Ruprecht-Karls-Universität Heidelberg
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WielandT0117 - Scientist (f/m) / PhD position
Project no:
WielandT0117

Project leader:

Project supervisor:
Wieland, Thomas
Application deadline:
19. Sep 2017
Start of PhD project:
1. Oct 2017

Project description:

Title:
Identification of novel signaling pathways causing diabetic retinopathy
Summary:
Pericyte loss in diabetic retinopathy is caused by upregulation of angiopoietin-2 (Ang2), partly through covalent protein GlcNAcylation. Nucleoside diphosphate kinase (NDPK) supplies NTPs including UTP for glucose metabolism to generate UDP-GlcNAc. Our published data showed that expression of Ang2 and protein GlcNAcylation are modulated by NDPK. The loss of NDPK-B leads to pericyte loss in the mouse retina and thus mimicking diabetic retinopathy. Ang2 overexpression was observed not only in NDPK B knockout retinas, but also in NDPK B-depleted human umbilical vein endothelial cells and mouse retinal Müller cells isolated from NDPK B knockout mice stimulated with high glucose. The data suggest that NDPK-B is an important player contributing to diabetic retinal endothelial damage possibly through multiple mechanisms. The aim of the study is to identify novel NDPK-B-dependent signaling pathways related to the cause of diabetic retinopathy. The study will provide novel understanding of the mechanisms underlying development of diabetic vascular damage. Thus the PhD candidate will analyze the signal transduction during the development of diabetic retinopathy in transgenic mice in vivo and in cultured cells in vitro.
References:
- Brownlee M. (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54: 1615-1625.

- Hippe HJ, Wolf NM, Abu-Taha HI, Lutz S, Le Lay S, et al. (2011) Nucleoside diphosphate kinase B is required for the formation of heterotrimeric G protein containing caveolae. Naunyn Schmiedebergs Arch Pharmacol 384: 461-472.

- Feng Y, Gross S, Wolf NM, et al. (2014) Nucleoside diphosphate kinase B regulates angiogenesis through modulation of vascular endothelial growth factor receptor type 2 and endothelial adherens junction proteins. Arterioscler Thromb Vasc Biol. 2014;34:2292-300.

- Qiu Y, Zhao D, Butenschön VM, et al. (2015) Nucleoside diphosphate kinase B deficiency causes a diabetes-like vascular pathology via up-regulation of endothelial angiopoietin-2 in the retina. Acta Diabetol. 2015 Apr 23

- Zhou XB, Feng YX, Sun Q, et al. (2015) Nucleoside diphosphate kinase B-activated intermediate conductance potassium channels are critical for neointima formation in mouse carotid arteries. Arterioscler Thromb Vasc Biol. 2015:35:1852-61.

- Gross S, Devraj K, Feng Y, Macas J, Liebner S, Wieland T. Nucleoside diphosphate kinase B regulates angiogenic responses in the endothelium via caveolae formation and c-Src-mediated caveolin-1 phosphorylation. J Cereb Blood Flow Metab. 2016 Jan
Methods that will be used:
Cell culture, transfection and viral infection, Pull-down assay, qRT-PCR, Western blot, immunofluorescence, Immunoprecipitation, Elisa, diabetic animal models (already started, this part will be mainly completed in July 2017), retinal digestion, retinal morphometry
Cooperation partners:
Martina Schmidt, Molecular Pharmacology, Groningen Research Institute of Pharmacy, University of Groningen

Hans-Peter Hammes, V. Medical Department, Medical Faculty Mannheim, University of Heidelberg

Jens Kroll, Vascular Biology & Tumorangiogenesis, Medical Faculty Mannheim, University of Heidelberg

Thomas Fleming, Department of Internal Medicine, Medical Faculty Heidelberg, University of Heidelberg)
Personal qualifications:
We are looking for a highly motivated Ph.D. student who is interested in diabetic microangiopathy. She or he should have a Masters Degree in Life sciences acceptable to HBIGS and a strong background in molecular biology and/or cell biology, and strong skills in experimental design and troubleshooting. She or he must be a team player but is able to work independently. Previous experience in working with cell culture and molecular/cell biology techniques would be an advantage.
Keywords: