Ruprecht-Karls-Universität Heidelberg
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Hecker_Wagner0118 - Scientist (f/m) / PhD position
Project no:

Project leader:

Project supervisor:
Hecker, Markus
Application deadline:
15. Nov 2018
Start of PhD project:
1. Jan 2019

Project description:

The role of lipid hydroperoxide-induced ferroptosis in diabetic nephropathy
Recent results from our group suggest that under conditions of a diabetic metabolic state pro-inflammatory cytokines released from dysfunctional glomerular endothelial cells cause downregulation of glutathione peroxidase-4 (GPx-4) on the protein level. GPx-4, one of the most important ROS-scavenging selenoproteins, is a unique antioxidant enzyme that can directly reduce phospholipid hydroperoxides in the adjacent podocytes. Since no other glutathione peroxidise, such asGPx-1 (1), can effectively detoxify these reactive lipids, the resulting lipid hydroperoxide stress may trigger ferroptosis (2) in podocytes, ultimately leading to podocyte loss, a hallmark of diabetic nephropathy. In fact, in patients with type 1 and in particular type 2 diabetes, GPx-4 abundance is decreased in both podocytes and tubular epithelial cells (3). The main objective of the proposed project is to induce diabetes in podocyte-specific conditional GPx-4 knockout mice by streptozotocin treatment and to study the consequences of a drastically reduced antioxidative capacity for podocyte function and survival. Furthermore it is planned to employ a specifically designed adeno-associated virus 2 (AAV2) delivery approach to the kidney cortex to re- or overexpress GPx-4 in these mice to establish GPx-4 as a novel therapeutic target in combatting diabetic nephropathy.
1. Sultan CS, Saackel A, Stank A, Fleming T, Fedorova M, Hoffmann R, Wade RC, Hecker M, Wagner AH. Impact of carbonylation on glutathione peroxidase-1 activity in human hyperglycemic endothelial cells. Redox Biol. 2018 Jun;16:113-122.

2. Friedmann Angeli JP et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice.
Nat Cell Biol. 2014 Dec;16(12):1180-91.

3. Wiedenmann T, Dietrich N, Fleming T, Altamura S, Deelman LE, Henning RH, Muckenthaler MU, Nawroth PP, Hammes HP, Wagner AH, Hecker M. Modulation of glutathione peroxidase activity by age-dependent carbonylation in glomeruli of diabetic mice. J Diabetes Complications. 2018 Feb;32(2):130-138.
Methods that will be used:
• Cell culture techniques (cell lines, isolation and culture of primary podocytes, co-culture models for evaluating cell-cell interactions)
• Animal models
• Protein biochemistry methods (Western blot, detection of posttranslational protein modifications, )
• high resolution mass spectrometry imaging of lipid hydroperoxides in kidney tissue, ESI-mass spectrometry of phospholipids
• Molecular biology techniques (incl. genotyping, RT-PCR for expression profiling)
• Laser capture microdissection (LCM)
• Immunohistochemistry
• Microscopy (immunofluorescence)

Cooperation partners:
Thomas Fleming (Internal Medicine I, Heidelberg), Hans-Hermann Gröne (DKFZ Heidelberg), Oliver Müller (Internal Medicine III, Kiel), Bernhard Spengler (Anorganic and Analytical Chemistry, Gießen), Nadine Volk (NCT, Heidelberg)
Personal qualifications:
• Qualified master or diploma in biology, biochemistry, pharmacy or related fields
• Advanced knowledge of biochemical, cell and molecular biological techniques as well as animal experimentation (FELASA B) or high motivation to acquire the necessary skills and certificates
• Team-minded and flexible
• Ability to rapidly familiarize him/herself with new research areas in theory and praxis
Diabetes, nephropathy, mouse models, ferroptosis, podocytes, reversed genetics, gene transfer, AAV