Associated Projects

Associated Projects are methodologically and thematically closely linked to the SFB/TRR, but are financially independent.

DFG Sachbeihilfe: STE 3162/2-1

Potential of small molecule Bcl-6 inhibitors as novel immunosuppressive agents in organ transplantation

PD Dr. med. Louisa Steines
Department of Nephrology, University Hospital Regensburg

Objectives
Antibody-mediated rejection (ABMR) has been identified as a major cause of graft failure in solid organ transplantation. The central hypothesis of this proposal is that an alloantigen driven Tfh cell – B cell interaction leads to the induction and amplification of allo-antibody producing B cells, which in turn may lead to ABMR. Since Bcl-6 is an essential factor for the generation of both Tfh and high affinity antibody producing B cells, we hypothesize that inhibiting Bcl-6 will block the formation of alloantibodies and consequently reduce ABMR. Bcl-6 inhibition could thus have potential as a maintenance immunosuppressive mechanism in solid organ transplantation and reduce rates of ABMR. To explore this hypothesis, our aims are to investigate the immunosuppressive potential of Bcl-6 inhibitors in a translational model of kidney transplantation in rats. In human samples, we aim to examine an association of Bcl-6 expression and immunological risk in kidney transplant patients. Finally, we aim to test small molecule Bcl-6 inhibitors in human lymphocytes and to define their mechanism of action in Tfh and B cells and their interactions in vitro. In summary, we aim to establish how Bcl-6 inhibition might serve as a novel immunosuppressive strategy to prevent antibody-mediated rejection (mechanism). The long-term perspective is to further develop Bcl-6 inhibitors for potential clinical use as maintenance immunosuppression in solid organ transplantation.

Aim 1: to investigate an association of Bcl-6 expression and immunological risk in Ktx patients.

Bcl-6 is a master regulator of humoral responses, but its role in alloresponses and immunological risk in solid organ transplant patients has not been assessed. We aim to assess Bcl-6 expression in peripheral blood lymphocytes and kidney transplant biopsies to determine an association with immunological risk.

Aim 2: to investigate the immunosuppressive potential and mode of action of Bcl-6 inhibitors on humoral alloresponses and ABMR development in a translational Ktx model in rats.

Since Bcl-6 is essential for Tfh and germinal center B cell development, we hypothesize that treatment with a Bcl-6 inhibitor will block humoral alloresponses and prevent ABMR. Using a translational Ktx model of ABMR in rats, we will test this hypothesis and assess the effect of Bcl-6 inhibition on humoral alloresponses and ABMR development.

Aim 3: to investigate the effect of Bcl-6 inhibitors on allogeneically stimulated human Tfh and B cells

Bcl-6 is required for differentiation and activation of Tfh and B cells. Since novel small molecule Bcl-6 inhibitors have not been examined in human cells, we aim to assess the effect of Bcl-6 inhibitors on human Tfh and B cells and their interactions in healthy donor cells and Ktx patients’ cells. Here, we also aim to dissect the mechanism by which Bcl-6 inhibitors act in Tfh and B cells.

DFG-Projekt AM 93/10-4 | VE 104/4-4

Significance of afferent renal nerve fibers under physiological and pathological conditions: Are there pharmacological options for intervention?

Prof. Dr. med. Kerstin Amann
Nephropathology, Friedrich-Alexander-Universität Erlangen

PD Dr. med. Kristina Rodionova
Nephrology, Friedrich-Alexander-Universität Erlangen

Prof. Dr. Roland Veelken
Nephrology, Friedrich-Alexander-Universität Erlangen

After several years of great uncertainty as to whether a denervation of the kidney would have a clinical future in the treatment of arterial hypertension, publications in recent years have provided new data in favor of the effectiveness of this method.

In this context, experimental (and clinical) studies point to an important function of afferent nerves that run from the tubulointerstitial area of the kidney to the central nervous system. These nerve tracts probably have the task of keeping the central sympathetic outflow low. However, under disease conditions such as high blood pressure, but also under high salt diet, these afferent nerve pathways lose their ability to dampen sympathetic nerve activity. Likely the intrarenal salt handling is one important mechanism in this respect.

