SFRRe/FEBS/IUBMB Summer School Spetses in September 2016 Action - - PowerPoint PPT Presentation

SFRRe/FEBS/IUBMB Summer School Spetses in September 2016 Action BM1203 (EU-ROS)

COST Domain - Biomedicine and Molecular Biosciences (BMBS)

Mission of COST

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The COST program (European Cooperation in Science and Technology) is one of the oldest funding instruments of the EU with the following aims:

• Strengthen the collaboration among European scientists
• Support early stage researchers
• Improve European economics & health of European population

Facts of COST Action BM1203

• Foundation in Dec 2012, first Budget in April 2013
• Chair of the Action: Prof. Andreas Daiber, University Medical

Center Mainz, Germany

• Vice Chair of the Action: Prof. Fabio di Lisa, Università di Padova,

Italy

• Founding Chair of the Action: Prof. Harald Schmidt, University of

Maastricht, The Netherlands

• 34 participating countries, 2 NNC
• 101 MC members/substitutes and > 150 WG members (w/o ESR,

STSM candidates)

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Scientific scope

Major Scientific Aims

• Unravel the paradox of diverging efficacy of antioxidants in clinical

therapy (chronic / systemic versus acute / local applications)

• Discriminate ROS sources and signalling in physiological pathways

from disease-relevant processes

• Overcome conservative dogma in oxidative stress and redox biology

research and provide the room for new hypotheses and verify these concepts by state-of-the-art drugs, tools and imaging techniques

• Develop new drugs with antioxidant properties (direct or indirect) for

the treatment of oxidative stress-associated disease

• Establish databases for drugs & tools as well as oxidative stress-

related biomarkers to advance the European research in this field and to provide the basis for new therapeutics and large clinical trials

• Establish long-lasting collaborations and support successful

applications for funding by EU-ROS consortia

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Scientific scope

Scientific Working Groups

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• Working Group 1 – Sources of ROS (Prof. Ulla Knaus)
• Working Group 2 – Molecular Mechanisms (Prof. Agnes Görlach)
• Working Group 3 – Drugs & Tools (Dr. Tamara Seredenina)
• Working Group 4 – Biomarkers (Prof. Pietro Ghezzi)
• Working Group 5 – Imaging (Dr. Yves Frappart)
• Working Group 6 – Technology Transfer & Funding (Dr. Vincent Jaquet)
• Within WG1&2 different consortia working on cardiovascular &

neurodegenerative disease, cancer, fibrosis and inflammation

Scientific scope

6 Casas et al. or Schmidt et al., Antioxid. Redox Signal. 2015

ROS sources Beneficial redox signaling Detrimental in disease A, B, C Should be preserved by redox drugs Should be specifically inhibited in disease A, B, C Possible strategies: Repair of damaged proteins (e.g. sGC, eNOS), source specific inhibitors (Nox, XO inhibitors), activators of endogenous antioxidant systems (Nrf2 activators), inhibition of toxifiers (MPO), direct RONS scavengers only cell- or organelle-specific, maybe also species-specific specific biomarkers to verify successful therapy of disease phenotype Requires advanced imaging techniques to verify successful inhibition and specific biomarkers to verify successful therapy of disease phenotype

Scientific Scope

Who’s the bad guy – or which biological source of ROS formation is the most detrimental one?

7 Daiber, Di Lisa et al. Br. J. Pharmacol. 2015

Scientific scope

Interaction (“crosstalk”) of different ROS sources

8 Modified from Daiber, Biochim. Biophys. Acta 2010

Scientific scope

Redox regulation of disease-relevant enzymes

9 Schulz et al. and Daiber, Antioxid. Redox Signal. 2014

Scientific scope

New antioxidant drugs

10 Vi Dao et al. Antioxid. Redox Signal. 2015

Scientific scope

In vivo RONS imaging

11 Maulucci et al. Antioxid. Redox Signal. 2016

Scientific scope

Redox biomarkers

12 Frijhoff et al. Antioxid. Redox Signal. 2015

Scientific outputs related to networking

Collaborative research meetings

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• 5 MC/WG meetings completed (Budapest, Istanbul, Padova, Munich, Bukarest), 4 WG

meetings completed (Athens, Madrid, Belgrade, Lisbon), 3 SFRRe congress symposia completed (Athens, Stuttgart, Budapest), final meeting will take place in Eilat, Israel (Nov 2016)

