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Researchers at Goethe University develop new protoeomics procedure
FRANKFURT. When cells are stressed, they initiate a complex and precisely regulated response to prevent permanent damage. One of the immediate reactions to stress signals is a reduction of protein synthesis (translation). Until now, it was difficult to measure such acute cellular changes. As reported in the latest online issue of the renowned journal Molecular Cell, researchers at Goethe University have now developed a method overcoming this hurdle.
The team led by biochemist Dr. Christian Münch, who heads an Emmy Noether Group, employs a simple but extremely effective trick: when measuring all proteins in the mass spectrometer, a booster channel is added to specifically enhance the signal of newly synthesised proteins to enable their measurement. Thus, acute changes in protein synthesis can now be tracked by state-of-the-art quantitative mass spectrometry.
The idea emerged because the team wanted to understand how specific stress signals influence protein synthesis. "Since the amount of newly produced proteins within a brief time interval is rather small, the challenge was to record minute changes of very small percentages for each individual protein," comments group leader Münch. The newly developed analysis method now provides his team with detailed insight into the molecular events that ensure survival of stressed cells. The cellular response to stress plays an important role in the pathogenesis of many human diseases, including cancer and neurodegenerative disorders. An understanding of the underlying molecular processes opens the door for the development of new therapeutic strategies.
"The method we developed enables highly precise time-resolved measurements. We can now analyse acute cellular stress responses, i.e, those taking place within minutes. In addition, our method requires little material and is extremely cost-efficient," Münch explains. "This helps us to quantify thousands of proteins simultaneously in defined time spans after a specific stress treatment." Due to the small amount of material required, measurements can also be carried out in patient tissue samples, facilitating collaborations with clinicians. At a conference on Proteostatis (EMBO) in Portugal, PhD student Kevin Klann was recently awarded with a FEBS journal poster prize for his presentation of the first data produced using the new method. The young molecular biologist demonstrated for the first time that two of the most important cellular signaling pathways, which are triggered by completely different stress stimuli, ultimately results in the same effects on protein synthesis. This discovery is a breakthrough in the field.
The project is funded by the European Research Council (ERC) as part of Starting Grant "MitoUPR", which was awarded to Münch for studying quality control mechanisms for mitochondrial proteins. In addition, Christian Münch has received funding within the German Research Foundation's (DFG, Deutsche Forschungsmeinschaft) Emmy Noether Programme and is a member of the Johanna Quandt Young Academy at Goethe. Since December 2016, he has built up a group on "Protein Quality Control" at the Institute for Biochemistry II at Goethe University's Medical Faculty, following his stay in one of the leading proteomic laboratories at Harvard University.
Dr. Christian Münch, Institute for Biochemistry II, Faculty of Medicine, Goethe University, Tel.: +49 69 6301-6599, firstname.lastname@example.org.
Klann K, Tascher G, Münch C. Functional translatome proteomics reveal converging and dose-dependent regulation by mTORC1 and eIF2α. Molecular Cell 77, 1-13, Feb 20, 2020. doi.org/10.1016/j.molcel.2019.11.010
Early career researcher Stephanie Döpper awarded funding by Gerda Henkel Foundation to study abandoned mud-brick settlements in Oman
FRANKFURT. Goethe University is sending researchers to Oman: As the Gerda Henkel Foundation has announced, Dr. Stephanie Döpper will receive funds of almost € 300,000 for the duration of three years in the framework of its “Lost Cities" programme.
To this end, the archaeologists in the project will be responsible over the coming years for mapping three mud-brick settlements in Central Oman and documenting the history of their buildings. This will take place in the framework of research visits lasting several months. In addition, by examining the artefacts they find, such as ceramic shards, they will be able to identify the former functions of the individual buildings in these settlements. Of particular significance here are their later uses, for example the repurposing of a house as a goat shed. The research team's hypothesis is that the abandoned mud-brick settlements are not only the deserted backdrops of a past way of life but instead still very lively and bustling places with a future.
