RADical reduction of OXidative stress in cardiovascular diseases

Project Information

RADOX

Grant agreement ID: 316738

Closed project

Start date 1 January 2013

End date 31 December 2016

Funded under

• Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

Total cost € 3 935 721,00

EU contribution € 3 935 721,00

Coordinated by

CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Germany

Final Report Summary - RADOX (RADical reduction of OXidative stress in cardiovascular diseases)

This is a short summary of the report. The contact person ist Prof. Vera Regitz-Zagrosek, Charité-Universitätsmedizin Berlin. Our project website address is http://radox.org. A detailed report about all important points is attached at the final report as a separate document. Additionally, we have attached an Appendix at the final report showing the progress of each single project.

1. General

The RADOX consortium, containing 9 full partners (8 academic and 1 private) and 5 associate partners (5 private) did train 15 ESR and 4 ER. The mission of RADOX was to create future leaders in this field. Our trainees received unequalled multidisciplinary scientific and transferable skills training which should prepare them for leading positions in academia or industry. The training in this program was be at 3 levels i.e. through research under supervision, transferable skill courses and secondments and had a strong intersectoral, international and interdisciplinary character. After completion of the project, the RADOX structure should serve as a European platform for outstanding doctoral training and oxidative stress research.

2. Science

The RADOX consortium was well focused on the objectives that have been set out in the technical annex of the grant agreement. The scientific aims of the RADOX – Radical Reduction of Oxidative Stress in cardiovascular disease – ITN were to characterize the specific sources of reactive oxygen species (ROS) and the interaction in cardiovascular disease and to use this knowledge to develop diagnostic tools for the detection and quantification of ROS and their subcellular targets.
This led to three major objectives in the projects.
Objective 1: to identify the relevant specific sources of ROS in different cardiovascular diseases, the linkages between them and the molecules targeted by these ROS. This deals with pathogenesis.
Objective 2: to develop biomarkers and genetic targets to quantify oxidative stress in cell culture systems and animal models and to predict risk for increased ROS generations in humans. This is related to diagnosis.
Objective 3: To prevent and/or to reverse the molecular damage caused by oxidative stress by effectively inhibiting specific sources of ROS. This is related to treatment.
To optimally fulfill the goals of the project we assembled our projects in one organizational (WP1), 3 scientific work packages (WP 2-4) and 2 training related WP (WP 5-6) in annex 1. The projects in WP2 were focusing on arrhythmia and myocardial pathophysiology and therapeutics, the projects in WP3 were focusing more on vascular developments and hypertension and projects in WP4 were focusing at the protection from ROS induced cardiac injury. Of note, most WPs and projects were aiming at several objectives.

3. Training program

Research training program and the whole project was in agreement with the timelines. Of note, the real start of the program was delayed by six months since hiring by the universities started only after acceptance of an amendment to annex 1 in June 2013 by REA and all partners.
After this initial delay the project started quickly and the scientific and transferable skills training workshops were scheduled almost at the foreseen time points.
The project had been successfully evaluated during the Midterm-Review-Meeting in December 2014 by the EU project officer and the external reviewer. Unfortunately, 3 of our fellows terminated their contracts prematurely. The reasons were communicated to our EU officer. In March 2016, she confirmed that we were allowed to hire 3 new fellows to use the left person month and to give 3 young researchers the possibility to benefit from the training program for several months.
All Fellows were integrated and visited during their fellowships all offered scientific and transferable skills workshops. The fellows were interacting with each other and with the scientists in charge. They have built together a Facebook site, a WhatsApp application and they were exchanging details on their methods and planned their secondments according to their own schedule.
All fellows had sufficient opportunities to interact with all network researchers. At all meetings we took care that enough time at dinners in breaks at common meals was available for interaction of all fellows with all researchers. Discussion between fellows and researchers were solicited and organized in informal manner. All fellows had the opportunities to plan secondments according to their own needs and schedules and at these secondments not only their fellow partners but also the researchers had been available.
Complementarity and multidisciplinarity were major characteristics of our network and were greatly exploited. The partners did offer experience in hypertension research, in physiology, in pharmacology, in internal medicine, in gender medicine. Industry brought their strength in drug development but also organizatorial skills. Thus the fellows were exposed to a very broad spectrum including clinical cardiology, stem cell research and gender research.
There was an extensive complementary training program organized by the network of partner exactly as it was seen in annex 1. The complementary skill training covered all areas, including management and communication aspects, data and project management in good laboratory practice, conflict management and assertiveness training, intellectual property rights, biomedical law and health economics as well as general management in communication skills for young researchers. In addition, all partner universities organized complementary and transferable skills trainings at their own institutions and fellows were invited to attend, if interested.
Associated partners like Sanofi Aventis or BMB had been involved in the training activities. Industry exposure in the training was provided by Bayer as a full partner, and by Sanofi Aventis and BMB as associated partners. They communicated their industrial viewpoints and experiences to the fellows.

