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PhD position in Molecular Biology - The role of DNA damage in the pathogenesis of nitrate tolerance

In the field of  “The role of DNA damage in the pathogenesis of nitrate tolerance” the research group of Prof. Andreas Daiber offers the following PhD project:

Identification of novel “redox switches” in Epigenetic and DNA repair pathways

High levels of reactive oxygen species (ROS) lead to oxidative stress, cellular damage and impaired physiological functions whereas low levels of ROS contribute to cellular signaling and essential physiological processes such as cell differentiation, proliferation and migration [Daiber Biochim. Biophys. Acta 2010 & Chen et al. Clinical Science 2012]. We have recently identified a vital “crosstalk” between different sources of ROS including mitochondria and NADPH oxidase in different models of oxidative stress (nitrate tolerance, aging, hypertension and MnSOD-deficiency) with clinical relevance for vascular function [Wenzel et al. Antioxid. Redox Signal. 2008 & Kröller-Schön and Steven et al. Antioxid. Redox Signal. 2013]. These detrimental effects of the interaction of mitochondria with NADPH oxidase via mitochondrial and cytosolic ROS on vascular function were mainly based on adverse regulation of endothelial nitric oxide synthase (eNOS) by redox-sensitive pathways, so-called “redox switches” in the enzyme [Kröller-Schön and Oelze et al. Diabetes 2011 & Schulz et al. Antioxid. Redox Signal. 2012].
With the present proposal we suggest to use animal models with reduced or increased ROS formation (p47phox-/- and Cu,Zn-SOD-/- mice) along with a clinically relevant oxidative stress challenge (pharmacologically-induced hypertension) in order to identify novel “redox switches” in epigenetic and DNA repair pathways. Relevant endpoints to identify redox regulation of DNA repair will include oxidized DNA lesions (8-oxoguanine by immunostaining), strand breaks (by comet assay), expression level of proteins of the DNA repair pathway (AMT, PARP, OGG1 and NEIL1 by RT-PCR and Western blotting) along with specific inhibitors for some of these proteins. Relevant strategies to identify the impact of epigenetic pathways on hypertensive phenotype (e.g. blood pressure, vascular function, oxidative stress parameters) will include treatment with the DNA methyltransferase (DNMT) inhibitor zebularine as well as histone deacetylase (HDAC) inhibitors leading to histone hypomethylation and hyperacetylation (e.g. can rescue MnSOD expression but also increases Nox2 and Duox1/2 expression) [Cyr et al. Antioxid. Redox Signal. 2013 & Hayes and Knaus, Antioxid. Redox Signal. 2013]. Targets of ROS in epigenetic pathways will be identified by determination of prominent footprints of epigenetic regulation such as H3K4me and H3K9ac marks (in collaboration with Dr. George Reid, IMB), activity of sirtuins (initially and later also other redox-sensitive HDACs) in the different animal models with high and low burden of oxidative stress. In conclusion, the present study aims at the identification of new therapeutic targets in the epigenetic and DNA repair machinery for potential translation into clinical use for the treatment of hypertension.

We offer
•    The possibility to work on a cutting-edge project using state-of-the-art technology in a highly motivated research team
•    A stimulating, diverse and international research environment
•    Advanced training opportunities
•    A competitive stipend

Required qualifications
•    Master or Diploma
•    Motivation to solve complex biological problems
•    Excellent communication skills

Starting date: October 2015 or later
Duration of stipend: 3 years, with the possibility of extension
Deadline for registration (exclusively online via web form):  20 June 2015

How to apply:
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Über Institute of Molecular Biology gGmbH

Our International PhD Programme on the “Gene Regulation, Epigenetics and DNA Damage Response” gives talented and enthusiastic students the opportunity to undertake PhD research at the cutting edge of modern biology. Our groups cover a broad range of expertise and include leading biochemists, geneticists, cell and developmental biologists who study the molecular mechanisms of...

Mehr über die Institute of Molecular Biology gGmbH

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