Center for Molecular Medicine Cologne

Bernhard Schermer / Max C Liebau - C 12

The role of the cilia-cell-cycle connection in tissue homeostasis of renal tubular epithelium in acute and chronic kidney diseases

Abstract

Recent groundbreaking work has revealed that mutations in genes encoding proteins localized to primary cilia are causative for a large number of different human diseases, now referred to as ciliopathies. A hallmark of most ciliopathies is the development of cystic kidneys caused by aberrant proliferation of epithelial cells.
Primary cilia are antenna-like organelles that project from the surface of virtually all mammalian cells. In addition to sensory functions cilia are linked to the cell cycle: while ciliogenesis typically occurs in interphase, cilia have to disassemble to allow mitotic re-entry. In this project we hypothesize that the process of ciliary disassembly is of extraordinary importance for tissue homeostasis and repair. This can be ideally studied in the kidney, where tissue homeostasis and repair after damage is mainly driven by resident ciliated epithelial cells making accurately timed and efficient ciliary disassembly indispensable and where cilia are important modulators of proliferation and differentiation as we learned from ciliopathies.
In this project we aim to study the impact of this cilia-cell-cycle-connection in 2D and 3D cell culture models and in vivo. We will address the fundamental but to date unanswered biological question of how cilia by regulating cell cycle re-entry modulate tissue homeostasis and repair. We utilize proteomics and live-imaging technologies in combination with genetic engineering to (1) understand the dynamics of ciliary disassembly during cell cycle progression in healthy cells and cells carrying ciliopathy mutations, and (2) investigate how the cilia-cell cycle connection and its perturbations affect tissue homeostasis and repair in vivo.

Clinical/medical relevance and sustainability in disease understanding

Our project aims to provide novel insights in the understanding of multiple human diseases that display aberrant proliferation rates in affected tissues: In fact, the majority of tissues consist of ciliated cells that have to resorb cilia before cell division. Thus, we expect that our studies will challenge several current pathophysiological concepts in the field of nephrology and beyond, by adding the dysregulated cilia-cell-cycle-connection as a novel disease mechanism and potential therapeutic target to the pathogenesis of many diseases. Ultimately this project has the potential to identify pharmaceutical targets able to interfere with ciliary dynamics in (renal) disease.

Braun, F., Blomberg, L., Brodesser, S., Liebau, M.C., Schermer, B., Benzing, T., and Kurschat, C.E. (2019). Enzyme Replacement Therapy Clears Gb3 Deposits from a Podocyte Cell Culture Model of Fabry Disease but Fails to Restore Altered Cellular Signaling. Cell Physiol Biochem 52, 1139-50.

Brinkkoetter, P.T., Bork, T., Salou, S., Liang, W., Mizi, A., Ozel, C., Koehler, S., Hagmann, H.H., Ising, C., Kuczkowski, A., Schnyder, S., Abed, A., Schermer, B., Benzing, T., Kretz, O., Puelles, V.G., Lagies, S., Schlimpert, M., Kammerer, B., Handschin, C., Schell, C., and Huber, T.B. (2019). Anaerobic Glycolysis Maintains the Glomerular Filtration Barrier Independent of Mitochondrial Metabolism and Dynamics. Cell Rep 27, 1551-66 e5.

Burgmaier, K., Kilian, S., Bammens, B., Benzing, T., Billing, H., Buscher, A., Galiano, M., Grundmann, F., Klaus, G., Mekahli, D., Michel-Calemard, L., Milosevski-Lomic, G., Ranchin, B., Sauerstein, K., Schaefer, S., Shroff, R., Sterenborg, R., Verbeeck, S., Weber, L.T., Wicher, D., Wuhl, E., Dotsch, J., Schaefer, F., and Liebau, M.C. (2019). Clinical courses and complications of young adults with Autosomal Recessive Polycystic Kidney Disease (ARPKD). Sci Rep 9, 7919.

Gimpel, C., Avni, E.F., Breysem, L., Burgmaier, K., Caroli, A., Cetiner, M., Haffner, D., Hartung, E.A., Franke, D., Konig, J., Liebau, M.C., Mekahli, D., Ong, A.C.M., Pape, L., Titieni, A., Torra, R., Winyard, P.J.D., and Schaefer, F. (2019). Imaging of Kidney Cysts and Cystic Kidney Diseases in Children: An International Working Group Consensus Statement. Radiology 290, 769-82.