• 27 STSM completed and 2 currently taking place
• 2 co-organized training schools in 2013 (Zurich, Birmingham), 1 co-organized TS in 2014

(Spetses), 1 COST-organized TS in 2015 (Alicante), 1 co-organized TS in 2016 (Spetses) – all together more than 70 trainees were supported

Scientific outputs related to networking

Alicante training school 2015 – 36 students, 12 trainers

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Scientific outputs related to networking

Joint publications

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• Special, ROS/antioxidants-dedicated Forum Issue on “Redox Medicine” was published

in Antioxidants & Redox Signaling 2015 with 10 contributions (Eds. Harald Schmidt, Fabio Di Lisa)

• Virtual issue on “Emerging concepts in redox biology and oxidative stress” was

published in Redox Biology 2016 with 18 contributions (Eds. Santiago Lamas, Fabio Di Lisa, Andreas Daiber)

• Themed review series on “Redox biology and oxidative stress in health and disease”

partly published in British Journal Pharmacology 2016 with 15 contributions (Eds. Peter Ferdinandy, Andreas Daiber)

• Final Action Dissemination on “Involvement of reactive oxygen species in physiology

and pathophysiology – outcome and position statements of COST Action BM1203 (EU- ROS)” with up to 170 authors and 9 section editors from EU-ROS to be published in Redox Biology 2017

• Plus more than 30 additional joint publications of WG members of EU-ROS

Scientific outputs related to networking

Forum issue in Antioxidants & Redox Signaling 2015

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5 of the review articles are in the top 10 of most read articles during the last 12 months

Scientific outputs related to networking

Virtual issue in Redox Biology 2015/2016

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5 of the review articles are in the top 25 of most read articles during the last 90 days

Scientific outputs related to networking

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Themed review series in British Journal Pharmacology on “Redox biology and

• xidative stress in health and disease” (Andreas Daiber / Peter Ferdinandy) with

the following published or submitted work from EU-ROS:

Fabio Di Lisa, Rainer Schulz, Peter Ferdinandy Accepted and Exported New aspects on P66Shc in ischemia/reperfusion injury and protection from it Andreas Daiber, Huige Li, Santiago Lamas, Thomas Münzel Accepted and Exported Targeting endothelial dysfunction Gabriella Aviello, Ulla Knaus, … Accepted and Exported Gastrointestinal Inflammation and ROS (Crohn's, ulcerative colitis, ileitis...) Serge Bottari, Neven Zarkovic, Olha Yelisyeyeva… Revision Biomarkers of oxidative and nitro-oxidative stress Andreas Daiber, Fabio Di Lisa, Matthias Oelze, Swenja Kröller-Schön, Sebastian Steven, Eberhard Schulz, Thomas Münzel Accepted and Exported Effects of the crosstalk of mitochondria with NADPH oxidase on endothelial dysfunction and vascular inflammation Huige Li et al. Accepted and Exported Antioxidant effects of resveratrol in the cardiovascular system Jeanette Marjorie Wood et al. Accepted and Exported Therapeutic potential of NOX1/4 inhibitors Gethin J. McBean, Javier Egea, Manuela G. López, Fredrik Wallner Accepted and Exported Redox-based therapeutics in neurodegenerative disease Jankovic A, Korac A, Buzadzic B, Stancic A, Otasevic V, Daiber A, Ferdinandy P, and Bato Korac Accepted and Exported Targeting the nitric oxide/superoxide ratio in adipose tissue - relevance in obesity and diabetes management Pavel Urbanek and Lars-Oliver Klotz Accepted and Exported Posttranscriptional regulation of FoxO formation Frederik Vilhardt et al Accepted and Exported NADPH oxidases in Microglia oxidant production: Activating Receptors, Pharmacology, and Association with Disease Frederik Vilhardt et al Accepted and Exported Microglia Antioxidants and Redox signaling Sebastian Steven et al. Accepted and Exported Glucagon-like peptide-1 receptor signalling reduces microvascular thrombosis, nitrosative and oxidative stress, systemic inflammation and platelet activation in endotoxemic mice Ioanna Andreadou, Peter Ferdinandy submitted Effect of hyperlipidemai on the heart: importance of oxidative stress Piero Ghezzi, Vincent Jaquet, Fabrizio Marcucci, Harald Schmidt Accepted and Exported The oxidative stress theory: Demystifying the evidence for reactive oxygen species in physiology and disease

