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Combatting the CardioRenal Syndrome: towards an integrative Analysis to reduce cardiovascular burden in chronic kidney disease

Periodic Reporting for period 1 - CaReSyAn (Combatting the CardioRenal Syndrome: towards an integrative Analysis to reduce cardiovascular burden in chronic kidney disease)

Reporting period: 2018-01-01 to 2019-12-31

Successfully combatting a complex disease requires multi-disciplinary and methodically well-trained scientists. CaReSyAn strives to accomplish exactly this: we are training young scientists to successfully integrate proteomics, clinical, experimental and bioinformatical analyses to enhance the understanding, diagnosis and therapy of the cardiorenal syndrome (CRS). CRS comprises disorders of the heart, vessels and kidneys, including the increased development of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). With ~45% of all deaths in CKD patients caused by CVD, the socio-economic burden of CRS is extremely high.
CaReSyAn is training scientists in a close cooperation between academia, SME and industry partners. Key objectives are to provide: 1) Excellent scientific training on CRS pathology, integrating clinical/mechanistic knowledge with technological skills (animals and in vitro, molecular and functional studies, proteomics and bioinformatics) to generate innovative insights triggering the understanding, diagnosis and treatment of the CRS; 2) Excellent complementary skills in personal and career development as well as business training required to extend beyond scientific research; and 3) ,, required to build bridges between researchers and entrepreneurs and support the future translation of research findings in innovative products and services.
CaReSyAn builds on advanced technologies and established cooperations. CaReSyAn is complementary to ongoing European programs focusing solely on CKD or CVD and strives to synergistically improve structural training on European level. CaReSyAn will nurture the development of young, broadly-trained scientists able to successfully bridge clinical with basic research as well as academia and industry. This is a cornerstone in effectively combatting complex diseases as the CRS, a major killer of this century.
We have trained early-stage researchers (ESRs) to successfully integrate proteomics, clinical and experimental analyses to enhance the understanding, diagnosis and therapy of the CRS. Trainings also included improvement of technological as well as complementary skills, and this with exposure to both academic and non-academic environments. Different training activities were organized in cooperation with complementary research consortia to synergistically improve structural training on European level.
On research level, we are contributing to the identification of CRS biomarkers. ESR1 and ESR2 already significantly advanced in the peptidomics/proteomics analysis of CRS biomarkers in plasma, and ESR3 performed a peptidomics analysis of CRS biomarkers in urine samples. Building on biomarker studies, ESR4 is being extensively trained to integrate omics datasets with clinical data in order to generate high dimensional network models of the CRS using a bioinformatics and biostatistics approach.
Complementary to biomarker studies, we are performing mechanistic studies to (i) Examine novel therapeutic strategies for CRS; (ii) Reveal underlying mechanisms of increased vascular calcification and aging in CKD patients; (iii) Reveal the direct effect of uremia on relevant cell types; and (iv) Perform proteomics/peptidomics analyses as measure for vascular calcification and cardiovascular disease in CKD. In the past period, ESR5 in very close cooperation with the associated partner RDN has tested the effect of novel identified peptides on vascular calcification. Also, ESR6 has worked hard to develop novel therapeutic strategies in CRS with a focus on a specific protein which was identified as a novel potential therapeutic target in CRS. ESR7 and ESR11 have studied the effect of uremia on vascular remodeling and calcification, respectively, cardiac cells, whereas ESR8 revealed novel mechanistic insights into vitamin K-deficiency as a mediator of vascular calcification in CKD. In relation to candidates for vascular calcification in CKD, ESR9 has studied post-translational modifications of calcification regulators as link between CKD and CVD in CRS. Finally, ESR10 has studied endothelial function and arterial stiffness in CKD, as well as premature vascular aging and biomarkers of vascular calcification in very close cooperation with associated partner RDN.
All combined, the ESRs have joined efforts to reveal novel biomarkers as well as novel mechanistic insights into CRS, which is a cornerstone in effectively combatting complex diseases as CRS. All deliverables have been submitted in time.
CRS forms a major socio-economic problem and current diagnostic and therapeutic possibilities are limited and not able to combat CRS. We are putting strong efforts in optimal dissemination of the scientific results to relevant stakeholders, including the scientific community, industry and reimbursement agencies, with the aim to increase awareness of the large socio-economic burden of CRS, the importance of biomarkers and disease network modelling, as well as the importance of functional studies in identifying pathological mechanisms and novel therapies.
In relation to training, CaReSyAn is providing mechanistic, technological and complementary training covering to the whole workflow of biomarker and therapy development. This also includes complementary skill training essential for personal and career development; business and ethical training. Also, the ESRs are being integrated with SME partners and industry partners as associated partners, being important stakeholders in the biomarker implementation process. Together, this will enable the generation of multidisciplinary researchers skilled to combat complex diseases and successfully build bridges between clinicians, researchers and companies. Furthermore, this multi-disciplinary training programme will ensure that the ESRs will graduate as scientists trained in facing current scientific challenges using advanced technological tools that are widely applicable in both academia and industry, thereby substantially enhancing their research career prospects.
Also on research level, CaReSyAn advances beyond the current state of art by combining all aspects of disease research (biomarkers, modelling, mechanistic insight, therapy and diagnosis methods). . Proteomics/peptidomics analyses of diseases have already been proven successful by our partners. The use of bioinformatics/systems medicine to mechanistically model diseases provides an unrivalled approach to understand, diagnose and treat diseases, and translate research results into innovative health care products. Complementary, we are investigating the role of previously identified biomarker candidates for CKD in the cardiovascular pathology of CRS in mechanistic studies, thereby contributing to novel therapeutic strategies and initiating translation of proteomics results.