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Modulation of glycolytic flux as a new approach for treatment of atherosclerosis and plaque stabilization: a multidisciplinary study

Periodic Reporting for period 2 - MOGLYNET (Modulation of glycolytic flux as a new approach for treatment of atherosclerosis and plaque stabilization: a multidisciplinary study)

Reporting period: 2017-09-01 to 2019-11-30

The mission of Moglynet has been to define a joint doctoral educational training model in Drug Discovery and Development where Academia and Industry, supported by other institutions and organizations, joined their forces to create a common knowledge and language for future researchers working in the Pharma-field.
The scientific activity was focused on atherosclerotic cardiovascular disease, which is an age-related major cause of death in the western world. Thanks to cholesterol-lowering drugs, the lifespan and wellbeing of patients have significantly improved, however, a large group of patients does not fully benefit from current pharmacological intervention. Our aim has been to find a new strategy to control neo-vessel formation in the atherogenic process. To reach this goal, a multidisciplinary consortium was created, bringing together researchers with different expertice (drug design, synthesis of new molecules, cell metabolism, angiogenesis, cardiovascular diseases and imaging technologies). The Consortium worked synergistically to design and develop new compounds for modulating the activity of a glycolytic flux enzyme, i.e. PFKFB3, as a new potential target for atherosclerosis. As a result, progression of atherosclerotic plaque growth and their rupture could be prevented, and consequently the occurrence of acute cardiovascular events such as myocardial infarctions and strokes may be reduced.
This PhD research program has been uniquely articulated as compared to the traditional doctoral courses s, where each graduate student pursues an individual research project, unrelated to that of other students. The multidisciplinary context of the MOGLYNET doctorate provided our 12 Early Stage Researchers (ESRs) a holistic view on different research approaches to the same overarching research question.
The contribution of the seven industrial partners belonging to the Consortium has been of fundamental importance in equipping our ESRs with a strengthened and complementary entrepreneurial culture.
The research work of the Moglynet Consortium was structured into two priority activities i) the scientific and ii) the training programme.

i) The scientific project was structured into three WPs, corresponding to the different objectives.
Two different strategies were pursued to achieve glycolysis inhibition that represents an attractive therapeutic approach to reduce pathological neovascularization and to delay the progression of plaque or induce regression, controlling excessive inflammation and improper immune response. Libraries of small molecules targeted to the kinase pocket and peptides targeting an allosteric site of PFKFB3 were designed and synthesized. The potential role of these modulators - and other glycolytic pathway flux key players - in endothelial dysfunctionality associated to comorbidities in patients with atherosclerosis was investigated.
In summary the main goals achieved in terms of targeting angiogenesis are
a) the selection of very active PFKFB3-Kinase modulators significantly suppressing the key steps of inflammatory angiogenesis and markedly impaired capillary-like tube formation. One of them was radio-synthesised and tested in vitro and in vivo, showing capacity and potential to image the atherosclerotic plaque in mice using Positron Emission Tomography;
b) the demonstration that 3PO inhibits glycolysis and angiogenesis in a PFKFB3-independent manner;
c) an innovative and indirect strategy for the modulation of PFKFB3 activity was achieved through allosteric bisphosphatase modulation. This new strategy might be of interest for achieving a finer regulation of glycolysis without the risk of an off-target interaction with other kinases. The identified compounds could be valuable probes to study PFKFB3 under a so far unexplored condition.

ii) Training activity. One of the main aims of the Moglynet programme has been to create a common knowledge and language for the next generation of researchers working in the highly multidisciplinary field of drugs design and development. Several courses and workshops were organized with different scientific topics related to the project, and two summer schools on i) “PET Imaging and Radiopharmaceutical Development” and ii) “Pharma skills” open to external scientists. Advanced courses on specific topics were delivered at the six Doctoral Courses/Schools of the five beneficiary institutions.
Dissemination Activity. The Consortium paved the way to establish fruitful communication and dissemination strategy about the Moglynet activities.
- The Moglynet website (http://www.moglynet.com/website/) a Moglynet Brochure were created
- a video on the Moglynet Consortium was produced (https://www.youtube.com/watch?v=f4UTwbVshnk);
- Articles on non-specialized press/Blogs were delivered (PLATINUM - BUSINESS LEADERS, IMPACT, Universiteit Antwerpen Magazine etc)
- Events “Tu lo conosci il farmaco” http://portalevideo.unimi.it/media?mid=664 for students of secondary schools; FOS and AIO at Leiden and others were delivered.
- 70 posters/oral communications were delivered by ESRs.
- 27 open-access scientific papers on peer reviewed journals were published.
- Events “Tu lo conosci il farmaco” http://portalevideo.unimi.it/media?mid=664 for students of secondary schools; FOS and AIO at Leiden and others were delivered.
- 70 posters/oral communications were delivered by ESRs.
- 27 open-access scientific papers on peer reviewed journals were published.
MoGlyNet operated in the firm belief that strategic alliance and partnership with industry has to be developed to a far greater extent with the aim of generating researchers with a holistic mind-set thoroughly educated and trained in Drug Discovery and Development. The Consortium exposed ESRs to both training and work practices with a focus on the development of critically important Pharma-skills , to enhance European competitiveness simultaneously increasing the ESRs chances of employment in a knowledge-based society.
The impact of the Moglynet programme in the ESRs future career has already proved to be extremely positive. As a main goal, out of the 12 ESRs, 7 have been already awarded a PhD and all of them currently have a new position in Academia or Industry.
The Consortium was very successful in terms of scientific dissemination of the results contributing to a better understanding of the atherosclerotic process. Since the atherosclerotic cardiovascular disease is a disease of aging and one of the major causes of death in the western world, Moglynet contributed to the generation of knowledge that will eventually have a positive social and economic impact in terms of improved citizens' health and better treatment options. Communication between the scientific community and the general public was promoted to raise knowledge and awareness on the progress of research on atherosclerosis.
As a final result, we believe that by successfully implementing the original Moglynet programme, we demonstrated that this “European Joint Doctorate Format” can be translated to future interdisciplinary joint doctoral schemes simply by changing research topic but maintaining the same training structure. Finally, thanks to the effectiveness of the communication and dissemination initiatives, we contributed to building a positive public attitude towards the researchers’ profession, thereby encouraging the next generation to embark on a career in research.
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