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SYSVASC Report Summary

Project ID: 603288
Funded under: FP7-HEALTH
Country: Austria

Periodic Report Summary 2 - SYSVASC (Systems Biology to Identify Molecular Targets for Vascular Disease Treatment)

Project Context and Objectives:
The goal of the sysVASC project is to identify molecular targets for cardiovascular disease (CVD) treatment. CVD is the leading cause of mortality and morbidity in Europe and worldwide. Before patients are diagnosed and treated, asymptomatic vascular damage can accumulate for years. Prognostic biomarkers remain widely elusive and personalised risk assessment relies on rough estimates based on traditional risk factors. The underlying pathophysiological changes remain incompletely understood, which is reflected in the lack of therapeutic options. The main clinical needs faced in CVD are: (i) a better understanding of the key pathogenic factors involved in the progression of CVD independent of aetiology, (ii) the diagnosis of asymptomatic disease and (iii) the prediction and prevention of cardiovascular events.
sysVASC aims to overcome this limitation by mounting a comprehensive systems medicine approach to elucidate pathological mechanisms, which will yield molecular targets for therapeutic intervention. The sysVASC Consortium compiles the multi-disciplinary skills and unique expertise necessary to tackle this ambitious task. We will integrate high quality, high resolution molecular omics data from clinical studies in order to comprehensively describe the molecular phenotype of progressive CVD. Statistical modelling will reveal key molecular nodes underlying the progression from early and asymptomatic disease to major clinical events in order to identify targets for specific interventions. These will be initially validated in models best mimicking key pathogenic processes in human disease.
Project Results:
During the second period the sysVASC Consortium has made substantial progress towards identifying molecular targets for cardiovascular disease (CVD) treatment. A public specialised cardiovascular disease knowledge base (CVDKB) was implemented and a live version is available under In parallel, the Consortium continued the collection of high resolution tissue proteomics, urinary peptidomics and metabolomics datasets from well characterized animal models (developed in period 1). In period 2 the Consortium has further expanded the “Graz de novo sample collection” of blood, tissue and urine samples from patients with and without vascular diseases. This sample collection now includes specimens (105 urine samples, 120 blood samples and 504 tissue samples) from nearly 130 patients including transplant recipients, transplant donors and patients with peripheral artery disease. Samples of coronary, iliac, femoral and carotid arteries are available to the Consortium. These were processed by high resolution mass spectrometry and compared to datasets collected in period 1. Placement of findings at individual molecule and pathway levels in the existing knowledge in the field via extensive literature mining and bioinformatics analysis revealed multiple “expected” changes in CVD versus controls (such as alterations in thrombospondins, vitronectin, multiple proteins involved in apoptosis, extracellular matrix remodelling and others) supporting the validity of the approach. Novel findings were prioritized for further investigation by immunohistochemistry (IHC) and interference studies based on a series of criteria including presumed function in disease, druggability, conservation of differential expression in animal models for CVD as well as antibody availability.
The molecular mechanisms behind the first selected targets were very diverse focussing on a not yet studied inflammatory pathway, on epigenetic modifications and control of specific transcription factors in atherosclerosis. The Consortium has selected 10 key targets identified from the initial screens for confirmatory expression studies using IHC; IHC analysis is ongoing and continuing beyond period 2. Interference experiments for the most promising targets have been designed and will be carried out in period 3.
A major advancement of the project was also the selection of the most optimal animal model among the sysVASC models suite based on the molecular similarity with human disease. This similarity analysis has been performed based on urinary peptides, plasma metabolites, as well as tissue protein changes. This result is of great help to guide the selection of the animal models for the interference studies and will generate additional output that describes the molecular make-up of these models.
In order to achieve strong project recognition from the very beginning, a consistent corporate identity was designed for sysVASC. Moreover, a public interest website was launched and regularly updated in period 2 to provide information material, insights into the project and the field of research as well as publications. The latter include a total of 23 publications generated by sysVASC partners in period 2. The Project Management Team has implemented financial and administrative management seamlessly and ensures that the project proceeds towards the anticipated objectives in an efficient and cost-effective manner. During the second reporting period the Consortium met in Athens and Berlin.
Based on the collected data, main specific aims for period 3 include:
a) Completion of interference studies in vivo and in vitro using two of the shortlisted compounds
b) Expansion of the list of druggable targets by cross-correlating the existing -omics datasets with new data (tissue RNA sequencing, plasma proteomics) that are currently generated by the Consortium.

Potential Impact:
Within sysVASC, we implement a systems biology approach to gain knowledge on the molecular pathways underlying CVD. The multidisciplinary effort benefits from (i) excellent preclinical and clinical research centres, (ii) cutting edge omics technological platforms and (iii) unique bioinformatics and statistics expertise. With the broad, essentially hypothesis-free approach sysVASC is designed to become a show-case for the application of systems biology in clinical research and development. The integration of currently disparate data sources will generate a unique comprehensive expandable resource for identifying and validating novel key molecular targets for treatment, thus tackling the lack of interventions specific for CVD and having major scientific, societal and economic impact. Identified targets for CVD treatment will be advanced towards translation into novel therapeutic approaches and may even result in additional products such as biomarkers for diagnostic/prognostic purposes, thereby relieving a major burden to patients and health care systems and promoting CVD treatment towards personalised patient management and individualised targeted therapy.
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