Nephro Lab

Unsere Kollegiatinnen und Kollegiaten im dritten Förderjahr

Im Folgenden möchten wir Ihnen unsere  Kollegiatinnen und Kollegiaten im 3. Förderjahr vorstellen. Sie wurden in einem spezifischen Auswahlverfahren von unserem EKFK-Direktorium in Zusammenarbeit mit dem Evaluierungskomitee ausgesucht.

The differential effects of immunoproteasome inhibitors and proteasome inhibitors on podocytes in mouse models of SLE Systemic lupus erythematosus (SLE) and other autoantibody-­?mediated diseases still pose a great challenge to the treatment of affected patients. In SLE renal involvement represents an important subject of research for new treatments, since lupus nephritis often leads to impaired kidney function and sometimes to renal failure. Kidney function is a critical factor in respect to prognosis and survival of patients with SLE. The research group of Prof. R. Voll investigates the pathogenesis of lupus nephritis and aims to develop new treatment strategies. Autoantibody producing plasma cells represent a promising treatment target. The research group of Prof. Voll found autoantibody-­?secreting cells with a frequency of long-­?lived plasma cells within the inflamed kidneys of NZB/W F1 lupus mice (Starke et al., 2011). Further research on this subject has lead to the discovery that proteasome inhibitor bortezomib does not only deplete plasma cells but was shown to be effective in treatment of lupus nephritis in the NZB/W F1 and MRL/Ipr mice (Neubert et al., 2008). In a first case series, proteasome inhibition was showing efficacy in the treatment of patients with refractory courses of SLE (Alexander et al., 2015).

Proteasome inhibitors such as bortezomib have a relatively high toxicity, especially in high dosis, whereas inhibitors of the immunoproteasome should have rather little general toxicity. The proposed project therefore focuses on the differential effects of immunoproteasome inhibitors versus proteasome inhibitors on renal plasma cells as well as podocytes in mouse models of SLE and is set out to include three major lines of experimental approaches on the issue:

We aim to assess the effects of increasing concentrations of conventional proteasome inhibitors in comparison to immunoproteasome inhibitors on the survival, metabolic activity and gene expression of podocyte cell lines in vitro in collaboration with Prof. Dr. Tobias Huber. It will be analyzed if podocyte cell lines express a substantial amount of immunoproteasomes after incubation with interferon alpha and gamma, cytokines which can be detected in inflamed kidneys in SLE. 

The second approach will focus on the effects of proteasome inhibitor treatment on podocytes in an in vivo setting with NZB/NZW F1 and MLR/lpr mice and include a direct comparison of bortezomib as an unselective proteasome inhibitor to a highly selective immuneproteasome inhibitor in respect to impact on antibody titres, glycosylation, proteinuria and renal function through histology, immunohistochemistry and electron microscopy of the kidneys. Furthermore, we will contrast the effectiveness in depletion of renal plasma cells of proteasome versus immunoproteasome inhibitors, each in combination with the BAFF and APRIL neutralizing TACI-­?Ig as combination treatment of lupus nephritis.

Mentoren/innen:

1) Prof. Reinhard Voll (Klinik für Rheumatologie und klinische Immunologie)
2) PD Dr. Marta Rizzi (Klinik für Rheumatologie und klinische Immunologie)
3) Prof. Tobias Huber (Abteilung Nephrologie)

Sowohl vererbte, wie auch erworbene Erkrankungen der renalen Tubuli führen nicht selten zu Nierenfunktionsverlust und Dialysepflichtigkeit der betroffenen Patienten. Durch die Analyse transkriptioneller Regulatoren soll untersucht werden, wie die zelluläre Identität und Stabilität renaler Tubuluszellen auf molekularer Ebene etabliert und erhalten wird. Basierend auf Vorarbeiten untersuchen wir derzeit systematisch Faktoren und Kulturbedingungen auf ihre Fähigkeit, segmentale Spezifikation zu vermitteln. Hierdurch soll der Aufbau von in vitro Systemen zur patientenspezifischen Modellierung renaler Tubulopathien ermöglicht werden, um renale Schädigungen im genetischen Kontext betroffener Patienten auf ihre molekularen Ursachen zu untersuchen.

Mentoren/innen:

1) Prof. Gerd Walz (Abteilung Nephrologie)
2) Prof. Anna Köttgen (Abteilung Genetische Epidemiologie)
3) Dr. Soeren Lienkamp (Abteilung Nephrologie)