Factsheet [PDF]

Our shared research interest aims to identify and functionally characterize novel factors regulating cellular cholesterol metabolism. Our long-term goals are a better molecular understanding of hypercholesterolemia and Niemann-Pick Type C [NPC] disease with the perspectives for the development of novel diagnostic and therapeutic tools. The experimental approaches we use are [i] identification of candidate genes by disease related gene expression analyses, [ii] cell biological characterisation of candidate genes with respect to lipid metabolism and [iii] analysis of possible gene defects in patient samples.

Previous and current research
One project that we are focussing on is the identification of genes pre-disposing for elevated blood cholesterol levels [hypercholesterolemia], a major risk factor for atherosclerosis and coronary heart disease. Candidate genes with a putative role in hypercholesterolemia are first identified by microarray-based gene expression analyses in cells with different sterol load. A putative cell biological function of these candidates is then further characterized by using systematic RNAi-based gene knockdown experiments and automated microscopy. To this end we have set up at EMBL a microscope based RNAi-screening platform that allows cell-based loss-of-function studies at a high throughput. We have developed fluorescence-based assays by which cellular uptake of fluorescence-labelled low-density lipoprotein [LDL] and its dynamics can be analysed under high-throughput conditions. Within this particular part of the project, we collaborate strongly with Martina Muckenthaler's MMPU group interested in identifying novel factors that regulate cellular iron metabolism.

In a second project we are aiming at the identification of novel regulators of Niemann-Pick Type C [NPC] disease. NPC disease is a rare autosomal-recessive lysosomal storage disease caused by mutations in the genes NPC1 or NPC2 that is typically accompanied by progressive impairment of nervous system and liver function. On a cellular level, the disorder presents with an inhibited transport of cholesterol and glycosphingolipids out of endosomal and lysosomal compartments, which we can visualize in cultured cells. Presently, we analyze if the knock-down of candidate genes leads to a cellular cholesterol distribution that resembles, aggravates or ameliorates the cellular NPC phenotype.

Future projects and goals

		To better understand the basic molecular and cell biological function of the metabolic processes studied and the candidate genes identified so far.
		To understand the role of the candidate genes in patient derived cell models.
		To perform genetic analyses of selected candidate genes in patient samples.
		To combine the cell biological and genetic studies for improving diagnostic tools and maybe opening novel therapeutic strategies.

Members:

Dr. Rainer Pepperkok
Team Leader in Cell Biology Cell Biophysics Unit
Head of Avanced Light Microscopy Facility [ALMF]
European Molecular Biology Laboratory
Meyerhofstraße 1
69117 Heidelberg
Tel: +49 6221 387-8332
E-mail: rainer.pepperkok@embl.de

PhD 1992 University of Kaiserslautern; Postdoc at the University of Geneva 1993-1996; Group Leader at the Imperial Cancer Research Fund London 1996-1998; Team Leader at EMBL since 1998.

Dr. Heiko Runz
Project Group Leader Molecular Metabolic Disease Unit
Institute of Human Genetics
University of Heidelberg
Im Neuenheimer Feld 366
69120 Heidelberg
Tel: +49 6221 56-39128
Fax: +49 6221 56-5080
E-mail: Heiko.Runz@med.uni-heidelberg.de

MD 2005 University of Heidelberg; specialising in medical genetics; visiting scientist at EMBL Heidelberg 2003-2005; project group leader at the Institute of Human Genetics, University of Heidelberg since 2007.

Luise Kern [PhD student]
Fabian Bartz [PhD student]

Link to the Institute of Human Genetics, University of Heidelberg