SFB 1453:  Nephrogenetics (NephGen)

Kidney disease represents a global public health challenge. Chronic kidney disease alone affects 10 15% of adults and increases the risk for kidney failure, adverse cardiovascular outcomes, and mortality. Kidney cancers add to this burden. Despite the high prevalence and the great costs associated with treating kidney diseases, the low number of clinical trials and specific treatments in nephrology attests to a shortage of therapeutic targets. The identification of druggable targets has been hampered by an incomplete understanding of the mechanisms underlying the etiology and progression of kidney diseases. Pharmacological compounds that operate on proteins or pathways connected to a given disease by human genetic evidence are at least twice as likely to gain approval, compared to those without genetic support. Therefore, the long-term vision of the CRC 1453 is to use evidence from genetic kidney diseases to identify, characterize, and modify molecules and pathways that represent targets to improve the prevention and treatment of kidney disease. During the first funding period of the CRC, we have assembled and genetically characterized large patient- and population-studies, resulting in the discovery of genes and genetic variants not previously linked to kidney diseases. As a general principle, we found that studies of both monogenic and complex genetic diseases can result in the identification of the same disease-related target, thereby providing complementary support. Moreover, our team has established a variety of model organisms and state-of-the-art methods for genome editing, structural biology, single cell sequencing and spatial transcriptomics, whole animal live imaging, and integrative analyses of high-dimensional data. These resources were used in a highly collaborative fashion to gain mechanistic insights into disease-relevant pathways, thereby yielding additional candidates such as previously unrecognized interaction partners of kidney disease risk genes. These resources and workflows now enable the team to efficiently and thoroughly characterize emerging kidney disease candidate genes across the range of complexity, from population to single molecule and back. In a second funding period, we plan to move our projects to the next stages of our conceptual framework. We will systematically address the principal questions of risk allele frequency, of target interactions, and of target localization for the kidney disease-related genes investigated in the CRC 1453. We also aim to extend our first translational studies of the implicated molecules through genetic and pharmacological modulation in disease-specific model organisms, and in large human population studies through modern statistical approaches. The CRC 1453 represents a focused research endeavor that unites a multidisciplinary team of scientists dedicated to turn findings from human genetics and mechanistic studies into novel approaches to treat and prevent kidney diseases.

DFG Programme Collaborative Research Centres

• INF - Information infrastructure project for research data management (Project Head Binder, Harald )
• P01 - Genetic and epigenetic dysregulation in congenital anomalies of the kidneys and urinary tract (Project Heads Lausch, Ekkehart Ullrich ;  Schmidts, Miriam )
• P02 - Discovery and characterization of new genes/proteins in cystic kidney disease and related ciliopathies (Project Heads Bergmann, Carsten ;  Ott, Elisabeth )
• P03 - Elucidating the function of NPHP gene products and compensatory mechanisms in nephronophthisis and related ciliopathies (Project Heads Walentek, Peter ;  Walz, Gerd ;  Yakulov, Toma Antonov )
• P05 - Applying the Concept of Synthetic Lethality to the Treatment of Autosomal Dominant Polycystic Kidney Disease (Project Head Köttgen, Michael )
• P06 - The role of endosomal regulators for slit diaphragm formation and maintenance (Project Head Hermle, Tobias )
• P09 - High-resolution proteomic analysis of native sodium-phosphate transporters SLC34A1 and SLC34A3 and their role in kidney disease (Project Head Fakler, Bernd )
• P10 - Structure and function of disease-relevant renal transport proteins (Project Head Hunte, Carola )
• P12 - VHL-dependent licensing of hetero-cellular crosstalks within the tumor micro-environment of clear cell renal cell carcinoma (ccRCC) (Project Heads Schell, Christoph B. ;  Schilling, Oliver )
• P13 - Deregulation of mTOR signaling pathways and metabolic reprogramming in VHL-dependent clear cell renal cell carcinoma (Project Heads Neumann-Haefelin, Elke ;  Schlosser, Pascal ;  Timmers, Marc )
• P14 - The role of MIF in the development and progression of renal carcinoma (Project Head Frew, Ian )
• P15 - Target identification across the allele frequency spectrum: from complex to monogenic kidney disease (Project Heads Schultheiss, Ulla T. ;  Wuttke, Matthias )
• P16 - Discovery and characterization of genes with cell-type and compartment-specific functions in the kidney and their role in disease (Project Head Köttgen, Anna )
• P17 - Gene regulatory programs in autosomal dominant polycystic kidney disease (Project Heads Köttgen, Michael ;  Preißl, Sebastian )
• P18 - Understanding differential disease manifestations of VHL mutations via the plurality of their molecular functions (Project Heads Diederichs, Sven ;  Ganner, Athina )
• P19 - Hereditary lysosomal storage and metabolic diseases in the kidney (Project Heads Huber, Tobias B. ;  Schumann, Anke )
• P20 - Deciphering the mechanistic role of formin DAAM2 in genetic podocytopathies (Project Heads Grosse, Robert ;  Hermle, Tobias )
• S01 - Planning, analysis, integration and modeling of high-dimensional data (Project Heads Binder, Harald ;  Börries, Melanie ;  Köttgen, Anna )
• Z - Central Tasks of the Collaborative Research Center (Project Head Köttgen, Anna )

• INFalt - Information Infrastructure Project for Research Data Management (Project Head Binder, Harald )
• P04 - Investigating alternative splicing and isoform functions in ciliopathy- and renal disease-genes (Project Head Walentek, Peter )
• P07 - Control of kidney morphogenesis by CAKUT- and kidney function-associated transcription factors (Project Head Arnold, Sebastian J. )
• P08 - Primary aldosteronism – genetics, pathophysiology and role in hypertensive kidney disease (Project Head Scholl, Ute )

Applicant Institution Albert-Ludwigs-Universität Freiburg

Spokesperson Professorin Dr. Anna Köttgen