Dr. Stephanie Döpper has been studying settlements and settlement systems in Central Oman for several years now, starting from the early Bronze Age in the 3rd millennium BC up until the mud-brick settlements in the research project approved by the Gerda Henkel Foundation, which were probably built in the 18th or 19th century AD and are today abandoned. In the back of her mind is always the question of what caused people in this region to settle and why such settlements were abandoned again.
Funding from the Gerda Henkel Foundation will make it possible to finance a doctoral scholarship and the research visits on site.
In total, the foundation has included 53 new research projects in its sponsorship programme, for which its committees approved € 8.6 million at their autumn meeting. This means support for researchers from almost 30 countries.
Pictures can be downloaded under: http://www.uni-frankfurt.de/83770372
Picture 1: House in the abandoned mud-brick settlement of Al-Mudhaybi. Photo: Stephanie Döpper
Picture 2: Ceramic vessels in the abandoned mud-brick settlement of Al-Mudhaybi. Photo: Stephanie Döpper
Picture 3: House with collapsed ceilings in the abandoned mud-brick settlement of Sinaw.
Picture 4: Abandoned mud-brick settlement of Sinaw. Photo: Stephanie Döpper
Picture 5: Abandoned mud-brick settlement of Sinaw. Photo: Stephanie Döpper
All pictures courtesy of Stephanie Döpper.
Further information: Dr. Stephanie Döpper, Institute of Archaeological Sciences, Archaeology, Westend Campus, Norbert-Wollheim-Platz 1, D-60629 Frankfurt am Main, +49(0)69-798-32320, email@example.com
Prolongation of Collaborative Research Centre on selective autophagy led by Goethe University
FRANKFURT. Four years ago, Collaborative Research Centre (CRC) 1177 on selective autophagy was established under the leadership of Goethe University – now the German Research Foundation has given the green light for its further funding. A total of over € 12 million has been approved for the period up until 2023. Partners alongside Goethe University are the universities of Mainz, Munich, Tübingen and Freiburg, the Georg Speyer Haus and the Max Planck Institute of Biophysics in Frankfurt as well as the Institute of Molecular Biology (IMB) in Mainz.
Selective autophagy is part of the cell's waste disposal system. With its help, defective or potentially damaging cellular components are degraded and recycled. It plays a central role in maintaining cellular homeostasis and fulfils important functions in ageing and developmental processes. Errors in this system contribute to cancer, neurodegenerative disorders and infections. The objective of the research alliance is a better understanding of autophagy at molecular and cellular level in order to be able in future to counteract imbalances in the system. CRC 1177 is the first consortium in Germany to tackle this important topic systematically.
“This is very good news for Goethe University," said Professor Birgitta Wolff, President of Goethe University. Thanks to this CRC, Frankfurt has become a national hub for autophagy research over the past four years. Especially through the integration of new partners in Munich, Tübingen and Freiburg and at the MPI for Biophysics, it has been possible to substantially strengthen the existing partnership between Mainz (IMB/JGU) and Frankfurt (GSH/GU). We expect this research alliance to advance autophagy research significantly, which will help in the fight against many diseases," said the President.
Autophagy is found from simple organisms, such as yeasts, up to humans. The underlying molecular mechanisms are always similar: Cellular components that need to be removed are recognized in a highly specific manner, enveloped by membranes and degraded. This is how, for example, aggregated proteins are destroyed that would otherwise cause severe damage and trigger cell death. This can especially be observed in neurodegenerative disorders such as Alzheimer's disease, where toxic protein aggregates accumulate which then promote the massive destruction of nerve cells. Apart from proteins, autophagy can also target defective cell organelles and pathogens for removal. The cell can reutilize the recovered material as building blocks for synthesizing new components, which is why autophagy is also an important survival strategy in times of need.
Autophagy is a very complex process which must be precisely regulated and is greatly dependent on the cellular context. Its analysis requires state-of-the-art technologies, the integration of a wide variety of data and close collaboration between researchers from different disciplines. “We will focus on novel concepts in autophagy research and its impact on major biological processes as well as pathogenesis and therapy of human diseases," explains Professor Ivan Dikic, CRC spokesperson and Director of the Institute of Biochemistry II at Goethe University. “Our vision includes close interactions between basic and translational research via centrally supported technology platforms."