Gimpel, C., Bergmann, C., Bockenhauer, D., Breysem, L., Cadnapaphornchai, M.A., Cetiner, M., Dudley, J., Emma, F., Konrad, M., Harris, T., Harris, P.C., Konig, J., Liebau, M.C., Marlais, M., Mekahli, D., Metcalfe, A.M., Oh, J., Perrone, R.D., Sinha, M.D., Titieni, A., Torra, R., Weber, S., Winyard, P.J.D., and Schaefer, F. (2019). International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people. Nat Rev Nephrol10.1038/s41581-019-0155-2.

Ignarski, M., Rill, C., Kaiser, R.W.J., Kaldirim, M., Neuhaus, R., Esmaillie, R., Li, X., Klein, C., Bohl, K., Petersen, M., Frese, C.K., Hohne, M., Atanassov, I., Rinschen, M.M., Hopker, K., Schermer, B., Benzing, T., Dieterich, C., Fabretti, F., and Muller, R.U. (2019). The RNA-Protein Interactome of Differentiated Kidney Tubular Epithelial Cells. J Am Soc Nephrol 30, 564-76.

Jain, M., Kaiser, R.W.J., Bohl, K., Hoehne, M., Gobel, H., Bartram, M.P., Habbig, S., Muller, R.U., Fogo, A.B., Benzing, T., Schermer, B., Hopker, K., and Slaats, G.G. (2019). Inactivation of Apoptosis Antagonizing Transcription Factor in tubular epithelial cells induces accumulation of DNA damage and nephronophthisis. Kidney Int 95, 846-58.

Kaiser, R.W.J., Ignarski, M., Van Nostrand, E.L., Frese, C.K., Jain, M., Cukoski, S., Heinen, H., Schaechter, M., Seufert, L., Bunte, K., Frommolt, P., Keller, P., Helm, M., Bohl, K., Hohne, M., Schermer, B., Benzing, T., Hopker, K., Dieterich, C., Yeo, G.W., Muller, R.U., and Fabretti, F. (2019). A protein-RNA interaction atlas of the ribosome biogenesis factor AATF. Sci Rep 9, 11071.

Mohr, J., Voggel, J., Vohlen, C., Dinger, K., Dafinger, C., Fink, G., Gobel, H., Liebau, M.C., Dotsch, J., and Alejandre Alcazar, M.A. (2019). IL-6/Smad2 signaling mediates acute kidney injury and regeneration in a murine model of neonatal hyperoxia. FASEB J 33, 5887-902.

Muller, R.U., and Schermer, B. (2019). Hippo signaling-a central player in cystic kidney disease? Pediatr Nephrol10.1007/s00467-019-04299-3.

Spath, M.R., Bartram, M.P., Palacio-Escat, N., Hoyer, K.J.R., Debes, C., Demir, F., Schroeter, C.B., Mandel, A.M., Grundmann, F., Ciarimboli, G., Beyer, A., Kizhakkedathu, J.N., Brodesser, S., Gobel, H., Becker, J.U., Benzing, T., Schermer, B., Hohne, M., Burst, V., Saez-Rodriguez, J., Huesgen, P.F., Muller, R.U., and Rinschen, M.M. (2019). The proteome microenvironment determines the protective effect of preconditioning in cisplatin-induced acute kidney injury. Kidney Int 95, 333-49.

Burgmaier K, Kunzmann K, Ariceta G, Bergmann C, Buescher AK, Burgmaier M, Dursun I, Duzova A, Eid L, Erger F, Feldkoetter M, Galiano M, Gessner M, Goebel H, Gokce I, Haffner D, Hooman N, Hoppe B, Jankauskiene A, Klaus G, Konig J, Litwin M, Massella L, Mekahli D, Melek E, Mir S, Pape L, Prikhodina L, Ranchin B, Schild R, Seeman T, Sever L, Shroff R, Soliman NA, Stabouli S, Stanczyk M, Tabel Y, Taranta-Janusz K, Testa S, Thumfart J, Topaloglu R, Weber LT, Wicher D, Wuhl E, Wygoda S, Yilmaz A, Zachwieja K, Zagozdzon I, Zerres K, Group ES, Group GPNS, Dotsch J, Schaefer F, Liebau MC, and consortium AR (2018). Risk Factors for Early Dialysis Dependency in Autosomal Recessive Polycystic Kidney Disease. J Pediatr 10.1016/j.jpeds.2018.03.052.

Dafinger C, Rinschen MM, Borgal L, Ehrenberg C, Basten SG, Franke M, Hohne M, Rauh M, Gobel H, Bloch W, Wunderlich FT, Peters DJM, Tasche D, Mishra T, Habbig S, Dotsch J, Muller RU, Bruning JC, Persigehl T, Giles RH, Benzing T, Schermer B, and Liebau MC (2018). Targeted deletion of the AAA-ATPase Ruvbl1 in mice disrupts ciliary integrity and causes renal disease and hydrocephalus. Exp Mol Med 50, 75.

