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During the last decades the development and function have blood vessels has been intensively studied and several fundamental biochemical, molecular and cellular mechanisms have been identified. In addition to several established cell culture systems, animal model systems including mice, rat and zebrafish, have served as a basis to understand fundamental processes of vascular development and vascular function in vivo. Yet, mechanisms leading to a diseased vasculature under pathological conditions, such as in diabetes mellitus, and how these alterations contribute to development of diabetic late complications are less understood. Thus, our work aims to identify and characterize diabetes induced vascular complications in zebrafish.
Specifically, we will address the following questions:
- Which signaling cascades are altered by hyperglycemia and by metabolic intermediates (reactive metabolites) in zebrafish?
- Which cellular and molecular alterations are induced by hyperglycemia and by reactive metabolites and how contribute these alterations to dysfunctional blood vessels, kidneys and neurons in zebrafish?
- How can the identified diabetes-induced alterations in zebrafish be prevented or regressed?
- Which significances have the identified alterations in zebrafish in the development of diabetic late complications (diabetic retinopathy, nephropathy and neuropathy) in human?
- Wiggenhauser LM, Qi H, Stoll SJ, Metzger L, Bennewitz K, Poschet G, Krenning G, Hillebrands JL, Hammes HP, Kroll J. Activation of retinal angiogenesis in hyperglycemic pdx1-/- zebrafish mutants. Diabetes, doi: 10.2337/db19-0873, 2020.
- Lodd E, Wiggenhauser LM, Morgenstern J, Fleming TH, Poschet G, Büttner M, Tabler CT, Wohlfart DP, Nawroth PP, Kroll J. The combination of loss of glyoxalase1 and obesity results in hyperglycemia. JCI insight, doi: 10.1172/jci.insight.126154, 2019.
- Schmöhl F, Peters V, Schmitt CP, Poschet G, Büttner M, Li X, Weigand T, Poth T, Volk T, Morgenstern J, Fleming T, Nawroth PP, Kroll J. CNDP1 knockout in zebrafish alters the amino acid metabolism, restrains weight gain, but does not protect from diabetic complications. Cellular and Molecular Life Sciences. doi:10.1007/s00018-019-03127, 2019.
- She J, Wu Y, Lou B, Lodd E, Klems A, Schmoehl F, Yuan Z, Noble FL, Kroll J. Genetic compensation by epob in pronephros development in epoa mutant zebrafish. Cell Cycle. doi: 10.1080/15384101.2019.1656019, 2019.
- 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.
- 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.
- 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, doi: 10.1074/jbc.M114.633701, 2015.
- 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, doi: 10.2337/db14-0352, 2015.
- Stoll SJ, Bartsch S, Augustin HG, Kroll J. The transcription factor HOXC9 regulates endothelial cell quiescence and vascular morphogenesis in zebrafish via inhibition of interleukin 8. Circ Res, doi: 10.1161/CIRCRESAHA.111.244095, 2011.
- Epting D, Wendik B, Bennewitz K, Dietz CT, Driever W, Kroll J. The Rac1 regulator ELMO1 controls vascular morphogenesis in zebrafish. Circ Res, doi: 10.1161/CIRCRESAHA.109.213983, 2010.
Prof. Dr. Jens Kroll
Working Group Vascular Signaling
Department of Vascular Biology and Tumor Angiogenesis
Center for Biomedicine and Medical Technology Mannheim (CBTM)
Medical Faculty Mannheim
Phone +49 621/383-9965