Our research integrates translational medicine studies in the metabolomics, medical biochemistry and functional-structural properties of arteries resultin outcomes concerning prevention of diseases, diagnostics (including subclinical conditions) and more targeted therapy. Our main task is to initiate research what provides systemic data needed for development of novel translational medicine platform (arteriobolomics) via metabolomical (MET) and arterial wall (AW) phenotyping. Our main focus is phenotyping of peripheral arterial disease (PAD) and chronic obstructive pulmonary disease (COPD) (crucial causes for disability and mortality in EU). We plan to combine for the first time MET and AW functional-structural (AWFS) phenotyping in setting of PAD and COPD. Integration between MET and other systems biology approaches allows to identify crucial molecular-metabolic changes and new risk markers. As an impairment in AWFS phenotype is a cornerstone of cardiovascular diseses (CVD) we will elucidate which exact interruptions of AWFS lead to the progression of PAD and COPD and their complications. We hope to start describe also subclinical phenotype of PAD and COPD. Additionally we investigate neuroendocrinologic aspects of various deseases (e.g. schizophrenia) concerning oxidative stress, prediabetes, diabetes, inflammation and metabolomics. Our group belongs to the Centre of Excellence for Translational Medicine, the Centre of Translational Genomics, the Comptence Centre for food biotechnology and our research is supported by different grants ( Estonian Research Council: 0182548As03, IUT20-42; ESF: 7856, 7494; Enteprise Estonia, European 5th Frameproject; European Union through the European Regional Development Fund)
Metabolomics is the qualitative and quantitative analysis of the human body's metabolism's low-molecular weight intermediates and end products to characterise the conditions/diseases of an organism caused by metabolic changes and to find new biomarkers for early disease detection, monitoring and description over the course of treatment. Bioinformatics: the analysis of metabolomical data needs comparison of large data sets (e.g. patients and control groups) to find distinctive variations and descriptors. The Metabolomics research group works in the core laboratory which was initiated by prof. Mihkel Zilmer and prof. Ursel Soomets. The laboratory is currently lead by the general manager Ursel Soomets and senior research fellow Kalle Kilk. The PhD students working in the lab on a daily basis are Argo Aug, Aigar Ottas and Rando Porosk. In general, mass-spectrometric or nuclear magnetic resonance based analyses are used for the description of different metabolomes. MALDI-TOF Voyager DE PRO, API 3200 and API 4500 ESI MS/MS apparatuses are available in our laboratory. ESI MS apparatuses also include high performance liquid chromatographs - two analytical chromatographs (Shimadzu and Agilent Technologies) and one nano HPLC (Agilent Technologies). Projects are carried out in collaboration with Estonian and foreign partners (Tartu and Tallinn Children's Hospital; UT Lung Clinic, Kings College, London; Institute of Biotechnology, Manchester; etc.).
The current bio- and translational medical studies of Metabolomics research group include:
- the metabolomical analysis of blood serums of patients with COPD and of peripheral arterial disease to explain how these diseases are related to each other;
- the metabolomical characterisation of COPD patients' blood serums and exhaled breath condensates and comparison with healthy individual's metabolomes;
- the description of changes in the lung cancer tissue metabolomes compared to healthy tissue metabolomes;
- the analysis and comparison of psoriasis, vitiligo and melanoma patients' skin biopsies, blood serum and exhaled breath condensate metabolomes to reveal the molecular background behind the development of these diseases;
- the analysis of neonatal blood serum acylcarnitines levels in collaboration with Estonian Children Hospitals to detect mitochondrial dysfunction in children;
- the description of wolframin Wfs1 knockout mice metabolomes in various tissues;
- the analysis of cow milk metabolome in cooperation with the Estonian University of Life Sciences to clarify the impact of low molecular weight compounds on the coagulation of milk and the effect of feeding and lactation stage on the health status of the cows;
- the design, synthesis and bioactivity studies of novel antioxidant glutathione analogues.