Fazeli W, Becker K, Herkenrath P, Duchting C, Korber F, Landgraf P, Nurnberg P, Altmuller J, Thiele H, Koy A, Liebau MC, Simon T, Dotsch J, and Cirak S (2018). Dominant SCN2A Mutation Causes Familial Episodic Ataxia and Impairment of Speech Development. Neuropediatrics 10.1055/s-0038-1668141.

Gimpel C, Avni FE, Bergmann C, Cetiner M, Habbig S, Haffner D, Konig J, Konrad M, Liebau MC, Pape L, Rellensmann G, Titieni A, von Kaisenberg C, Weber S, Winyard PJD, and Schaefer F (2018). Perinatal Diagnosis, Management, and Follow-up of Cystic Renal Diseases: A Clinical Practice Recommendation With Systematic Literature Reviews. JAMA Pediatr 172, 74-86.

Hackl A, Becker JU, Korner LM, Ehren R, Habbig S, Nusken E, Nusken KD, Ebner K, Liebau MC, Muller C, Pohl M, and Weber LT (2018). Mycophenolate mofetil following glucocorticoid treatment in Henoch-Schonlein purpura nephritis: the role of early initiation and therapeutic drug monitoring. Pediatr Nephrol 33, 619-629.

Hohne M, Frese CK, Grahammer F, Dafinger C, Ciarimboli G, Butt L, Binz J, Hackl MJ, Rahmatollahi M, Kann M, Schneider S, Altintas MM, Schermer B, Reinheckel T, Gobel H, Reiser J, Huber TB, Kramann R, Seeger-Nukpezah T, Liebau MC, Beck BB, Benzing T, Beyer A, and Rinschen MM (2018). Single-nephron proteomes connect morphology and function in proteinuric kidney disease. Kidney Int 93, 1308-1319.

Janssens P, Weydert C, De Rechter S, Wissing KM, Liebau MC, and Mekahli D (2018). Expanding the role of vasopressin antagonism in polycystic kidney diseases: From adults to children? Pediatr Nephrol 33, 395-408.

 

Bartram MP, Habbig S, Pahmeyer C, Hohne M, Weber LT, Thiele H, Altmuller J, Kottoor N, Wenzel A, Krueger M, Schermer B, Benzing T, Rinschen MM, and Beck BB (2016). Three-layered proteomic characterization of a novel actn4 mutation unravels its pathogenic potential in fsgs. Hum Mol Genet 25, 1152-1164.

De Rechter S, Kringen J, Janssens P, Liebau MC, Devriendt K, Levtchenko E, Bergmann C, Jouret F, Bammens B, Borry P, Schaefer F, and Mekahli D (2017a). Caregivers' Attitude Towards Family Planning and Timing of Diagnosis in Autosomal Dominant Polycystic Kidney Disease. Pediatric Nephrology 32, 1757-8.

De Rechter S, Kringen J, Janssens P, Liebau MC, Devriendt K, Levtchenko E, Bergmann C, Jouret F, Bammens B, Borry P, Schaefer F, and Mekahli D (2017b). Clinicians' attitude towards family planning and timing of diagnosis in autosomal dominant polycystic kidney disease. PLoS One 12, e0185779.

Ebner K, and Liebau MC (2017). [No general treatment recommendation for nephrectomy in prenatal suspicion of ARPKD]. Urologe A 56, 1465-6.

Ebner K, Dafinger C, Ortiz-Bruechle N, Koerber F, Schermer B, Benzing T, Dotsch J, Zerres K, Weber LT, Beck BB, and Liebau MC (2017a). Challenges in establishing genotype-phenotype correlations in ARPKD: case report on a toddler with two severe PKHD1 mutations. Pediatr Nephrol 32, 1269-73.

Ebner K, Feldkoetter M, Ariceta G, Bergmann C, Buettner R, Doyon A, Dursun I, Duzova A, Galiano M, Gessner M, Goebel H, Goekce I, Haffner D, Hero B, Hoppe B, Illig T, Jankauskiene A, Klopp N, Konig J, Kunzmann K, Litwin M, Massella L, Mekahli D, Melek E, Miklaszewska M, Ranchin B, Sander A, Shroff R, Testa S, Weber LT, Wicher D, Yuzbasioglu A, Zachwieja K, Zerres K, Dotsch J, Schaefer F, and Liebau MC (2017b). Characterization of Potential Risk Markers of the Renal Arpkd Phenotype. Pediatric Nephrology 32, 1768-9.