The platforms with their ultramodern equipment are a key factor in the research alliance's success: Since 2016, over 20 scientific publications have been produced in cooperation with the proteomics platform alone. In the second funding period, centrally available technologies will be significantly extended to include modelling and simulation methods, genomic and chemical high-throughput screening, and imaging methods to quantify autophagy in model organisms. Another equally important matter within the consortium is support for early career researchers. To this end, the Research Training Group set up in the first funding period will be continued. “Training the next generation of autophagy researchers is a matter close to our hearts and for this reason we've planned a diverse and advanced training programme," said Dikic.
Participating in the CRC on the part of Goethe University – in addition to its faculties of Biological Sciences, Biochemistry, Chemistry and Pharmacy, and Medicine – is the Buchmann Institute for Molecular Life Sciences.
Further information: Dr. Kerstin Koch, Institute of Biochemistry II, Faculty of Medicine, Goethe University, Tel.: +49(0)69- 6301-84250, firstname.lastname@example.org.
Goethe University is a participant in a project receiving 3.2 million Horizon 2020 grant
FRANKFURT. The European research project “Working, Yet Poor“ (WorkYP) was recently awarded 3.2 million euros for three years by the EU's Horizon 2020 programme. The project will investigate the social and legal reasons behind the increasing number of EU citizens who are at risk of living below the poverty line despite being employed. Law Professor Bernd Waas from Goethe University is heading a subproject.
“Countries implement certain measures to prevent in-work poverty, but there is not a set approach towards reducing or eliminating it. EU Member States – individually and collectively – need a better understanding of the problem, an understanding supported by pertinent data and which allows them to monitor and successfully attack it," says Luca Ratti, the WorkYP Project's coordinator and Associate Professor of European and Comparative Labour Law at the University of Luxembourg.
The distribution of in-work poverty differs substantially across Europe, due to different social and legal systems or measures implemented to reduce poverty. For example, 13.4% of the working population were at risk of poverty in Luxembourg in 2018, compared to 5.2% in Belgium. The reasons for such differences have not been sufficiently investigated. Therefore, the WorkYP Project will analyse seven representative countries with different social and legal systems (Luxembourg. Belgium, Germany, Italy, the Netherlands, Poland and Sweden) to document the problem and to propose best practice solutions to combat in-work poverty across all systems. “With this study, we intend to help EU Member States, and the EU as a whole, to better target their policies and regulatory action," Ratti explains.
The WorkYP Project has identified specific groups of people that are at greater risk of in-work poverty, on which the analysis will focus. These include low wage workers; self-employed people; those with temporary or flexible employment contracts; and casual or “zero-hours" workers. Because women are more frequently employed in low-paid jobs or are more vulnerable to unequal working conditions, the household's composition and income will be considered in the research.
Luca Ratti will lead a multinational and interdisciplinary research team comprised of researchers from eight European universities (Frankfurt, Bologna, Leuven, Rotterdam, Tilburg, Gdansk and Lund) as well as three social rights institutions active in Europe.
Goethe University will have a key role in this project. It will assume project leadership for the part of the project dedicated to consideration of employees with atypical work contracts. It will furthermore coordinate the work of the experts in the comparative analysis of the various models for combatting poverty at the workplace, and the system for guaranteeing a minimum living standard and a minimum catalogue of social rights. Overall, 320,000 euros in project funds will go to Goethe University. Professor Waas, who already heads the European Commission's labour law expert network, and also coordinates the project on the restatement of labour law in Europe, is pleased with his new task. “The days will be a bit longer, but it will be worth it," he says. “In particular with regard to the rapid digitalisation of the workplace and the emergence of completely new forms of work, numerous problems have come about that are in urgent need of answers."
“I am happy that Goethe University is involved in such an important European research project. Decent working and living conditions in all countries of the Community are of critical significance for Europe's future," says Professor Simone Fulda, who as Goethe University Vice President is in charge of research.
