WG Fritsche: Alternative method development for environmental toxicity testing

Projects

VIP

funded by the Federal Ministry of Research and Education (BMBF)

Currently, the biological application domain of the ‘Neurosphere Assay’ within a putative integrated testing strategy for DNT as well as the human-specificity of cell signaling during NPC development are evaluated by performing -omics analyses. Moreover, the Neurosphere Assay is challenged by specific pathway inhibitors and environmental chemicals to generate pathway-related fingerprints for DNT.

Major cooperation partners are Prof. Dr. Karl Köhrer (BMFZ, University Clinic Düsseldorf), Dr. Cornelia Prehn (Helmholtz Zentrum München) and Maria Teresa Colomina (University Rovira i Virgili, Tarragona/Spain).

Thyroid Hormone

funded by US Environmental Protection Agency (US-EPA, Star Grant) and until 2014 by the German Research Foundation (DFG).

Thyroid Hormone (TH) is the longest known neurotrophic factor for brain development. However, there is a profound data gap on understanding of TH transport and specific TH action within individual brain cell types. We are evaluating species- and cell-type specific TH transporter expression as well as TH-dependence of individual neurodevelopmental processes in a species-specific context. This information will form the basis for a better understanding of cellular TH disruption by environmental chemicals, contribute to building of TH-dependent AOPs and help establishing specific assays that aim to identify TH disruptors in a fast and reliable way.

Major cooperation partners are Prof. Dr. Pamela J. Lein (University of California, Davis, USA), Prof. Dr. Thomas Scanlan (Oregon Health & Science University, Portland, USA), Tom Knudsen, Kevin Crofton (both US EPA), PD Dr. Heike Heuer, PD Dr. Joachim Altschmiedt (both IUF).

Omnisphero

For a more efficient chemical testing the usage of HCA is encouraged. As evaluation software is generally designed for low density pure neuronal cell cultures, one cannot reliably study high density mixed 3D cultures, with these programs. Therefore, we have developed the novel software Omnisphero, to assess relevant endpoints of the ’Neurosphere Assay’ with high accuracy and precision. Omnisphero was developed as a user-friendly software by utilizing intuitive, supervised learning assisted, algorithms for a faster adaptation to the daily laboratory routine (www.omnisphero.com). In the future, this program will facilitate data evaluation of the Neurosphere Assay and enable analyses of mechanisms of highly complex endpoints like neuronal migration on a glia scaffold in vitro.

Major cooperation partner is Prof. Dr. Axel Mosig (Ruhr University Bochum).

Molecular aspects of skin aging

As we age, our skin ages intrinsically (pure chronological aging) and extrinsically (influenced by environmental factors like UV-irradiation). During extrinsic skin aging an increased degradation of collagen fibers is caused by the collagen-degrading enzyme matrix metalloproteinase-1 (MMP-1). MMP-1 is up-regulated by UV-irradiation, tobacco smoke as well as traffic related particulate matter, the latter two both containing polycyclic aromatic hydrocarbons e.g. benzo(a)pyrene (B(a)P). As UV-irradiation and B(a)P treatment leads to an activation of the aryl hydrocarbon receptor, we investigate the role of this molecule in extrinsic aging.

Main cooperation partners are Dr. Thomas Haarmann-Stemmann, Dr. Susanne Grether-Beck, Prof. Dr. Jean Krutmann, Prof. Dr. Petra Boukamp (all IUF), Prof. Dr. Karl Köhrer, Prof. Dr. Kai Stühler (both BMFZ, University Clinic Düsseldorf), Prof. Dr. Monika Schäfer-Korting (FU Berlin), Prof. Dr. Jens Fischer (Heinrich-Heine-University Düsseldorf), Prof. Dr. Fritz Boege (University Clinic Düsseldorf).

Molecular investigations of neurological defects observed in patients with nucleotide-excision-repair (NER)-deficiency by employment of iPS cells

funded by iBrain, the interdisciplinary graduate school for brain research and translational neuroscience at Heinrich Heine University Düsseldorf

Patients with genetically-determined defects in nucleotide-excision-repair (NER) exert a high photosensitivity. At the same time, such individuals display neurological symptoms although the central nervous system is protected against UV-induced DNA defects due to its anatomical location. Cockayne Syndrome (CS) is one of these diseases caused by a mutation either in the CSA or CSB gene with a higher prevalence in CSB. In this project, human induced pluripotent stem cells (hiPSCs) derived from CSB patients are differentiated into neurospheres to determine neurodevelopmental differences in CSB-hiPSC derived neurospheres compared to healthy controls.

Major cooperation partners are Prof. Dr. Jean Krutmann (IUF), Prof. Dieter Willbold (FZ Jülich), Prof.  Dr. James Adjaye (University Clinic Düsseldorf) and Prof. Dr. Jean-Marc Egly (Institut Génétique Biologie Moléculaire Cellulaire, Strasbourg).