Ebner K, Reintjes N, Feldkotter M, Korber F, Nagel M, Dotsch J, Hoppe B, Weber LT, Beck BB, and Liebau MC (2017c). A case report on the exceptional coincidence of two inherited renal disorders: ADPKD and Alport syndrome. Clin Nephrol 10.5414/CN109123.

Ebner K, Schaefer F, Liebau MC, and Consortium AR (2017d). Recent Progress of the ARegPKD Registry Study on Autosomal Recessive Polycystic Kidney Disease. Front Pediatr 5, 18.

Eich G, Bartosova M, Tischer C, Wlodkowski TT, Schaefer B, Pichl S, Kraewer N, Ranchin B, Vondrak K, Liebau MC, Hackert T, and Schmitt CP (2017). Bicarbonate buffered peritoneal dialysis fluid upregulates angiopoietin-1 and promotes vessel maturation. PLoS One 12, e0189903.

Gimpel C, Avni FE, Bergmann C, Cetiner M, Habbig S, Haffner D, Konig J, Konrad M, Liebau MC, Pape L, Rellensmann G, Titieni A, von Kaisenberg C, Weber S, Winyard PJD, and Schaefer F (2017). Perinatal Diagnosis, Management, and Follow-up of Cystic Renal Diseases: A Clinical Practice Recommendation With Systematic Literature Reviews. JAMA Pediatr 10.1001/jamapediatrics.2017.3938.

Hackl A, Becker JU, Korner LM, Ehren R, Habbig S, Nusken E, Nusken KD, Ebner K, Liebau MC, Muller C, Pohl M, and Weber LT (2017a). Mycophenolate mofetil following glucocorticoid treatment in Henoch-Schonlein purpura nephritis: the role of early initiation and therapeutic drug monitoring. Pediatr Nephrol 10.1007/s00467-017-3846-6.

Hackl A, Cseprekal O, Gessner M, Liebau MC, Habbig S, Ehren R, Muller C, Taylan C, Dotsch J, and Weber LT (2016). Mycophenolate mofetil therapy in children with idiopathic nephrotic syndrome: Does therapeutic drug monitoring make a difference? Ther Drug Monit 38, 274-279.

Hackl A, Mehler K, Gottschalk I, Vierzig A, Eydam M, Hauke J, Beck BB, Liebau MC, Ensenauer R, Weber LT, and Habbig S (2017b). Disorders of fatty acid oxidation and autosomal recessive polycystic kidney disease-different clinical entities and comparable perinatal renal abnormalities. Pediatr Nephrol 32, 791-800.

Janssens P, Weydert C, De Rechter S, Wissing KM, Liebau MC, and Mekahli D (2017). Expanding the role of vasopressin antagonism in polycystic kidney diseases: From adults to children? Pediatr Nephrol 10.1007/s00467-017-3672-x.

Lechner F, and Liebau MC (2017). Nephrological Laboratory Diagnostics Parameters, Timing and Methods. Monatsschrift Kinderheilkunde 165, 581-7.

Liebau MC, and Muller RU (2017). Kidney Week 2016 News about Cystic Kidney. Nephrologe 12, 45-8.

Liebau MC, and Weber LT (2017). Proteinuria in childhood. Diagnostic and therapeutic approach. Monatsschrift Kinderheilkunde 165, 727-35.

Loos S, Aulbert W, Hoppe B, Ahlenstiel-Grunow T, Kranz B, Wahl C, Staude H, Humberg A, Benz K, Krause M, Pohl M, Liebau MC, Schild R, Lemke J, Beringer O, Muller D, Hartel C, Wigger M, Vester U, Konrad M, Haffner D, Pape L, Oh J, and Kemper MJ (2017). Intermediate Follow-up of Pediatric Patients With Hemolytic Uremic Syndrome During the 2011 Outbreak Caused by E. coli O104:H4. Clin Infect Dis 64, 1637-43.