Assessment of functional-structural properties of arteries
Atherothrombotic cardiovascular diseases are the leading cause of death in the world, as well as in Estonia. In comparison with the other European Union countries, the mortality of cardiovascular diseases within working-age women and men is two- to threefold higher. The key point for reduction of atherothrombotic cardiovascular diseases could be improvement of present prevention and treatment strategies, and scientific elaboration of novel integrated evidence-based strategies. Very important are interdisciplinary clinical-molecular investigations in the clarification of the mechanisms of atherogenesis and in evaluation of prognosis and efficiency of treatment. The importance of understanding the mechanisms of atherosclerotic cardiovascular disease reflects the need to reduce human morbidity and mortality. Understanding of these disease states and their disturbances requires clarification of biochemical (e.g. metabolomic), functional and structural changes in the vascular phenotype over time, and the effects of pharmacologic, surgical, and interventional treatments. The main scientific aim of our project is to develop novel “know-how” for pathogenesis-based management of atherosclerosis. We carried out the biochemical (oxidative stress- and inflammation-based biomarkers, low-molecular metabolites), functional (endothelial function and arterial stiffness) and structural (intima-media thickness (IMT) and arterial calcification) profiling of arterial damage in atherosclerosis. This project gives an opportunity for integrated approach to research, prevention, optimization of treatment and assessment of prognosis. Moreover, for this purpose, the first specialized scientific laboratory in Estonia for functional-structural assessment of arteries – Endothelial Centre – was established within the Clinic of Cardiology in 2004. There were defended successfully 3 master and 5 doctoral dissertations during last nine years, and three doctoral dissertations are in progress. We have established international scientific contacts between the University of Tartu and Kuopio, Uppsala, Cardiff, Cambridge and Macquarie Universities. Our main reasearch staff includes professors Mihkel Zilmer and Jaan Eha, senior researhers and physicians Priit Kampus and Jaak Kals, doctors Maksim Zagura, Martin Serg and Erik Salum, PhD students Kaido Paapstel, Kaspar Tootsi and Triin Kaldur. For assessment of endothelial function, arterial stiffness and central blood pressure we used pulse wave analysis and pulse wave velocity measurements (Sphygmocor Px, 7.0, AtCor Medical®, Australia; HDI/Pulse Wave CR-2000, Hypertension Diagnostics Inc®, USA), for IMT as well as for heart studies we used ultrasonogaphy (SonoSite M-Turbo, SonoSite Inc., USA; Sonos7500, Philips Medical Systems,Inc., USA), for aortic calcification we used computed tomography (GE LightSpeed 16, General Electrical Medical Systems, Milwaukee, Wisconsin, USA) and for measurement of severity of lower limb atherosclerosis we used ankle-brachial pressure index (D.E, Hokanson, Bellevue, Washington, USA).
Ongoing translational studies in Endothelial Centre:
- Scientific elaboration of the most effective complex of methods for arterial biochemical (low-molecular metabolites, biomarkers), functional (endothelial function, arterial stiffness) and structural (IMT, calcification) profiling and introduction into clinical practice (in collaboration with Departments of Cardiology and Vascular Surgery).
- Evaluation the impact of arterial dysfunction in progression of atherosclerosis, development of complications and total mortality and cardiovascular disease mortality (in collaboration with Department of Vascular Surgery).
- Assessment of effects of remonte ischemic preconditioning on arterial stiffness in healthy volunteers.
- Measurement of relationships between aortic calcification and vitamiin D level in progression of aortic stiffness in atherosclerosis (in collaboration with Department of Vascular Surgery).
- Assessment of different effects of drugs on periperal and central blood pressure, arterial stiffness and left ventricle wall thickness (in collaboration with Department of Cardiology).
- Elucidate the potential vasculoprotective effects of vitamiin D in rat diabetes mellitus model.