Hence, an approach to maintain the sensitivity of afferent renal nerves to NaCl in their intrarenal tubulointerstitial environment under pathological conditions is being investigated experimentally in this project by pharmacological means (e.g. SGLT2 inhibitors). In vivo experiments in rats and mice with neurophysiological techniques for direct recording of efferent and afferent renal nerve activity will be used as well as primary cultures of afferent neurons in vitro from respective dorsal root ganglia with projections from the kidneys. Finally, the mechanisms that alter the reactivity of afferent neural pathways are investigated using molecular genetic approaches.

The rationale of the investigations is to find pharmacological measures to therapeutically influence neurogenic regulatory circuits of the kidneys with their putatively far-reaching systemic consequences, which should always have priority over deletion therapies like denervation procedures.

DFG-Projekt IL 257/1-1

Structure-based electrophysiological analysis of polycystin-2 ion channel function as homomer or in complex with polycystin-1

PD Dr. Alexandr Ilyaskin

Institut für Zelluläre und Molekulare Physiologie - Lehrstuhl für Physiologie (Vegetative Physiologie)
Friedrich-Alexander-Universität Erlangen-Nürnberg

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic renal disease in humans and is characterized by the progressive development of fluid-filled renal cysts that disrupt renal architecture, ultimately leading to kidney failure. It is caused by mutations in the PKD1 or PKD2 genes, which encode polycystin-1 (PC1) or polycystin-2 (PC2), respectively. Germline mutations affect PC1 in ~85 % and PC2 in ~15 % of ADPKD patients. For cyst development a second somatic mutation is required. PC2 is a member of the transient receptor potential (TRP) family of non-selective cation channels which can functionally interact with PC1. Despite intensive research over more than two decades, no clear consensus has emerged regarding the physiological roles of PC2 alone or in complex with PC1. Moreover, the pathomechanisms involved in cyst formation due to PC1 or PC2 mutations remain unclear. Recently published cryo-electron microscopy (cryo-EM) data suggest that PC2 can function as homotetrameric channel or form a heterotetrameric complex together with PC1 with a 3:1 stoichiometry. This available structural information opens exciting new horizons to study the function of PC2 and PC2/PC1 at the molecular level. In particular, we will investigate how ADPKD-associated mutations alter the ion channel function of PC2 alone or in complex with PC1. Furthermore, we will clarify the functional importance of different PC2 and PC1 domains, and try to identify novel modulators of these ion channels. In the long term, a better understanding of the molecular mechanisms of PC2 and PC2/PC1 ion channel function may promote the development of novel personalized ADPKD treatment strategies.

DFG-Projektnummer 517717827

Heterogenität Neutrophiler Granulozyten in rheumatoider Arthritis und Systemischem Lupus

Prof. Dr. Ricardo Grieshaber-Bouyer
www.rgb-lab.de

Medizinische Klinik 3 – Rheumatologie und Immunologie
Friedrich-Alexander-Universität Erlangen-Nürnberg

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.

DFG-Projekt LE 5009/3-1

Editing CaMKIIδ As A Therapy For Diabetic Cardiomyopathy

PD Dr. Simon Lebek

Cardiology
Universität Regensburg

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

DFG-Project SCHI 587/13-1

The role of podocytic and tubular β-catenin in proteinuric kidney disease

Prof. Dr. Mario Schiffer
Nephrology
Friedrich-Alexander-Universität Erlangen-Nürnberg

Dr. Tilman Jobst-Schwan
Nephrology
Friedrich-Alexander-Universität Erlangen-Nürnberg

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.

DFG-PROJECT EN 453/15-1

Aufklärung der Funktion und Signalübertragung von Gpr126 bei der Entwicklung und Erkrankung der Niere

Prof. Dr. rer. nat. Dipl. Ing. Felix B. Engel
Nephropathology
Friedrich-Alexander-Universität Erlangen-Nürnberg

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.