van den Bruck R, Weil PP, Ziegenhals T, Schreiner P, Juranek S, Godde D, Vogel S, Schuster F, Orth V, Dorner J, Pembaur D, Roper M, Storkel S, Zirngibl H, Wirth S, Jenke ACW, Postberg J, Boy N, Heringer J, Haege G, Glahn EM, Hoffmann GF, Garbade SF, Burgard P, Kolker S, Chao CM, Yahya F, Moiseenko A, Shrestha A, Ahmadvand N, Quantius J, Wilhelm J, El-Agha E, Zimmer KP, Bellusci S, Staufner C, Kolker S, Prokisch H, Hoffmann GF, Seeliger S, Muller M, Hippe A, Steinkraus H, Wauer R, Lachmann B, Hofmann SR, Hedrich CM, Zierk J, Arzideh F, Haeckel R, Rascher W, Rauh M, Metzler M, Thieme S, Bandola J, Richter C, Ryser M, Jamal A, Ashton MP, von Bonin M, Kuhn M, Hedrich CM, Bonifacio E, Berner R, Brenner S, Hammersen J, Has C, Naumann-Bartsch N, Stachel D, Kiritsi D, Soder S, Tardieu M, Metzler M, Bruckner-Tuderman L, Schneider H, Bohne F, Langer D, Cencic R, Eggermann T, Zechner U, Pelletier J, Zepp F, Enklaar T, Prawitt D, Pech M, Weckmann M, Heinsen FA, Franke A, Happle C, Dittrich AM, Hansen G, Fuchs O, von Mutius E, Oliver BG, Kopp MV, Paret C, Russo A, Theruvath J, Keller B, El Malki K, Lehmann N, Wingerter A, Neu MA, Aslihan GA, Wagner W, Sommer C, Pietsch T, Seidmann L, Faber J, Schreiner F, Ackermann M, Michalik M, Rother E, Bilkei-Gorzo A, Racz I, Bindila L, Lutz B, Dotsch J, Zimmer A, Woelfle J, Fischer HS, Ullrich TL, Buhrer C, Czernik C, Schmalisch G, Stein R, Hofmann SR, Hagenbuchner J, Kiechl-Kohlendorfer U, Obexer P, Ausserlechner MJ, Loges NT, Frommer AT, Wallmeier J, Omran H, Oner-Sieben S, Gimpfl M, Rozman J, Irmler M, Beckers J, De Angelis MH, Roscher A, Wolf E, Ensenauer R, Nemes K, Fruhwald M, Hasselblatt M, Siebert R, Kordes U, Kool M, Wang H, Hardy H, Refai O, Barwick KES, Zimmerman HH, Weis J, Baple EL, Crosby AH, Cirak S, Hellmuth C, Uhl O, Standl M, Heinrich J, Thiering E, Koletzko B, Blumel L, Kerl K, Picard D, Fruhwald MC, Liebau MC, Reifenberger G, Borkhardt A, Hasselblatt M, Remke M, Tews D, Wabitsch M, Fischer-Posovszky P, Westhoff MA, Nonnenmacher L, Langhans J, Schneele L, Trenkler N, and Debatin KM (2017). Abstracts of the 52nd Workshop for Pediatric Research : Frankfurt, Germany. 27-28 October 2016. Mol Cell Pediatr 4, 5.

 

Prof. Dr. Bernhard Schermer CMMC Cologne
Prof. Dr. Bernhard Schermer

Dept. II of Internal Medicine / RG location - CECAD Building

Principal Investigator C 12 Executive Board Member

+49 221 478 89030

+49 221 478 6360

Dept. II of Internal Medicine / RG location - CECAD Building

Joseph-Stelzmann-Str. 26

50931 Cologne

http://www.kidneyresearchcenter.org/52/Research/Cystic-Kidney-Diseases-and-Cilia-Biology/Cilia-Biology-and-Cystic-Kidney-Disease-%E2%80%93-Bernhard-Schermer.htm

CMMC Profile Page

Publications - Bernhard Schermer

Link to PubMed

PD Dr. Max C Liebau CMMC Cologne
PD Dr. Max C Liebau

Dept. of Children and Adolescent Medicine / RG location - CECAD Building

Co-Principal Investigator C 12

+49 221 478 4359

+49 221 478 97295

Dept. of Children and Adolescent Medicine / RG location - CECAD Building

Kerpener Straße 62

50937 Cologne

http://www.kidneyresearchcenter.org/49/Research/Cystic-Kidney-Diseases-and-Cilia-Biology/Molecular-pathogenesis-of-ARPKD-%E2%80%93-Max-Liebau.htm

CMMC Profile Page

Publications - Max C Liebau

Link to PubMed

Group Members

Lori Borgal (former PostDoc)
Martyna Brütting (technician)
Claudia Dafinger (PostDoc)
Lena Ebert (PhD candidate)
Laura Frech (MD student)
Rajesh Kumar Gandhirajan(former PostDoc)
Sophie Haumann (Postdoc)
Priyanka Kohli (PhD candidate)
Amrei Mandel (MD student)
Lea Münkner (MD student)
Lukas Schlößer (MD student)
Felix Seelemeyer (MD student)
Gisela Slaats (PostDoc)
Benedikt Walla (MD student)