Heart at Target, joint meeting of three FP7 consortia on Cardiovascular research

Heart at Target, joint meeting of three FP7 consortia on Cardiovascular research

On Tuesday the 27th and Wednesday 28th of September 2016, three consortia of EU FP7 projects which are focused on identification and validation of new targets for drugs in cardiovascular disease organized a joint meeting in Zandvoort, The Netherlands.  The three projects started in October 2013.

The meeting started on Tuesday afternoon with a session opened by the project officer of the CarTarDis project officer, Dr. Grzegorz Owsianik. Dr. Owsianik stressed that CVD is still the main cause of death in Europe and therefore a very important research area supported by the EU in FP7 projects but also several projects under the H2020 funding. Demonstration of this support are the three project consortia that were presented by their coordinators and he called this joint meeting an excellent and unique initiative in which the important issue of knowledge sharing in R&D is shown in optima forma.

The CarTarDis consortium, introduced by the coordinator, prof. Dr. A. van Gool (TNO) aims to identify and clinically validate targets that are suitable to start pharmaceutical drug screening and further development. The coordinator of the CVgenes@target consortium, prof. Dr. H. Schunkert (German Heart Centre Munich) explained that this project aims the exploitation of genomic variants affecting coronary artery disease and stroke risk for therapeutic intervention, while the Transcard consortium, presented by coordinator prof. Dr. J.A. van Kuivenhoven (UMCG) aims for translating disease into cardiovascular health by identifying new targets for pharmaceutical intervention.

The introductions were followed by presentations of two highlights from each consortium.

Dr. N. Samani from the University of Leicester, UK, representing CVgenes@target informed the audience on the latest developments in the translation of genetic discovery into mechanisms and development of novel therapies. Dr. P. Gibbon from Fraunhofer Institute, Germanyshowed the added value of phenotypic screening in target validation strategies and in compound repurposing.

Prof. dr. A. Tybjærg Hansen from Rigshospitalet in Copenhagen in Denmark and representing The Transcard project showed how very valuable information can be extracted and different hypotheses on targets can be validated in large human populations. One example is the Copenhagen cohort in which thousands of individuals are followed for an average of 24 years, collecting genetic data, clinical data and incidence of cardiovascular events. Second highlight from the Transcard project was presented by Dr. A. von Eckardstein, University of Zurich. He showed new technology development in high-troughput microscopy and high-content screening using optimized in-vitro assays.

Dr. E. Hurt-Camejo, AZ, Stockholm, Sweden from the CarTarDis consortium is a representative of big pharma industry and gave the audience a comprehensive overview of pharma workflows in target discovery. She explained that the high attrition rates for new drugs, that pharma industry has been confronted with in the past few years, despite high investments in discovery can partially be explained by the fact that the new targets were often not causally linked to the disease and often the genetic evidence was very weak. These observations were now incorporated into the AZ target discovery workflow which was also adopted by the CarTarDis consortium.

Dr. K. Holmstrøm from Bioneer, Copenhagen presented the multimodal molecular imaging capabilities of the CarTarDis consortium, which are quite unique as they are comprised of several state of the art technologies, such as mass spectrometry imaging, in-situ-hybridisation for mRNA detection and classical IHC stainings. These imaging techniques were used to visualize the expression of the CarTarDis selected targets in biobanked CVD tissues.

In addition to the goals and highlights from the consortia, the second day was a networking event with pitches of the available technologies presented by the academia and SME’s. The three FP7 consortia seek further collaboration and aim to efficiently use the resources and expertise represented within the consortia.

With 60 participants from the three consortia, represented by researchers from academia, several SME’s and big pharma, from 15 European countries, the attendance exceeded our expectations. This joint meeting resulted in informal interactions, discussions and new collaborative initiatives. This open sharing of technologies and latest research results leads to optimal dissemination of latest developments supported by the EU and thus aids the increase of output from these research projects in a very relevant disease area.

For more information about the two other consortia please follow the links below:

http://cartardis.eu/

http://cvgenesattarget.eu/

 

Srividya Velagapudi about her research in the TransCard project

Atherosclerosis is a leading cause of death worldwide and is characterized by accumulation of lipids and lipoproteins in the arterial vessel wall. Low density lipoproteins (LDL) as well as high density lipoproteins (HDL) have to pass the endothelial layer, which is the inner cell layer of blood vessels to exert their pro- and anti-atherogenic activities respectively. The best documented anti-atherogenic effect of HDLs is their capacity to remove excess cholesterol from the peripheral tissues and transport it back to the liver for its subsequent elimination in bile. This process is called Reverse cholesterol transport (RCT). The first step of RCT is transfer of cholesterol from lipid-laden macrophages (foam cells) to HDLs. However, in order to reach the foam cells within the arterial wall, circulating HDLs have to cross the endothelial layer via transcellular route (transcytosis). Our laboratory identified ATP binding cassette transporters A1 and G1, scavenger receptor B1, endothelial lipase and ectopic beta-ATPase/P2Y as rate limiting factors. However, they are docking receptors rather than endocytic receptors. Therefore, we are now focused on identifying the endocytic receptor as well as signaling events regulating the internalization of HDL into endothelial cells. We performed a high content screening (HCS) that allows multi-parametric analysis of biological features in single cells following treatment with drugs inhibiting kinases which are critical in cell signaling, metabolism, cellular transport and many other cellular pathways. The sublime expertise of our lab supported to breeze-through all phases of HCS workflow: assay development and validation, lab automation and screening, automated microscopy, and data analysis. Widefield-fluorescence microscopy helped to track the location and intensity of fluorescent labelled HDL in drug-treated human aortic endothelial cells (HAECs). This screening identified a signaling cascade that we are currently validating. Based on our preliminary data, we are confident that our project addresses a key question in the pathogenesis of atherosclerosis namely how HDL enters the vascular wall.