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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?
- 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.
- 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: 213-25, 2015.
- Kather JN, Friedrich J, Woik N, Sticht C, Gretz N, Hammes HP, Kroll J. Angiopoietin-1 is regulated by miR-204 and contributes to corneal neovascularization in KLEIP-deficient mice. Invest Ophthalmol Vis Sci. 55: 4295-303, 2014.
- Woik N, Dietz CT, Schäker K, Kroll J. Kelch-like ECT2-interacting protein KLEIP regulates late-stage pulmonary maturation via Hif-2a in mice. Dis Model Mech. 7: 683-92, 2014.
- Hollenbach M, Stoll SJ, Jörgens K, Seufferlein T, Kroll J. Different regulation of physiological and tumor angiogenesis in zebrafish by protein kinase D1 (PKD1). PLoS One. 8:e68033, 2013.
- Stoll SJ, Bartsch S, Kroll J. Hoxc9 regulates formation of parachordal lymphangioplasts and the thoracic duct in zebrafish via stabilin 2. PLoS One. 8:e58311, 2013.
- Hahn N, Dietz CT, Kühl S, Voßmerbäumer U, Kroll J. KLEIP deficiency in mice causes progressive corneal neovascular dystrophy. Investigative Ophthalmology & Visual Science 53: 3260-3268, 2012.
- Stoll SJ, Bartsch S, Augustin HG, and Kroll J. The transcription factor HOXC9 regulates endothelial cell quiescence and vascular morphogenesis in zebrafish via inhibition of interleukin 8. Circ Res 108: 1367-1377, 2011.
- Epting D, Wendik B, Bennewitz K, Dietz CT, Driever W, Kroll J . The Rac1 regulator ELMO1 controls vascular morphogenesis in zebrafish. Circ Res 107: 45-55, 2010.
- Nacak TG, Alajati A, Leptien K, Fulda C, Weber H, Miki T, Czepluch FS, Waltenberger J, Wieland T, Augustin HG, Kroll J. The BTB-kelch protein KLEIP controls endothelial migration and sprouting angiogenesis. Circ Res 100: 1155-63, 2007.
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