Projects

Nutrigenomics

A new focus of the research group consists in nutrigenomics. We have recently developed a mass spectrometric assay for protein-ligand binding. This procedure is suitable for identification of interacting small molecular ligands of a protein of interest from a mixture of synthetic compounds or natural products. We mainly use this assay for initial high-throughput screening in large libraries of natural products, provided by our project partners. Hits are further characterised using surface plasmon resonance detection and targeted cell culture assays. We use RNA expression profiling to study global effects of hit compounds. By screening for ligands of drug targets, the method will be useful for the development of medical therapeutics or nutraceuticals.

Sirtuin Biology

 Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase, has been implicated in the prevention of diabetes and obesity. Using a number of high-throughput screening methods and applying novel nutrigenomics approaches such as second generation sequencing we identified and characterised a number of well-known and new molecules that interact with SIRT1. As fluorescence-based assays for SIRT1 activation produce artefacts, we developed a novel, unambiguous mass spectrometry-based assays including natural peptide substrates. Our studies reveal so far unknown mechanisms of action of SIRT1 activation, which indicate specific effects of SIRT1 activating molecules such as resveratrol on a network gene regulatory processes. These results shed light on the mechanism of action of SIRT 1 activation and provide new basic principles for the development of compounds for prevention and treatment of type 2 diabetes.

Interaction of Natural Products with Nuclear Receptors

 Nuclear Receptors such as the Peroxisome-Proliferator-Activated Receptor (PPAR) and the Retinoid X Receptor (RXR) are fundamental regulators of the lipid and glucose metabolism and present pharmacological targets for therapy of the metabolic syndrome. Unfortunately, drugs as the insulin sensitizer class of glitazones, which interact with PPARy, are accompanied by severe side effects. Therefore, tissue- and gene-selective agonists with specific activity profiles are sought after to provide improved strategies for treatment of metabolic diseases. A number of our projects are devoted to the discovery of new nature-derived ligands for nuclear receptors such as PPARalpha, PPARgamma and LXRalpha, to the biophysical and biochemical characterisation of their binding, whole-genome RNA and proteion expression analysis, and to the determination of the ligands effects on gene regulation by differential recruitment of cofactors and selective gene promoter occupancy. Subsequently, validated ligands will be examined in appropriate mouse models and pharmacological assays. Recently, we have published a first article of a series of follow-up studies introducing the amorfrutins as metabolically exciting new natural products derived from liquorice roots or fruits of Amorpha fruticosa (press release).

Mathematical Modeling of Adipocyte Differentiation

Obesity is a prime condition predisposing to a number of common diseases such as type II diabetes, cardiovascular diseases and certain cancers. The process of adipocyte differentiation from fibroblast precursor cells is dependent on an intricate interplay between external cues and intracellular factors, such as the master regulator PPARg. Although the molecular players for maturation of preadipocytes into mature fat-loaded adipocytes are rather well characterized, little is known about the underlying dynamics leading to the commitment of mesenchymal stem cells to the preadipocytic cell lineage. In order to obtain further insights, we are developing a mathematical model to simulate the regulatory circuits controlling adipocyte differentiation. An understanding of these processes will elucidate new rationales for the prevention and treatment of obesity.

Sequencing Technologies

The group is involved in the coordination of a new EU FP-7 project, the European Sequencing and Genotyping Infrastructure (ESGI). More information can be found at: www.esgi-infrastructure.eu. ESGI pools the efforts of leading European genetics and bioinformatics facilities to ensure that the larger scientific community can access genetic data and use emerging analytic tools. The goal of ESGI is to enable scientists across many disciplines to use new technologies to decipher the complex cellular functions of genes. In our group, we apply sequencing methodologies to analyse gene-regulation processes in cell differentiation and metabolic processes. Thereby we focus on the analysis of differentiation in fat and immuno cells. Emerging sequencing technologies of the next generation will not require amplification and will produce read lengths far beyond current methodologies. These new methods will make it possible to sequence whole mammalian genomes in a few hours and in real-time for reasonable costs, and allow even single cell analyses. In a joint effort with other European institutes and under the umbrella of the READNA project we currently work on the development of new sequencing methods, e.g. for diagnostic applications.

Diagnostic Tools

For precise (clinical) diagnosis new comprehensive tools are required, which provide combined information on different biological levels. MALDI mass spectrometry has a great potential for this application as it offers high sensitivity and high accuracy to detect nucleic acids and proteins. A number of diagnostic applications based on the analysis of nucleic acids and proteins can in principle be combined on a single MALDI platform. However, integration of these applications has so far not been achieved. A primary goal of our work consists in the (efficient) integration of these analyses strategies and application to relevant common diseases such as inflammatory bowel diseases (which amongst others deal with genetic susceptibility and anomalies of the gut flora), and to bacterial diagnosis.