  • (2) How does genome instability promote CKD development?
  • (3) The contribution of regulated cell death (RCD) pathways to kidney degeneration in ciliopathies. 1

B. Glomerular diseases and the (patho-) physiology of filtration

The majority of kidney diseases affect glomeruli, the microvascular subunits of the kidney. Here, primary urine, which is almost free of proteins, is generated by a complex filtration process. One essential part of the glomerular filter is podocytes, highly specialized epithelial cells that enwrap the glomerular capillaries. Injury and loss of podocytes lead to the clinical symptom of proteinuria and glomerular sclerosis (FSGS). To gain insights into the filtration process, we used CRISPR/Cas9 to generate knock-in mouse models mimicking late-onset human glomerular disease 2. With superresolution imaging (STED) 3 and mathematical modeling4we suggested a novel model for the understanding of the filtration barrier in the kidney 2,5,6.

Research questions (selection):

  • (1) Identify molecular signatures of podocyte damage on the level of single cells
  • (2) Understand transcriptional and epigenetic networks and their alterations in FSGS
  • (3) Investigate the mechanisms of podocyte damage on the level of single cells

 

3. Possible project(s):

Possible projects for Ph.D. candidates include, but are not limitedto the following topics:

  • Deciphering the initial (still reversible) steps in the pathogenesis of glomerular diseases using single-cell RNA-Seq and AI-based imaging analyses.
  • The role of YAP/TAZ signaling in the pathogenesis of FSGS and of age-related glomerular disease (based on models from2,7)
  • Mechanisms of premature aging in ciliopathy models and mice lacking cilia (including the model from8): Impact of R-loops on disease progression.
  • Dynamic changes of the composition of cilia in kidney disease in vitro and in vivo (based on ciliary proximity labeling 9)

Details will be discussed and developed together with the Ph.D. candidate.

4. Applied Methods and model organisms:

  • Models and model organisms: M. musculus, C. elegans, human and murine cell lines, primary cells, iPSCs, 3D organoids, human biopsy material.
  • Methods (selection, depending on the specific project): 2D/3D cell culture; genome editing primarily based on CRISPR/Cas9 in mice, cultured human cells and worms; lenti-/retroviral gene transfer; molecular cloning; FACS; genomics (RNA-seq, ChIP-seq, Cut&Tag, Cut&Run); RBP analysis; proteomics; confocal imaging; superresolution microscopy (STED/GSD); 2P- intra vital-imaging of the kidney; hybridoma techniques; etc.

5. Desirable skills and qualifications:

We are searching for a highly motivated young scientist with great enthusiasm for biomedical research and with the qualities of a great team player.

6. References and key publications:

  1. Kieckhofer, E., Slaats, G.G., Ebert, L.K., Albert, M.C., Dafinger, C., Kashkar, H., Benzing, T., and Schermer, B. (2022). Primary cilia suppress Ripk3-mediated necroptosis. Cell Death Discov 8, 477. 10.1038/s41420-022-01272-2.
  2. Butt, L., Unnersjo-Jess, D., Hohne, M., Edwards, A., Binz-Lotter, J., Reilly, D., Hahnfeldt, R., Ziegler, V., Fremter, K., Rinschen, M.M., Helmstadter, M., Ebert, L.K., Castrop, H., Hackl, M.J., Walz, G., Brinkkoetter, P.T., Liebau, M.C., Tory, K., Hoyer, P.F., Beck, B.B., Brismar, H., Blom, H., Schermer, B., and Benzing, T. (2020). A molecular mechanism explaining albuminuria in kidney disease. Nat Metab 2, 461-474. 10.1038/s42255-020-0204-y.
  3. Unnersjo-Jess, D., Butt, L., Hohne, M., Witasp, A., Kuhne, L., Hoyer, P.F., Patrakka, J., Brinkkotter, P.T., Wernerson, A., Schermer, B., Benzing, T., Scott, L., Brismar, H., and Blom, H. (2021). A fast and simple clearing and swelling protocol for 3D in-situ imaging of the kidney across scales. Kidney Int. 99, 1010-1020. 10.1016/j.kint.2020.10.039.
  4. Butt, L., Unnersjo-Jess, D., Hohne, M., Schermer, B., Edwards, A., and Benzing, T. (2021). A mathematical estimation of the physical forces driving podocyte detachment. Kidney Int. 100, 1054-1062. 10.1016/j.kint.2021.06.040.
  5. Benzing, T., and Salant, D. (2021). Insights into Glomerular Filtration and Albuminuria. N. Engl. J. Med. 384, 1437-1446. 10.1056/NEJMra1808786.
  6. Unnersjö-Jess, D., Butt, L., Höhne, M., Sergei, G., Fatehi, A., Witasp, A., Wernerson, A., Patrakka, J., Hoyer, P.F., Blom, H., Schermer, B., Bozek, K., and Benzing, T. (2023). Deep learning–based segmentation and quantification of podocyte foot process morphology suggests differential patterns of foot process effacement across kidney pathologies. Kidney Int. 103, 1120-1130. https://doi.org/10.1016/j.kint.2023.03.013.
  7. Rinschen, M.M., Grahammer, F., Hoppe, A.K., Kohli, P., Hagmann, H., Kretz, O., Bertsch, S., Hohne, M., Gobel, H., Bartram, M.P., Gandhirajan, R.K., Kruger, M., Brinkkoetter, P.T., Huber, T.B., Kann, M., Wickstrom, S.A., Benzing, T., and Schermer, B. (2017). YAP-mediated mechanotransduction determines the podocyte's response to damage. Sci Signal 10. 10.1126/scisignal.aaf8165.
  8. Jain, M., Kaiser, R.W.J., Bohl, K., Hoehne, M., Gobel, H., Bartram, M.P., Habbig, S., Muller, R.U., Fogo, A.B., Benzing, T., Schermer, B., Hopker, K., and Slaats, G.G. (2019). Inactivation of Apoptosis Antagonizing Transcription Factor in tubular epithelial cells induces accumulation of DNA damage and nephronophthisis. Kidney Int. 95, 846-858. 10.1016/j.kint.2018.10.034.
  9. Kohli, P., Hohne, M., Jungst, C., Bertsch, S., Ebert, L.K., Schauss, A.C., Benzing, T., Rinschen, M.M., and Schermer, B. (2017). The ciliary membrane-associated proteome reveals actin-binding proteins as key components of cilia. EMBO Rep. 18, 1521-1535. 10.15252/embr.201643846.