Hans AR Bluyssen,
Department of Human Molecular Genetics,
Lab. of High Throughput Technologies,
Adam Mickiewicz University Poznan

Title: The multiple roles of STAT1 in IFN signaling and vascular inflammation: Towards diagnostic potential and therapeutic target.

http://dhmg.amu.edu.pl/team-members/

Hans Bluyssen’ group aims at genome-wide and mechanistic understanding of the STAT- and IRF-dependent signal integration between TLR4 and IFNs (Type I and II) in vascular and immune cells in culture, and in experimental and clinical atherosclerosis.

Researchers from the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in collaboration with the Vetmeduni Vienna (including members of Richard Moriggl’s group), MedUni Vienna, Hannover Medical School, St. Gallen Cantonal Hospital and Bio-Cancer Treatment International Ltd identified a key mechanism that explains how antiviral immune responses can reprogram liver metabolism. 

The liver is a crucial organ for the systemic metabolism in our body. In addition to the turnover of biomolecules and drug metabolism, the liver removes toxic substances from the organism. The liver is thus a central metabolic hub in a healthy organism, but is also a central organ in the immune defence against infections - previous studies have shown how immune cells improve the liver metabolism to fight pathogens or cancer. Based on this, the authors of the article now published in the journal Immunity examined these immune metabolic changes during viral infection of mice. In addition to the expected inflammatory changes, the authors identified strong changes in liver metabolism. They were able to show that many central metabolic pathways, including the urea cycle, are suppressed when an infection occurs. The antiviral cytokine type I interferon (IFN-I) was then identified as a regulator of the urea cycle - after removal of the receptor for IFN-I from the surface of hepatocytes, the metabolic changes were no longer observed. This was a surprising observation that shows that IFN-I influences important biological processes during an infection. The results shed a new light on how the body's immune system has developed to regulate liver metabolism so that it controls T cell responses while reducing collateral tissue damage during infection.

Published in Immunity

Alexander Lercher*, Anannya Bhattacharya*, Alexandra M. Popa, Michael Caldera, Moritz F. Schlapansky, Hatoon Baazim, Benedikt Agerer, Bettina Gürtl, Lindsay Kosack, Peter Májek, Julia S. Brunner, Dijana Vitko, Theresa Pinter, Jakob-Wendelin Genger, Anna Orlova, Natalia Pikor, Daniela Reil, Maria Ozsvár-Kozma, Ulrich Kalinke, Burkhard Ludewig, Richard Moriggl, Keiryn L Bennett, Jörg Menche, Paul N. Cheng, Gernot Schabbauer, Michael Trauner, Kristaps Klavins and Andreas Bergthaler (*shared first authors)

Doi: https://doi.org/10.1016/j.immuni.2019.10.014

On November 27th 2019, Science was celebrated as part of the Science Day at Vetmeduni Vienna with a keynote by Nuno Maulide (UniVienna), awards for outstanding scientific work, the kick-off of the entrepreneurial Vetmed initiative and networking among researchers.

Rectorate of Vetmeduni Vienna honors employees and their scientific performance scientists by awarding internal science prizes for “invention of the year”, “most cited scientist”, “highest third-party funding” and the "major project of the year" with internal science prizes. The prizes were awarded according to the different career stage, in clinical and non-clinical categories, as well as in two age groups (younger than 35 years and older than 35 years). Of note, Richard Moriggle and Heidi Neubauer, from the Department of Functional Cancer Genomics, won Prizes for “most cited scientist” in the non-clinical category. Pictures of the event can be found here.

Acute lymphoblastic leukemia (ALL) is a rare form of cancer that commonly affects children, mostly under the age of five years. In the search for new therapeutic options, researchers at Vetmeduni Vienna funded by the FWF SFB ‘JAK-STAT & Chromatin Landscapes’ have discovered cyclin-dependent kinase 8 (CDK8) as part of the disease process and have developed a novel drug treatment line that is pioneering for future cancer therapies.

 

Using leukemia mouse models, first author Ingeborg Menzl from the Institute of Pharmacology and Toxicology at Vetmeduni Vienna and her colleagues demonstrated that CDK8-deficient leukemia cells show an increase in cell death. Notably, this function of CDK8 in ALL is independent of enzymatic activity, which means that conventional kinase inhibitors are ineffective. The search for CDK8 interaction partners revealed a previously unknown link to mTOR signaling in cancer cells.

Dual degrader – a therapy line with combined effect. In collaboration with the research team of Nathanael Gray from the Harvard Medical School, the researchers used a new generation of drugs that do not block enzymatic activity but induce the degradation of proteins (called PROTACs). Using a newly synthesized PROTAC mTOR signaling was blocked while simultaneously CDK8 was degraded. With this concept of a dual degrader, the researchers are pioneering for future cancer therapies.

