PhD SP09

The function of the Rac1 regulator ELMO1 in the vasculature and in renal development under high glucose in zebrafish and in human diabetic nephropathy

Supervisor (Mannheim): Jens Kroll
Co-Supervisor (Groningen): Jan-Luuk Hillebrands
Graduate: Mike Boger

Project description

Glucose-induced microangiopathy and nephropathy are diabetes-associated diseases. The Rac1 regulator ELMO1 is an important regulator of vascular development in zebrafish and polymorphisms in different regions of the human ELMO1 gene are associated with diabetes-associated nephropathy. The aim of this project is to analyze ELMO1’s function in the development of glucose-associated pathophysiological disorders in zebrafish and in diabetic patients. The project will include expression analyses in zebrafish and in diabetic patient samples; loss-of-function and gain-of-function experiments in zebrafish and biochemical studies in vitro.

References

1. Hitzel J, Lee E, Zhang Y, Bibli SI, Li X, Zukunft S, Pflüger B, Hu J, Schürmann C, Vasconez AE, Oo JA, Kratzer A, Kumar S, Rezende F, Josipovic I, Thomas D, Giral H, Schreiber Y, Geisslinger G, Fork C, Yang X, Sigala F, Romanoski CE, Kroll J, Jo H, Landmesser U, Lusis AJ, Namgaladze D, Fleming I, Leisegang MS, Zhu J, Brandes RP. Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells. Nat Commun. 12;9(1):2292. doi: 10.1038/s41467-018-04602-0, 2018.
2. She J, Yuan Z, Wu Y, Chen J, Kroll J. Targeting erythropoietin protects against proteinuria in type 2 diabetic patients and in zebrafish. Mol Metab. doi: 10.1016/j.molmet.2017.11.006, 2018.
3. Wiggenhauser LM, Kohl K, Dietrich N, Hammes HP, Kroll J. Studying diabetes through the eyes of a fish: Microdissection, visualization and analysis of the adult tg(fli:EGFP) zebrafish retinal vasculature. J Vis Exp, doi: 10.3791/56674, 2017.
4. Sharma KR, Heckler K, Stoll SJ, Hillebrands JL, Kynast K, Herpel E, Porubsky S, Elger M, Hadaschik B, Bieback K, Hammes HP, Nawroth PP, Kroll J. ELMO1 protects renal structure and ultrafiltration in kidney development and under diabetic conditions. Sci Rep. Nov 16;6:37172. doi: 10.1038/srep37172, 2016.
5. Schaeker K, Bartsch S, Patry C, Cramer-Stoll S, Hillebrands JL, Wieland T, Kroll J. The bipartite Rac1 guanine nucleotide exchange factor engulfment and cell motility 1/dedicator of cytokinesis 180 (Elmo1/Dock180) protects endothelial cells from apoptosis in blood vessel development. J Biol Chem 290: 6408- 6418, 2015.
6. Jörgens K, Stoll SJ, Pohl J, Fleming TH, Sticht C, Nawroth PP, Hammes HP, Kroll J. High tissue glucose alters intersomitic blood vessels in zebrafish via methylglyoxal targeting the VEGF receptor signalling cascade. Diabetes 64(1):213-25, 2015.

Methods used

Expression studies and functional analyses in zebrafish; Imaging of zebrafish, CRISPR/Cas mutagenesis, expression studies in human patient samples

Collaboration Partners

• Hans-Peter Hammes, Mannheim
• Harry van Goor, Groningen
• Peter Nawroth, Heidelberg
• Verena Peters and Claus Schmidt, Heidelberg
• Metabolome Core Unit Heidelberg University
• SFB1118 analytical platform