Ruprecht-Karls-Universität Heidelberg
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Zemva_Nawroth0118 - Scientist (f/m) / PhD position
Project no:
Zemva_Nawroth0118

Project leader:

Project supervisor:
Zemva, Johanna
Nawroth, Peter
Application deadline:
31. Aug 2018
Start of PhD project:
1. Oct 2018

Project description:

Title:
Mechanisms and function of methyglyoxal induced hormesis for the development of diabetic late complications
Summary:
Hormetic effects, meaning that low levels of a toxic substance can have positive effects on an organism, have been proven for a variety of substances, including radiation or reactive oxygen species (ROS). Lately, we were able to show that the reactive dicarbonyl methylglyoxal (MG), which is formed non-enzymatically during glycolysis, can also exert a hormetic response leading to increased resistance towards toxic levels of MG but also ROS. This increased resistance is achieved by up-regulation of detoxifying enzymes but also of the protein quality control system, including heatshock protein 70 (Hsp70). Pharmacological induction of Hsp70 in diabetic mice leads to reduction of hyposensitivity in case of diabetic neuropathy. Furthermore, we found that Hsp70 expression levels are reduced in patients with diabetic nephropathy. This project will aim to understand the function of Hsp70, as part of MG-hormesis, in handling of MG-modified proteins in vitro and in vivo in the context of diabetic nephropathy.
References:
Zemva J, Pfaff D, Groener JB, Fleming T, Herzig S, Teleman A, Nawroth PP, Tyedmers J (2018) Effects of the Reactive Metabolite Methylglyoxal on Cellular Signalling, Insulin Action and Metabolism – What We Know in Mammals and What We Can Learn From Yeast. Exp Clin Endocrinol Diabetes. doi: 10.1055/s-0043-122382. [Epub ahead of print]

Zemva J, Fink CA, Fleming TH, Schmidt L, Loft A, Herzig S, Knieß RA, Mayer M, Bukau B, Nawroth PP, Tyedmers J (2017) Hormesis enables cells to handle accumulating toxic metabolites during increased energy flux. Redox Biol 13:674-686.

Groener JB, Oikonomou D, Cheko R, Kender Z, Zemva J, Kihm L, Muckenthaler M, Peters V, Fleming T, Kopf S, Nawroth PP (2017) Methylglyoxal and Advanced Glycation End Products in Patients with Diabetes - What We Know so Far and the Missing Links. Exp Clin Endocrinol Diabetes doi: 10.1055/s-0043-106443. [Epub ahead of print]
Methods that will be used:
Biochemical analysis of post-translational modifications associated with reactive metabolites, chaperone biochemistry, molecular biology, genomics and proteomics, fluorescence microscopy, (immuno-)histochemistry, cell culture based methods and mouse handling.
Cooperation partners:
The project is part of the CRC 1118, with close collaborations within the clinic (Nawroth/Fleming lab), DKFZ (Gröne lab, Teleman lab), ZMBH (Tyedmers lab, Bukau lab) and the Helmholtz Diabetes Centre (Herzig lab).
Personal qualifications:
We are looking for a highly motivated PhD student (m/f) with a keen interest in diabetes research and regenerative medicine, in an environment that truly thinks and works from bench to bedside. Previous experience in working with cell culture and molecular biology techniques would be an advantage. The candidate should be comfortable to work in young team of international researchers with both medical and biochemical background. Due to the collaborative nature of the project, excellent communication skills and working efficiently both independently and as part of a team are required.
Keywords:
Hormesis, reactive metabolites, post-translational modifications, molecular chaperones, Hsp70, diabetes