SFB 1140:  Kidney Disease - from Genes to Mechanisms (KIDGEM)

• Subject Area: Medicine ; Biology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 246781735

High throughput sequencing technologies have enabled remarkable progress in understanding the genetic contribution to human disease. However, efficient identification of gene function and effective translation into new therapeutic approaches remain challenging. To address this challenge, KIDGEM implemented three research areas: area A, focusing on hereditary glomerular disease, area B focusing on hereditary tubular disease, and area C focusing on signaling pathways important for hereditary kidney disease. Major accomplishments in area A include the identification of the protein modules of the slit diaphragm, the development of new structural models of the glomerular filtration barrier as well as uncovering the role of epigenetic modification in podocyte homeostasis. Area B unraveled novel molecular links between ciliary protein modules, actin dynamics and metabolism as well as the transcriptional mechanisms that specify tubular cell identity. Area C, focusing on actin cytoskeleton remodeling, ciliogenesis, apoptosis, autophagy and mitochondrial metabolism, provided fundamental insights into overarching pathogenic mechanisms in hereditary kidney disease. By combining genetic epidemiology and genome-wide association studies with genetically tractable animal models, KIDGEM rapidly transitioned putative candidates to confirmed human disease genes, and created an infrastructure that connects gene discovery to gene function. In the next funding period, area A will 1) provide a comprehensive concept of the slit diaphragm, 2) continue to unravel the importance of chromatin modification in podocyte survival, and 3) use large-scale sequencing studies to uncover novel candidates for hereditary kidney diseases. New projects, originating from patient-derived mutations responsible for proteinuria and renal failure, will elucidate the role of endocytosis and the impact of nuclear actin rearrangement in podocytes. Area B will continue to target ciliopathies and congenital anomalies of the kidney urinary tract (CAKUT). New projects will elucidate the role of alternative splicing in ciliogenesis, characterize the trafficking routes of cilia-associated proteins, and determine the connection between cilia and inflammation. Area C will continue to investigate pathogenic pathways in hereditary kidney disease, focusing on the von Hippel-Lindau (VHL) syndrome and metabolic reprogramming during the next funding period. KIDGEM has become a highly interactive collaborative research center. Generating novel molecular insight into hereditary kidney diseases, KIDGEM will continue to provide the framework for targeted therapeutics applicable to inherited disease.

• DFG Programme: Collaborative Research Centres

Completed projects

• A01 - High-resolution proteomics and functional analyses of the podocyte slit diaphragm and its disease-induced dynamics (Project Heads Fakler, Bernd ;  Grahammer, Florian )
• A02 - The role of NEPH-NEPHRIN proteins as regulators of neuron and kidney morphogenesis (Project Head Neumann-Haefelin, Elke )
• A03 - High-resolution structural and global signaling network identification of the NEPH-NEPHRIN protein complex (Project Head Huber, Tobias B. )
• A04 - Characterization of genes in renal-skin syndromes (Project Head Has, Cristina )
• A05 - Genetische Risikovarianten für chronische Nierenerkrankungen in einer prospektiven Studie von 5.217 Patienten (Project Head Köttgen, Anna )
• A06 - The role of epigenetic regulators MOF and KANSL1 in kidney homeostasis (Project Head Akhtar, Ph.D., Asifa )
• B01 - The role of the nephronophthisis Anks6 module in development and tissue homeostasis (Project Heads Kammerer, Bernd ;  Walz, Gerd )
• B02 - Functional analysis of the polycystin-1-signaling module (Project Head Köttgen, Michael )
• B04 - Identification of TULP3-mutations in patients with cystic kidney disease and related ciliopathies (Project Head Bergmann, Carsten )
• B06 - Organ-specific outcomes in ciliary signaling defects (Project Heads Lausch, Ekkehart Ullrich ;  Schmidts, Miriam )
• B07 - Conserved transcriptional programs for renal specification and reprogramming (Project Heads Arnold, Sebastian J. ;  Lienkamp, Soeren )
• C01 - Structure, function and regulation of toxin-induced microtubule-based cell protrusions (Project Heads Aktories, Klaus ;  Schwan, Carsten )
• C02 - Identification of novel kinase targets up- and downstream of mTOR by Kinase Correlation Profiling (Project Head Dengjel, Jörn )
• C03 - Role of Bim and apoptosis in the development of polycystic kidney disease (PKD) (Project Head Borner, Christoph )
• C04 - Organization of mitochondrial DNA-protein complexes and mitochondrial cytopathy of the kidney (Project Head Wiedemann, Nils )
• Z01 - Central imaging facility for advanced light and correlated light and electron microscopy (Project Heads Eimer, Stefan ;  Nitschke, Roland )
• Z02 - Spatio-temporal analysis of confocal microscopic kidney data (Project Heads Brox, Thomas ;  Ronneberger, Olaf )
• Z03 - Central Tasks (Project Head Walz, Gerd )

• Applicant Institution: Albert-Ludwigs-Universität Freiburg
• Participating Institution: Max-Planck-Institut für Immunbiologie und Epigenetik; Abteilung Zelluläre und Molekulare Immunologie
• Spokesperson: Professor Dr. Gerd Walz