Role of Role of factor H related proteins in glomerular diseases
Complement is associated with several human kidney dieases and complement therapy is approved for atypical Hemolytic Uremic Syndrome. Sequence- and copy number variations in the human Factor H-CFHR (Complement Factor H Related) gene cluster are linked to the kidney diseases, atypical Hemolytic Uremic Syndrome, C3 Glomerulopathy, Membranous Nephropathy, IgA Nephropathy and lupus nephritis. Mutant CFHR-genes, FHR::FHR- and FHR::Factor H-hybrid-proteins and an altered FHR-plasma repertoire show that variant FHR proteins are associated with kidney pathology. FHRs are emerging immune and complement modulators: We have shown in the first funding period that FHR1 is an inflammatory mediator, FHR2 blocks C3 convertase action and inhibits FHR1 mediated inflammation. FHR5 is a complement activator binding to actin in damaged glomeruli. FHRs together with Factor H, the central C3 convertase regulator, adjust complement activity in glomeruli. In this project we aim to define how altered FHR variants cause pathology in the kidney, and evaluate whether FHR deposition in renal biopsies serve as diagnostic and predictive markers. To this end we plan to: 1) Define the physiological roles of FHR2 and FHR5 and evaluate how new FHR2 mutants (not listed in the exome aggregation consortium database) influence complement action, affect surface binding and complement regulation, 2) correlate FHR1-, FHR2- and FHR5 deposition with morphological changes, immunohistological staining or cellular modifications in glomeruli to define unique patterns for the various glomerular diseases, and 3) develop FHRs as diagnostic markers and coordinate with clinicians to extrapolate the altered FHR profiles for personalized, complement targeting therapies.
Zipfel PF, Wiech T, Stea ED, Skerka C.J Am Soc Nephrol. 2020 Feb
Sarah Irmscher, Silke R. Brix, Svante L. H. Zipfel, Luke D. Halder, Sibel Mutlutürk, Sonia Wulf, Evaldas Girdauskas, Hermann Reichenspurner, Rolf A. K. Stahl, Berit Jungnickel, Thorsten Wiech, Peter F. Zipfel & Christine SkerkaNat Commun. 2019 Jul
Zhao F, Afonso S, Lindner S, Hartmann A, Löschmann I, Nilsson B, Ekdahl KN, Weber LT, Habbig S, Schalk G, Kirschfink M, Zipfel PF, Skerka C.Front Immunol. 2019 May
Smith RJH, Appel G, Blom AM, Cook HT, D’Agati V, Fakhouri F, Véronique Fremeaux-Bacchi V, Józsi M, Kavanagh D, Lambris J, Noris M, Pickering MC, Remuzzi G, Santiago Rodriguez de Córdoba S, Sethi S, Van der Vlag J, Zipfel PF, Nester CMNat Rev Nephrol. 2019 Mar
Brix S, Noriega M, Tennstedt P, Vettorazzi E, Busch M, Nitschke M, Jabs W, Özcan F, Wendt R, Hausberg M, Sellin L, Panzer U, Huber T, Waldherr R, Hopfer H, Stahl R, Wiech TKidney Int. 2018 Dec
Moter A, Janneck M, Wolters M, Iking-Konert C, Wiessner A, Loddenkemper C, Hartleben B, Lütgehetmann M, Schmidt J, Langbehn U, Janssen S, Geelhaar-Karsch A, Schneider T, Moos V, Rohde H, Kikhney J, Wiech T.Clin Infect Dis. 2018 Oct
Brix S, Noriega M, Herden E, Goldmann B, Langbehn U, Busch M, Jabs W, Steinmetz O, Panzer U, Huber T, Stahl R, Wiech THistopathology. 2018 Jun
Rudnick RB, Chen Q, Stea ED, Hartmann A, Papac-Milicevic N, Person F, Wiesener M, Binder CJ, Wiech T, Skerka C, Zipfel PFJ Immunol. 2018 Apr
Buhlmann D, Eberhardt HU, Medyukhina A, Prodinger WM, Figge MT, Zipfel PF, Skerka CJ Immunol. 2016 Jul
Project Leaders
Prof. Dr. Thorsten Wiech
Prof. Dr. Peter Zipfel
Co-Workers
Tim Petschull
Dr. Sara Afonso
Ramona Rudnick
Martinistrasse 52
20246 Hamburg, Germany
Tel: +49-40-7410-51557
Fax: +49-40-7410-59036
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Martinistrasse 52
20246 Hamburg, Germany