|Associated Projects are methodologically and thematically closely linked to the SFB/TRR, but are financially independent.
Medizinische Klinik 3 – Rheumatologie und Immunologie
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease and lupus nephritis is one of the most dangerous organ manifestations. Neutrophils are phenotypically and functionally heterogenous and play an important pathophysiologic role in SLE and rheumatoid arthritis (RA), another prototypical autoimmune disease. However, it is unclear which heterogeneity neutrophils display in RA and SLE on the single cell level and how specific effector functions in neutrophils can be targeted selectively. In this project, we will systematically dissect neutrophil heterogeneity in RA and SLE, quantify the conservation of neutrophil polarization states across humans and mice and mechanistically examine which genes influence different functional parameters in neutrophils.
The overall objective of the current project is to develop a CRISPR-Cas9 gene editing strategy to ablate the glycosylative activation site of CaMKIIδ in vivo. Several gene editing constructs will be designed and tested in vitro in HEK293 cells and extensively characterised in human iPSC-cardiomyocytes. The best editing approach will then be further optimized and applied in mice to test it as a potential therapy for diabetic cardiomyopathy in vivo. This could potentially lead to a new therapy for patients with diabetes mellitus and cardiac disease. Plus, treatment of the diabetic cardiomyopathy could also convey beneficial effects for the cardiorenal syndrome and the kidney. Specifically, our approach will include:
Objective 1: Design and optimization of the gene editing constructs in vitro
Objective 2: Functional characterization of edited human cardiomyocytes
Objective 3: Editing CaMKIIδ in vivo as a therapy for diabetic cardiomyopathy
Prof. Dr. Mario Schiffer
Dr. Tilman Jobst-Schwan
Wnt/β-catenin signaling is a biologically highly conserved cellular signal transduction pathway that has important functions in embryogenesis, cell proliferation, cell differentiation and migration. It has been shown that the Wnt/β-catenin pathway is essential for regeneration and repair of tubular damage in acute kidney injury. In contrast, constant activation of Wnt/β-catenin signaling in chronic kidney disease leads to progression of the disease, so that in this case β-catenin inhibition may have protective effects. In this project, we aim to investigate how we can promote the beneficial function of β-catenin in both glomerulus and tubule, focusing particularly on proteinuric kidney disease.
Prof. Dr. rer. nat. Dipl. Ing. Felix B. Engel
Chronic kidney disease represents the fastest growing pathology worldwide. Elucidating new regulators of kidney development and disease will promote the development of strategies for kidney repair. Based on our preliminary data, we conclude that
1) Gpr126 is expressed in the collecting duct,
2) in contrast to the heart, where only the NTF is required for proper development, kidney development depends on CTF and NTF,
3) Gpr126 expression is upregulated during renal disease, and
4) in renal disease Gpr126 is ectopically expressed in renal cells other than collecting duct cells.
Thus we hypothesize that Gpr126
1) contributes to the differentiation of the nephron establishing segment identity,
2) might be useful as diagnostic marker in kidney disease, and/or
3) is a promising new therapeutic target for renal diseases. Therefore, we propose to characterize the expression pattern of Gpr126 in kidney development and disease and to elucidate the role of Gpr126 function during kidney development.