 

 

Publication in Nature Communications

Ingeborg Menzl, Tinghu Zhang, Angelika Berger-Becvar, Reinhard Grausenburger, Gerwin Heller, Michaela Prchal-Murphy, Leo Edlinger, Vanessa M. Knab, Iris Z. Uras, Eva Grundschober, Karin Bauer, Mareike Roth, Anna Skucha, Yao Liu, John M. Hatcher, Yanke Liang, Nicholas P. Kwiatkowski, Daniela Fux, Andrea Hoelbl-Kovacic, Stefan Kubicek, Junia V. Melo, Peter Valent, Thomas Weichhart, Florian Grebien, Johannes Zuber, Nathanael S. Gray and Veronika Sexl;

Doi: https://doi.org/10.1038/s41467-019-12656-x

Concept of a Dual Degrader, © Ingeborg Menzl

Luka Cicin-Sain,
HZI Helmholtz Center for Infection Research,
Braunschweig

Title: It takes two to tango: the immune system and the CMV

https://www.helmholtz-hzi.de/en/research/research-topics/immune-response/immune-aging-and-chronic-infections/luka-cicin-sain/

Luka Cicin-Sain‘s research group studies ubiquitous viruses that are persist for life in most people worldwide. In particular, our focus is on herpesviruses, whose persistence during latent infection shapes the immune system and its functionality.

Michael Sixt,
Institute of Science and Technology (IST)
Austria

Title: How leukocytes navigate through tissues

http://ist.ac.at/de/research-groups-pages/sixt-group/

Michael Sixt's laboratory is interested in morphodynamic processes both at the cellular and at the tissue level. They focus on the immune system and try to understand the molecular and mechanical principles underlying leukocyte dynamics during processes such as migration and intercellular communication.

 

Acute lymphoblastic leukemia (ALL) is a rare cancer that affects mostly affects children. In the search for new therapeutic options, researchers at Vetmeduni Vienna have now discovered a new mechanism of disease development and proposed a completely new treatment - a pioneering work for future cancer therapies. The study has just been published in Nature Communications.

 

Cyclin-dependent kinases (CDKs) are frequently deregulated in cancer and represent promising drug targets. The research team of Veronika Sexl at the Vetmeduni Vienna - in collaboration with the research team of Nathanael Gray from Harvard Medical School (USA) - focused on CDK8 in the search for new therapeutic routes for ALL. The reason for this is that tumorigenic cells are dependent on CDK8 function, while healthy cells are not. This opens up a therapeutic window by targeting CDK8: healthy cells are spared while cancer cells will be affected.

The research team was able to show that leukemia cells that lose CDK8 in leukemia mouse models significantly enhance disease latency and prevents disease maintenance. Furthermore, CDK8-depleted cancer cells are highly sensitive to mTOR inhibitors, a previously unknown connection. Thus, the authors have synthesized a small molecule (YKL-06-101) that combines mTOR inhibition and degradation of CDK8, and induces cell death in human leukemic cells. This represents a new therapeutic line in drug development: a dual degrader drug is sufficient to break down a molecule - CDK8 - and at the same time enzymatically block a signalling pathway. They propose that by affecting both simultaneously a potential therapeutic strategy for the treatment of ALL patients might be developed.

Published in Nature Communications

Ingeborg Menzl, Tinghu Zhang, Angelika Berger-Becvar, Reinhard Grausenburger, Gerwin Heller, Michaela Prchal-Murphy, Leo Edlinger, Vanessa M. Knab, Iris Z. Uras, Eva Grundschober, Karin Bauer, Mareike Roth, Anna Skucha, Yao Liu, John M. Hatcher, Yanke Liang, Nicholas P. Kwiatkowski, Daniela Fux, Andrea Hoelbl-Kovacic, Stefan Kubicek, Junia V. Melo, Peter Valent , Thomas Weichhart, Florian Grebien, Johannes Zuber, Nathanael S. Gray and Veronika Sexl

Doi: https://doi.org/10.1038/s41467-019-12656-x

Iris Uras Jodl, from the Institute of Pharmacology and Toxicology at Vetmeduni Vienna, was awarded the Wilhelm Türk Prize of the Austrian Society for Hematology & Medical Oncology for the best scientific work in the field of hematology. The award ceremony took place on October 12th 2019 as part of the joint annual conference of the German, Austrian and Swiss societies for hematology and medical oncology, in Berlin.

The Wilhelm Türk Prize is primarily intended to promote young scientists and is awarded once a year for outstanding research work in the field of hematology. The award is endowed with € 5,000. This year Iris Uras was able to convince the reviewers with her article "Cdk6 coordinates Jak2 V617F mutant MPN via NFkB and apoptotic networks" published in journal Blood, under the supervision of Veronika Sexl. Uras Jodl researched the role of Cyclin-dependent kinase 6 (CDK6) in the development of myeloproliferative neoplasia (MPN) using mouse models.

Christoph Binder,
Department of Laboratory Medicine MedUni Vienna,
Center for Molecular Medicine (CeMM), Austrian Academy of Sciences

Title: Oxidation-specific epitopes act as danger-associated molecular pattern in chronic inflammation

https://www.meduniwien.ac.at/hp/phd-mst/research-labs/christoph-j-binder-md-phd/

Christoph Binder is interested in the immune mechanisms of atherosclerosis and the immune recognition of oxidation-specific epitopes, and particularly how these responses can be exploited to protect from atherosclerotic lesion formation.