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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
 
Final Report Year 2020

Final Report Abstract

High throughput technologies have enabled remarkable progress in understanding the genetic contribution to human disease. The CRC 1140 (KIDGEM) was implemented to bridge the gap between high dimensional genetic data and mechanistic insight necessary to prevent or treat hereditary disease, focusing on hereditary glomerular disease, hereditary tubular disease, and on signaling pathways in hereditary kidney disease. During the first funding period, KIDGEM made significant progress in all research areas, resulting in more than 200 publications. Major accomplishments include the characterization of the protein modules that constitute the slit diaphragm (SD), the characterization of evolutionary conserved signaling cascades, and the development of new structural models of the glomerular filtration barrier. Rather than acting as a static barrier, freeze-substitution electron microscopy revealed that SD molecules act in a dynamic fashion, constantly adjusting the space in between podocyte foot processes. Studying integrin alpha 3 (ITGA3) mutations that lead to a hereditary renal-skin syndrome revealed that ITGA3 mutations alter the cellular microenvironment. Genome-wide association studies not only identified novel chronic kidney disease genes, but connected single nucleotide polymorphisms to previously unknown metabolic pathways. Analysis of protein complexes involved in histone modifications revealed that podocytes use epigenetic programs to adapt to stress. Although the observation that most gene products responsible for cystic kidney diseases localize to the cilium, the precise molecular functions of most cilia-associated proteins remain unknown. A novel, UV-crosslinking method to examine protein-RNA interactions (FLASH) revealed that some cilia display RNA-binding properties. Furthermore, first candidate ligands for polycystin-1 were isolated, providing novel insights into the molecular pathogenesis of autosomal dominant polycystic kidney disease. While PKHD1 was long considered the only gene responsible for autosomal recessive polycystic kidney disease (ARPKD), KIDGEM identified DAZ Interacting Protein 1-Like (DZIP1L) as a second ARPKD gene, and discovered that several components of the DYNEIN-2 complex are mutated in patients with skeleto-renal ciliopathies. Attempting to characterize proteins involved in congenital ananomalies of the kidney and the ureteric tract (CAKUT), KIDGEM discovered transcription factors that can trans-differentiate fibroblasts into renal tubule-like cells. The induced renal tubular epithelial cells can repopulate decellularized kidney tissue and form kidney tubule-like structures. These findings may have significant implications not only for generating ex vivo models of hereditary kidney disease, but also provide novel approaches to ameliorate chronic kidney disease. KIDGEM also discovered fundamental insights into overarching pathogenic mechanisms in hereditary kidney disease, ranging from the role of autophagy in polycystic kidney disease to the biogenesis of mitochondria, emphasizing the overall strategy of KIDGEM in creating a research environment that connects gene discovery to gene function.

Publications

 
 

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