Ruprecht-Karls-Universität Heidelberg
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Hoeglinger0217 - Scientist (f/m) / PhD position
Project no:
Hoeglinger0217

Project leader:

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

Project description:

Title:
The role of membrane contact sites in lipid transport
Summary:
Throughout evolution, eukaryotic cells have compartmentalized more and more crucial functions into specialized organelles. This led however to a greater need for efficient organellar communication and exchange of material between organelles. Such exchange of signals and molecules is greatly facilitated by membrane contact sites (MCS) which are defined as places inside cells where membranes of different organelles are in close proximity (<30nm) without ever fusing. Recent research has uncovered many proteins responsible for forming and maintaining contacts and identified signalling pathways relying on such close contacts. Our group is especially interested in the MCS between the endoplasmic reticulum and the late endocytic compartments (late endosomes and lysosomes) and their role in lipid transport. Disruption of these type of processes can lead to lysosomal storage diseases (such as Niemann-Pick disease type C (NPC)) which are characterized by an accumulation of lipids in late endosomes and lysosomes and manifest in severe and often neurodegenerative symptoms. In this project, we will use knock-down of lipid metabolizing enzymes as well as NPC patient cells to simulate those pathologies. We will then endeavour to alleviate lipid accumulation by manipulating the MCS rate of occurrence, length and stability via chemical biology approaches such as genetically-encoded and chemically inducible artificial tethers and novel lipid probes developed in our lab. Using a combination of lipid biochemistry and molecular biology methods, we aim to dissect the function of the disease-causing NPC1 protein.
References:
M.J. Phillips, G.K. Voeltz, Structure and function of ER membrane contact sites with other organelles, Nat. Rev. Mol. Cell Biol., 17 (2015) 1–14.

W.M. Henne, Organelle remodeling at membrane contact sites, J. Struct. Biol., 196 (2016) 15–19.

D. Höglinger, A. Nadler, P. Haberkant, J. Kirkpatrick, M. Schifferer, F. Stein, S. Hauke, F.D. Porter, C. Schultz, Trifunctional lipid probes for comprehensive studies of single lipid species in living cells, Proc. Natl. Acad. Sci. U. S. A., 114 (2017) 1566–1571.
Methods that will be used:
Within this project you will use molecular biology techniques to design and apply new, chemically inducible tethers between the ER and lysosomes (as well as other organelles) and validate them using live-cell fluorescence microscopy or electron microscopy (in collaboration). Functional validation will be performed using lipid biochemistry approaches such as thin-layer chromatography and high-pressure liquid chromatography. Working in a chemical biology lab, you will also have access to specifically designed lipid probes for directly monitoring lipid transport in intact cells.
Cooperation partners:
Emily Eden (University College London, UK), Fran Platt (University of Oxford, UK)
Personal qualifications:
We are seeking a highly motivated scientist with a strong background in molecular biology or biochemistry. You should be able to perform experiments independently and troubleshoot as required. Previous experience in live-cell microscopy is an asset, but not essential. Excellent written and spoken English skills are required.
Keywords:
Organelle communication, lysosomal storage disorders, lipid transport, membrane contact sites, chemical biology