4. Management

The organization of the network and distribution was perfectly adapted to the joint project and exactly as foreseen in the project plan. We have generated a scientific advisory board. However, most decisions are made by consensus among all partners. We were using regular and ad hoc conference, skype conferences, and personal meetings at congresses. Protocols of our communications were put in protected area of our homepage where they were visible to all partners at any time what enhances transparency of our project. We have installed our board meetings and internal reports were presented as we have planned. The website had been created and was permanently updated and used by all fellows. All personal career development plans had been generated, updated yearly and subjected to the training of officer. The reports on the scientific outputs in work package 2, 3 and 4 are available as single reports and attached as a separate file. The secondments for all fellows were planned and performed in a timely manner. All scientific workshops and transferable skills training were successfully carried out during the project period.
The network coordinator had all the necessary scientific and organizational competences. She was organizing the scientific meetings, the midterm report, and monitoring the training activities of the fellows. The training officer was supervising the personal career development and was in close contact with all fellows.

5. Impact

The scientific and transferable skills trainings for the fellows will have impact on their careers. E.g. one of the ER fellows was employed by the end of his RADOX contract as a lead scientist in a lab, under a 5 years contract. Now he is supervising students and he is on track to become an independent researcher/principal investigator. Further, some of ESR fellows have been offered a new contract in their groups and will start working as a post-doc after completion of their PhD.
By hands on trainings that were available for all fellows at their institutions and during the RADOX, the fellows gained new knowledge on experimental work. These structured trainings improve the employability of the fellows and lead them to scientific and professional maturity.

Findings from our studies may have impact beyond what we originally anticipated. E.g. in the vascular studies of WP3 we explored the role of PARP-1-TRPM2-NOX-ROS, and used a PARP-1 pharmacological inhibitor, Olaparib. This agent is also used as a drug to treat cancer. We found that inhibition of PARP-1-TRPM2-NOX-ROS has vasoprotective effects. As such, targeting this pathway in cancer patients may protect against vascular and cardiac toxicities of other anti-cancer drugs, such as tyrosine kinase inhibitors. Hence combination treatment with Olaparib may be cardiovascular-protective with added anti-cancer effects. This new paradigm may have important impact in the growing field of cardiovascular-oncology.
Further, the implementation of results obtained in WP4.3 (Padua) into clinical setting could have an important socio-economic impact. MAO inhibitors have been used for years for the treatment of psychiatric disorders and neurodegenerative diseases and recently (last year) a new MAO-B inhibitor was marketed for the treatment of Parkinson’s disease. Repurposing of these already available MAO inhibitors for the treatment of cardiovascular complications would have a great beneficial impact for the society, without the excessive costs related to drug discovery and development.

The project also may have impact on European society. During the funding period we developed some new infrastructures. One example is the development of amperometric detection of H2S in Oxford. The responsible fellow pioneered with adapting the method into measuring H2S from human biological material. This led to new collaborations between the University of Oxford and the University of Texas (Dr Gabor Olah), University of New Orleans (Prof David Lefer) and University of Texas (Prof Andreas Papapetropoulos). These are now ongoing international collaborations created through the project. Through these collaborations, we have transferred new knowledge to Europe, as they are experts in H2S biology and helped us set up analytical methods to quantify H2S.
Transfer of knowledge between partner institutions within Europe through fellow’s secondments was very extensive and will have impact on these European institutions through transfer of knowledge. Some fellows who had secondments in Oxford, received training on using HPLC to quantify DHE as a reading of redox state. They also learnt about using chemiluminescence to measure O2- and transferred that method to their own institutions to include it to their own projects. Another example is University of Padua hosting some RADOX fellows to impart knowledge and skills about specific measurements of mitochondrial activity to improve scientific skills of these fellows and to improve the scientific content of their projects.