News
ERC Consolidator Grant for Peter Walentek
European Union funds research into the adaptability of tissues
Second Funding Period for NephGen!
The DFG confirmed in their latest press release that the CRC 1453 will receive funding for a second...
Model organisms of polycystic kidney disease
Many advances in PKD research have originated from work with model organisms. PKD proteins were first found to localize to cilia in Chlamydomonas and C. elegans, which led to the “ciliary hypothesis” of polycystic kidney disease. The CRU employs four model organisms (Drosophila, Xenopus, C. elegans, zebrafish) to complement the traditional rodent model of polycystic kidney disease. These animal models will be used to elucidate the fundamental signalling pathways of ADPKD and to design novel therapeutic approaches. Each model system has specific advantages to exploit. PCP signalling is best established in Drosophila; therefore this animal model will be used to study PKD protein-dependent PCP signalling mechanisms. In Xenopus, the Wnt signalling-dependent formation of a double-axis will be used to elucidate the role of PKD proteins in canonical Wnt signalling. RNAi screens in C. elegans are an effective way to identify novel components of signalling pathways.
 | |
|
Lastly, the zebrafish pronephros recapitulates early renal development and cyst formation in an animal amendable to rapid genetic manipulations. These animal models are a powerful means to identify evolutionary conserved signalling pathways, allowing further analysis of the function of a gene product through genetic, yeast-two-hybrid, and biochemical studies. Defining the underlying signalling pathways will deepen our mechanistic understanding of polycystic kidney disease and provide additional therapeutic targets for suppressing cyst formation. These new molecules will provide candidate targets for therapeutic interventions. Project P1 (M. Köttgen) will use the Drosophila model system to identify novel components of the polycystin-signalling complex. The polycystin complex is thought to translate ciliary stimuli into intracellular calcium transients, but it is unclear whether this activation is mechanosensory, chemical or ligand-based. Genetic screening provides an unbiased means to identify new molecules instrumental to the pathogenesis of polycystic kidney disease.
Since mTOR deregulation appears to play a prominent role in cystogenesis and progression of renal disease, novel components of this pathway will be identified through genetic screening in C. elegans in project P2 (E. Neumann-Haefelin & R. Baumeister). Of particular interest are upstream regulators of mTOR in this model organism, since it is unknown how ciliary dysfunction results in an upregulation of mTOR activity. Project P3 (A. Kramer-Zucker) will systematically analyse the function of PKD genes during zebrafish pronephros development. This project will establish transgenic zebrafish expressing fluorescent markers to visualize cell divisions and calcium signalling. Using morpholino-oligonucleotides to target PKD genes in these novel fish lines, P3 will help to delineate the function of PKD proteins in vivo, and identify the molecular components that link these molecules to tubular homeostasis.
Project P4 (S. Lienkamp & J. Gloy) will define the role of PKD proteins in canonical and non-canonical Wnt signalling during Xenopus embryogenesis. In projects P3 and P4, candidate molecules identified from projects P1 and P2 will be studied in these two model organisms. Candidate molecules identified in projects P1 and P2 will also be further evaluated for their role in flow-induced signalling, using the in vitro model system of project P6 (part B). Information from projects P1-4 and P6 will be utilized in project P9 to design novel therapeutic approaches (part C). Thus, the projects of part A will not only deepen our fundamental understanding of polycystic kidney disease, but will also provide essential components for projects in part B and C.