Horizon 2020, the EU Framework Programme for Research and Innovation launched in 2014, funds collaborative projects in research and innovation. Research organisations, universities, and companies are all eligible to participate. Horizon 2020 funds 6,000 projects each year and Luxembourg entities have already received approximately 40 million euros for more than 120 projects.
Caption: Professor Bernd Waas, labour law expert at Goethe University, heads the Frankfurt subproject of the Horizon 2020 collaborative project “Working, yet poor“.
Further information: Professor Bernd Waas, Chair for Labour Law and Civilian Law, Institute for Civil and Economic Law, Faculty of Law, Westend Campus, Phone+49 69-798 34232, E-Mail email@example.com
Sex-specific processes in schizophrenia and bipolar disorder
FRANKFURT. Recent studies have found a high genetic similarity of the psychiatric diseases schizophrenia and bipolar disorder, whose disease-specific changes in brain cells show an overlap of more than 70 percent. These changes affect gene expression, i.e., transcription of genes for the purpose of translation into functional proteins. A collaborative study carried out by the Institute of Pharmacology and Clinical Pharmacy at Goethe University (Professor Jochen Klein) and the Institute of Neurosciences at the Hebrew University of Jerusalem (Professor Hermona Soreq) now shows sex-specific biases in these changes, as well as in cellular control mechanisms based on endogenous short ribonucleic acid (RNA) chains.
The scientists identified an important role of microRNAs, a special group of these small RNA molecules, known for their extensive control of gene expression in all human cells. Targeting of a gene by one of these microRNAs can lead to a significant restriction of its expression. “The main problem is the enormous variety of possible combinations," says Sebastian Lobentanzer, lead author of the article published in the journal Cell Reports. “The human expresses about 2,500 of these microRNAs, and a single one can influence hundreds, maybe even thousands of genes."
For this reason, the researchers investigated gene expression in patient brains as well as human cultured nerve cells with a combination of RNA sequencing and bioinformatics. They found a difference in the expression of immune-related genes between men and women, especially with regard to cytokines, the messenger substances of immune cells. Upon exposition of the cultured male and female neuronal cells to some of these cytokines, the researchers found a transformation of nerve cells into to cholinergic neurons, defined by their use of the neurotransmitter “acetylcholine".
By sequencing the microRNAs at several time points during this process, the scientists were able to paint a detailed picture of the microRNA interface between the immune and neuronal systems. They identified the involvement of 17 partially sex-dependent families of microRNAs and generated an extensive network of 12,495 regulated genes. Using a multi-stage selection process, the most influential of these microRNA families were identified and confirmed in dedicated experiments. This led to the identification of the two sex-specifically expressed families mir-10 and mir-199 as interface between cytokines and cholinergic functions.
Psychiatric diseases are an important field for new therapeutic approaches because of their high genetic complexity and their inaccessibility to conventional forms of therapy. On the one hand, the current study demonstrates molecular parallels to the long-observed but previously unexplained clinical differences between disease-affected men and women. On the other hand, mechanisms on the basis of small RNA molecules could open up new avenues by influencing a large number of disease-relevant genes – a promising approach in the search for alternatives to traditional antipsychotic drugs. “Studies such as ours, which enable a comprehensive representation of microRNA interactions, are the first step on the path to developing new therapeutic substances," says Lobentanzer.
Publication: Lobentanzer S, Hanin G, Klein J & Soreq H (2019). Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder. CellReports. ElsevierCompany. 1–19. doi: 10.1016/j.celrep.2019.09.017.
An image may be downloaded here: www.uni-frankfurt.de/83258617
The illustration shows a network of 212 microRNAs and their 12,495 targeted genes, deconstructed into four fields according to their sex-specific changes. (Copyright: Sebastian Lobentanzer)
Further information: Sebastian Lobentanzer, research scientist; Professor Jochen Klein; Institute for Pharmacology and Clinical Pharmacy, Riedberg Campus; firstname.lastname@example.org, email@example.com. https://slobentanzer.github.io/cholinergic-neurokine.