Ruprecht-Karls-Universität Heidelberg
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Hoeglinger0117 - Scientist (f/m) / PhD position
Project no:
Hoeglinger0117

Project leader:

Project supervisor:
Höglinger, Doris
Application deadline:
18. Jul 2017
Start of PhD project:
1. Sep 2017

Project description:

Title:
Novel probes for studying lipid-mediated cellular processes
Summary:
Working on the interface of chemistry and cell biology, we will design and synthesize new lipid probes, which will expand our limited knowledge of the roles of lipid at the cellular level. Lipids are crucial for the functioning of all organisms and any malfunction of lipid metabolism or transport lead to devastating, often neurodegenerative diseases. However, the lack of tools which allow us to investigate the function of lipids in their native environment has been hindering research. This project will focus on designing a suite of novel lipid probes based on the trifunctional lipid principle (c.f. Reference 1) which are equipped with photo-reactive groups that enable us to release and track lipids within intact cells. In a second phase, these probes will be applied to different eukaryotic models including human patient cells and primary mouse fibroblasts to first describe the localisation of the lipids in these cells. We will then investigate questions regarding lipid metabolism and intra-cell dynamics as well as their disruption in diseases and also aim to identify new lipid-binding or lipid-trafficking proteins.
References:
Höglinger D., Nadler A., Haberkant P., Kirkpatrick J., Schifferer M., Stein F., Hauke S., Porter F.D., Schultz C. (2017). Trifunctional lipid probes for comprehensive studies of single lipid species in living cells. Proc Natl Acad Sci U S A 114(4), 1566-1571

Haberkant P., Stein F., Höglinger D., Gerl M.J., Brügger B., Van Veldhoven P.P., Krijgsveld J., Gavin A.C., Schultz C. (2016) Bifunctional Sphingosine for Cell-Based Analysis of Protein-Sphingolipid Interactions. ACS Chem Biol 11(1), 222-230, doi: 10.1021/acschembio.5b00810

Höglinger D., Haberkant P., Aguilera-Romero A., Riezman H., Porter F.D., Platt F.M., Galione A., Schultz C. (2015). Intracellular sphingosine releases calcium from lysosomes. ELife doi:10.7554/eLife.10616

Höglinger D., Nadler A., Schultz C. (2014). Caged lipids as tools for investigating cellular signalling. Biochim Biophys Acta 1841(8), 1085-96
Methods that will be used:
You will be using a wide variety of methods starting with chemical synthesis, chromatographic purification and compound characterization by nuclear magnetic resonance and mass spectrometry. The synthesized lipid probes will then be used to monitor lipid metabolism using thin-layer chromatography and lipid mass spectrometry (in collaboration). To identify protein-lipid interactions, we will photo-crosslink the lipid probes, modify them using click chemistry and perform proteomic screens via Mass Spectrometry. The candidate proteins will then be validated using various biochemical characterisation techniques such as Western Blot, pull down experiments as well as live-cell microscopy assays.
Cooperation partners:
Britta Brügger (BZH Heidelberg), Fran Platt (University of Oxford, UK), Sarah Spiegel (Virginia Commonwealth University, USA)
Personal qualifications:
We are looking for a highly motivated candidate with a strong background and practical experience in chemical synthesis and characterization. The design and optimization of these novel tools will require strong skills in experimental design and troubleshooting as well as an ability to work independently. Interest in molecular and cell biology is required, and previous hands-on experience would be an asset. Excellent written and spoken English skills are essential.
Keywords:
Lipid biochemistry, signal transduction, chemical synthesis, protein-lipid interaction