Scientific outputs related to networking

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Final Action Dissemination on “Involvement of reactive oxygen species in physiology and pathophysiology –

• utcome

and position statements of COST Action BM1203 (EU-ROS)” with up to 170 authors and the following section editors from EU-ROS to be published in Redox Biology 2017: ROS sources and oxidative stress pathways (WG1) - Ulla Knaus ROS targets and redox signaling (WG2) - Agnes Görlach Redox biomarkers (WG4) - Pietro Ghezzi Imaging of ROS (WG5) - Yves Frappart ROS in the cardiovascular system - Rainer Schulz ROS and the aging process - Jose Vina ROS in inflammation and neurodegeneration – M. Garcia Lopez ROS in other pathologies - Santiago Lamas ROS, antioxidants and toxins - Thomas Kietzmann

Scientific scope

Redox regulation of gene expression by controlling classical pathways of transcription factors and epigenetic pathways

20 Mikhed, Görlach, Knaus, Daiber, Redox Biol. 2015

OxyR

Thiol

• xidation

Oxidation of thiols in Keap-1

Nrf2 NFκB

AP-1, IκB thiol redox

HIF-1α

Prolyl hydroxylases

• xidation of Fe2+

center

Classical gene regulation Epigenetic gene regulation

DNA methylation

Heritable false genomic imprinting

Processing of 5- chloroC to 5-mC

Scientific scope

Redox regulation of FOXO activity

21 Urbanek and Klotz, Br. J. Pharmacol. 2016

Scientific scope

Redox regulation of proteasome activity and its regulation of transcription factors

22 Pajares et al. and Cuadrado, Redox Biol. 2015

Scientific scope

Interaction (“crosstalk”) of ROS and calcium signaling

23 Görlach et al., Redox Biol. 2015

Capacity building related to networking

Establishment of a website: www.eu-ros.eu

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Capacity building related to networking

Establishment of a Drugs & Tools database

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Capacity building related to networking

Establishment of a Biomarker database

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Challenges, draw-backs and chances

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Challenges and draw-backs

• The size of our Action per se is a problem since the email load and to do list for any member of the core group is

very high due to the number of active members

• Due to the size not all members can be invited to the WG and MC meetings
• Due to the size of our Action and the broad field covered by oxidative stress research we have many disciplines in
• ur Action, which complicates the implementation of all members and defining the foci of our working groups
• Clinical data so far do not support clinical applications of antioxidants in major diseases.

Chances

• The clinical use of site- and source-specific antioxidants is so far unexplored and provides a wide field of

attractive pharmacological applications

• The size of our Action provides unique opportunities for integrating the various aspects of oxidative stress. This

integration is pivotal not only for attracting the interest of the scientific community, but also for achieving a broad consensus on messages and guidelines to be delivered to the general public. This might be especially relevant in the case of nutritional and therapeutic aspects of oxidative stress and use of antioxidants.

• Our Action covers a broad range of disciplines in biomedical research ranging from fine structural details to

clinical applications. In addition, oxidative stress and redox signalling are relevant topics for many other research fields. Therefore, successful collaborations with other COST Actions (BM1005 and CM1001) could/should be established.