DFG Research Training Group "TJ-Train" (GRK 2318)
Background: The kidney’s collecting duct system consists of epithelial tubules that connect the nephron to the renal pelvis. It consists of two major epithelial cell types, principal cells (making up the major portion of cells) and intercalated cells (interspersed between rosettes of principal cells). Together, these cells participate in central physiological processes, including osmoregulation, blood pressure control, and acid-base homeostasis.
In contrast to most other epithelia in the kidney, collecting ducts are made up of a tight epithelium, exhibiting a high transepithelial resistance. The tight barrier characteristics of the collecting duct relate to its unique molecular composition of the tight junction. The molecular mechanisms of tight junction assembly in the collecting duct are of fundamental importance for our understanding of normal kidney function and kidney diseases. Previous studies of our group have focused on transcription factors in the control of epithelial function and tight junction biogenesis.
Recently, we have identified a series of novel candidate transcriptional regulators of tight junction biogenesis in the collecting duct. The two proposed thesis projects are based on the hypothesis that these transcription factors, individually or in combination, regulate the expression of collecting duct-specific tight junction components thereby controlling epithelial barrier characteristics relevant for normal kidney function and kidney diseases.
PhD thesis project: The project aims for a systematic and comprehensive analysis of transcription factor function in the collecting duct. This will include the generation of individual and combinatorial transcription factor knockouts in cultured collecting duct cells using gene editing technology, and a detailed analysis of the phenotypic effects, including gene expression control, epithelial structure and function. Methods include next generation sequencing techniques (RNA-seq, CHiP-seq), advanced imaging techniques, and a wide spectrum of molecular, cellular and developmental biology assays using different model systems available with our consortium. In parallel, novel model systems will be developed to study transcription factor function in vivo.
MD thesis project: The project aims to provide a correlation of transcription factor and target gene expression in the normal and diseased human kidney. For this purpose, normal and diseased tissues will be stained using specific antibodies targeting transcription factors, proteins encoded by their target genes, and nephron segment-specific anchor proteins. The project will be carried out in close coordination with the above PhD project.
PhD doctoral student
MD doctoral student
Xu K, Rosenstiel P, Paragas N, Hinze C, Gao X, Huai Shen T, Werth M, Forster C, Deng R, Bruck E, Boles RW, Tornato A, Gopal T, Jones M, Konig J, Stauber J, D'Agati V, Erdjument-Bromage H, Saggi S, Wagener G, Schmidt-Ott KM, Tatonetti N, Tempst P, Oliver JA, Guarnieri P, Barasch J (2016) Unique transcriptional programs identify subtypes of AKI. J. Am. Soc. Nephrol. 28: 1729-1740.
Aue A*, Hinze C* (*shared first authorship), Walentin K, Ruffert, Yurtdas Y, Werth M, Chen W, Rabien A, Kilic E, Schulzke JD, Schumann M, Schmidt-Ott KM (2015) A grainyhead-like 2/ovo-like 2 pathway regulates renal epithelial barrier function and lumen expansion.
Walentin K, Hinze C, Werth M, Haase N, Varma S, Morell R, Aue A, Pötschke E, Warburton D, Qiu A, Barasch J, Purfürst B, Dieterich C, Popova E, Bader M, Dechend R, Staff AC, Yurtdas ZY, Kilic E, Schmidt-Ott KM (2015) A Grhl2-dependent gene network controls trophoblast branching morphogenesis.
Paragas N*, Kulkarni R*, Werth M*, Schmidt-Ott KM* (*shared first authorship), Forster C, Deng R, Zhang Q, Singer E, Klose AD, Shen TH, Francis KP, Ray S, Vijayakumar S, Seward S, Bovino ME, Xu K, Takabe Y, Amaral FE, Mohan S, Wax R, Corbin K, Sanna-Cherchi S, Mori K, Johnson L, Nickolas T, D'Agati V, Lin CS, Qiu A, Al-Awqati Q, Ratner AJ, Barasch J (2014) α-Intercalated cells defend the urinary system from bacterial infection.
Paragas N, Qiu A, Zhang Q, Samstein B, Deng SX, Schmidt-Ott KM, Viltard M, Yu W, Forster CS, Gong G, Liu Y, Kulkarni R, Mori K, Kalandadze A, Ratner AJ, Devarajan P, Landry DW, D'Agati V, Lin CS, Barasch J (2011) The Ngal reporter mouse detects the response of the kidney to injury in real time.
Werth M*, Walentin K* (*shared first authorship), Aue A, Schonheit J, Wuebken A, Pode-Shakked N, Vilianovitch L, Erdmann B, Dekel B, Bader M, Barasch J, Rosenbauser F, Luft FC, Schmidt-Ott KM (2010) The transcription factor grainyhead-like 2 (Grhl2) regulates the molecular composition of the epithelial apical junctional complex.
Li JY, Paragas N, Ned RM, Qiu A, Viltard M, Leete T, Drexler IR, Chen X, Sanna-Cherchi S, Mohammed F, Williams D, Lin CS, Schmidt-Ott KM, Andrews NC, Barasch J (2009) Scara5 is a ferritin receptor mediating non-transferrin iron delivery.
Lu BC, Cebrian C, Chi X, Kuure S, Kuo R, Bates CM, Arber S, Hassell J, Macneil L, Hoshi M, Jain S, Asai N, Takahashi M, Schmidt-Ott KM, Barasch J, D'Agati V, Costantini F (2009) Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis.
Schmidt-Ott KM, Masckauchan TN, Chen X, Hirsh BJ, Sarkar A, Yang J, Paragas N, Wallace VA, Dufort D, Pavlidis P, Jagla B, Kitajewski J, Barasch J (2007) β-catenin/TCF/Lef controls a differentiation-associated transcriptional program in renal epithelial progenitors.
Schmidt-Ott KM, Yang J, Chen X, Wang H, Paragas N, Mori K, Li JY, Schiffer M, Bottinger E, Barasch J (2005) Novel regulators of kidney