Ruprecht-Karls-Universität Heidelberg
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Peters0118 - Scientist (f/m) / PhD position
Project no:
Peters0118

Project leader:

Project supervisor:
Peters, Verena
Application deadline:
30. Sep 2018
Start of PhD project:
1. Nov 2018

Project description:

Title:
The role of Carnosinase 2 in Diabetic Nephropathy
Summary:
Diabetic nephropathy (DN) is a major complication in patients with type 1 and type 2 diabetes and represents the leading cause of end-stage renal disease. Current therapeutic options only slightly retard progression but do not prevent the development of DN. A variant in the carnosinase 1 (CNDP1) gene is associated with lower carnosine degradation and significant DN risk reduction, despite unchanged circulating carnosine concentrations. In diabetic rodents, which do not have a serum carnosinase, carnosine supplementation reduces diabetes associated metabolic stress and preserves renal function. We now have established a kidney specific CNDP1 knockout mouse model to analyse the specific impact of renal carnosine metabolism in DN and under MG stress.
CNDP2 variants are also associated with DN risk reduction and with slower disease progression; the metabolic function of the enzyme (CN2) is still unclear. We therefore established renal cells with functional CNDP2-knockout by CRISP/Cas. Characterization of the CN2 metabolism under diabetic conditions by means of metabolomics and establishing a CNDP2-knockout mouse and its biochemical and functional characterization are the major aims of the current project.
References:
Qiu J et al. Identification and characterisation of carnostatine (SAN9812), a potent and selective carnosinase (CN1) inhibitor with in vivo activity. Amino Acids. 2018 [Epub ahead of print]

Peters V, Zschocke J, Schmitt CP. Carnosinase, diabetes mellitus and the potential relevance of carnosinase deficiency. J Inherit Metab Dis 2018 41(1):39-47

Weigand T et al. Carnosine Catalyzes the Formation of the Oligo/Polymeric Products of Methylglyoxal. Cell Physiol Biochem. 2018;46(2):713-726

Peters V et al. Allosteric inhibition of carnosinase (CN1) by inducing a conformational shift. J Enzyme Inhib Med Chem. 2017;32(1):1102-1110

Peters V et al. Intrinsic carnosine metabolism in the human kidney. Amino Acids. 2015b;47(12):2541-50.

Peters V et al. Carnosine metabolism in diabetes is altered by reactive metabolites. Amino Acids. 2015;47(11):2367-76
Methods that will be used:
Metabolomics, CRISP/Cas knockdown, biochemical analysis of post-translational modifications associated with reactive metabolites, molecular biology, fluorescence microscopy, (immuno-)histochemistry, cell culture based methods and mouse handling
Cooperation partners:
The project is part of the Sonderforschungsbereich (SFB) 1118, with close collaborations within the Clinic (Prof Nawroth/Dr Fleming), Institut für Physiologie und Pathophysiologie (Prof Hecker/PD Dr Wagner), the Institute of Pharmacology (Prof Freichel) and other members of SFB 1118.
Personal qualifications:
We are looking for a highly motivated PhD student (m/f) with a keen interest in diabetes research. Previous experience in working with cell culture, molecular biology techniques and mouse handling 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:
Diabetes, Diabetic nephropathy, Carnosinase 1, Carnosinase 2, reactive metabolites, oxidative stress response, metabolomics, Crisp/Cas knockdown