Fritsche research group: modern risk assessment and sphere biology

Head of research group:
Univ.-Prof. Dr. med. Ellen Fritsche
Phone: +49 (0)211-3389-217
Postdocs:
Dr. rer. nat. Ines Lauria
Dr. rer. nat. Stefan Masjosthusmann
Dr. rer. nat. Julia Tigges
PhD students:
Kristina Bartmann, MSc
Mohamed Elgamal, MD, MSc
Eike Keßel, MSc
Jördis Klose, MSc
Laura Nimtz, Diplom Biologin
Saskia Wuttke, MSc
Technical assistance:
Farina Bendt, biology laboratory assistant
Gaby Brockerhoff, biologic-technical assistent
Ulrike Hübenthal, biology laboratory assistant
Lynn-Christin
Stürzl, biology laboratory assistant
Research profile
A major issue in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are needed to provide adequate experimental data that allow regulatory decisions. The Fritsche lab has developed a 3D method for DNT hazard assessment based on human, rat and mouse neurospheres that mimic early neurodevelopmental processes like neural progenitor cell (NPC) proliferation, migration, differentiation into neurons and glial cells as well as apoptosis in vitro. This system is thus suited to perform pathway-to-function analyses in a species-specific context. Such data is also valuable to translate rodent in vivo data to humans on a mechanistic basis within the Adverse Outcome Pathway (AOP) concept. The Fritsche lab focuses currently on the assay’s scientific validation in order to define its biological application domain. Furthermore, algorithms are developed for the analysis of neurospheres in medium-throughput Hight Content Imaging Analyses (HCA).
The Fritsche lab contributes to the ‘Neurotoxicology’ subject of the IUF by integrating life-stage specificity, the developmental period, into neurotoxicity assessment. Mechanisms of DNT are very different compared to adult neurotoxicity and thus need special attention and specific testing methods. The Neurosphere Assay is complementary to the animal work with transgenic animals performed by the AGs Heuer and Schins. Collaborations with these groups allow studying molecular mechanisms in developing brain cells of these animals. Human relevance can then be added by gene manipulation of human neurospheres. In addition, the group operates the Cellomics Array Scan for HCA and helps with individual application needs of other groups at the IUF, the Heinrich Heine University and external laboratories like VITO (Belgium).
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).
Consultation for political organizations
Mrs. Fritsche is working group member of the panel ‚Plant Protection Products and their Residues’ (PPR): ‘Scientific Opinion of the PPR Panel investigating experimental toxicology data of pesticides and their potential link to Parkinson's disease and childhood leukaemia’ (European Food Safety Authority, EFSA). She is also member of the EU expert group: Horizon 2020 Advisory Group for health, demographic change and wellbeing (E02942).
Cooperations
IUF internal:
Haarmann-Stemmann junior research group
Haendeler research group
Heuer research group
Krutmann research group
Schins research group
National:
Prof. Dr. Adjaye, University Hospital Düsseldorf
Dr. Cornelia Prehn, Helmholtz Zentrum München (German Research Center for Environmental Health, Munich)
Prof. Dr. Orhan Aktas, University Hospital Düsseldorf
Prof. Dr. Karl Köhrer, BMFZ, University Hospital Düsseldorf
Prof. Dr. Kai Stühler, BMFZ, University Hospital Düsseldorf
Prof. Dr. Mosig, Ruhr University Bochum
Prof. Dr. Monika Schäfer-Korting, Freie
Universität Berlin (one of the universities in Berlin)
Prof. Dr. Jens Fischer, Heinrich Heine University,
Düsseldorf
Prof. Dr. Fritz Boege, University Hospital Düsseldorf
International:
Prof. Dr.
Egly, IGBMC Strasbourg, France
Prof.
Pamela J. Lein, UC Davis, California, USA
Dr. Anna
Bal-Price, JRC Joint Research Center European Commission, Brussels, Belgium (Cooperation
partner for AOPs, EFSA)
Tom
Knudsen, Environmental Protection Agency, USA
Kevin
Crofton, Environmental Protection Agency, USA
Hilda
Witters, VITO, Belgium
Maria
Teresa Colomina, Universität Rovira i Virgili, Tarragona, Spain
Prof. Dr.
Thomas Scanlan, Oregon Health & Science University, USA
Selected publications
Bal-Price
A, Crofton KM, Sachana M, Shafer TJ, Behl M, Forsby A, Hargreaves A,
Landesmann B, Lein PJ, Louisse J, Monnet-Tschudi F, Paini A, Rolaki A,
Schrattenholz A, Suñol C, van Thriel C, Whelan M, Fritsche E: Putative
adverse outcome pathways relevant to neurotoxicity. Crit Rev Toxicol 45(1): 83-91, 2015. [pubmed]
Gassmann K, Schreiber T, Dingemans MM, Krause G,
Roderigo C, Giersiefer S, Schuwald J, Moors M, Unfried K, Bergman Å,
Westerink RH, Rose CR, Fritsche E: BDE-47 and 6-OH-BDE-47 modulate
calcium homeostasis in primary fetal human neural progenitor cells via
ryanodine receptor-independent mechanisms. Arch Toxicol 88(8): 1537-1548, 2014. [pubmed]
Tigges J, Weighardt H, Wolff S, Götz C, Förster I,
Kohne Z, Huebenthal U, Merk HF, Abel J, Haarmann-Stemmann T, Krutmann J,
Fritsche E: Aryl hydrocarbon receptor repressor (AhRR) function
revisited: repression of CYP1 activity in human skin fibroblasts is not
related to AhRR expression. J Invest Dermatol 133(1): 87-96, 2013. [pubmed]
Schreiber
T, Gassmann K, Götz C, Hübenthal U, Moors M, Krause G, Merk HF, Nguyen
NH, Scanlan TS, Abel J, Rose C, Fritsche E: Polybrominated Diphenyl
Ethers Induce Developmental Neurotoxicity in a Human in Vitro Model:
Evidence for Endoctrine Disruption. Environ Health Perspect 118(4):
572-578, 2010. [pubmed] (open access)
Gassmann K, Abel J, Bothe H, Haarmann-Stemmann T, Merk HF,
Quasthoff KN, Rockel TD, Schreiber T, Fritsche E: Species-specific
differential AhR-expression protects human neural progenitor cells
against developmental neurotoxicity of PAHs. Environ Health Perspect 118: 1571–1577, 2010. [pubmed] (open access)