Institute of Experimental Endocrinology
Slovak Academy of Sciences
The Institute of Experimental Endocrinology of the Slovak Academy of Sciences (SAS) was established in 1954 on the basis of the Institute of Endocrinology of the Ministry of Health, founded in 1951. Over the years 1951 – 1971, the mailing address of the Institute was Štefánikova Str. 1a. Since 1971 up to the present, it has been located within the area of institutes of medical sciences at the “SAS Kramáre campus”, on Vlárska Str. 3, Bratislava.
The founder and first Head of the Institute was Assoc. Prof. Julian Podoba, MD, PhD. (1954-1969). He was succeeded by Ladislav Mikulaj, MD, PhD (1969-1971), Ladislav Macho, MD, PhD, DSc. (1971-1990, 1991-1995), Milan Vigaš, MD, PhD, DSc. (1990-1991), Dr. Richard Kvetňanský, PhD, DSc. (1995-2003), Vladimir Štrbák, MD, PhD, DSc. (2003-2007), Prof. Iwar Klimeš, MD, PhD, DSc. (2007-2013), doc. Boris Mravec, MD., PhD. (2013). At present, Head of the Institute is Štefan Zórad, Ing., CSc. (2013-2015).
For the time being, the staff of the Institute consists of 89 employees. Of these, 40 are scientific workers, 8 hold the title of DSc, 32 of PhD, two are Full Professors and one is Associate Professor, all at the Comenius School of Medicine in Bratislava. The Institute is accredited as an educational institution in postgraduate studies in Normal and Pathologic Physiology, Animal Physiology and Biochemistry.
Scientific orientation of the Institute
In the initial phase, research of the Institute was focused on elucidation of the occurrence and causes of origin of the endemic goiter in Slovakia. A negative relationship was established between the prevalence of goiter in individual regions of the country and the intake of iodine. Based on these results, addition of iodine to table salt has been implemented. This preventive measure resulted in increased iodine intake and decreased incidence of goiter, particularly in the younger generation. Further, the scientific activities of the Institute developed in accordance with the existing world trends in research into functions of the endocrine system and its regulation in the course of ontogenesis, and on exposure of the body to different kind of stress.. The focus was also on mechanisms of the hormone action and on the pathogenesis of selected endocrinopathies and metabolic derangements, with special attention also on issues concerning social and health care requirements of the society.
In the year 2000, the Institute became a Centre of Excellence of the European Union based on the project “Reduction of negative impact of environmental factors on human health” (STRESSNUTS). Moreover, the Institute was involved in a remarkable number of other important scientific projects of the 5th and 6th Framework Program of the European Commission (e.g. PCBRISK, VITAGE, ENDOMET, DROSDEL, DANUBIAN BIOBANKING, and CASCADE).
At present, the Institute is involved in a large-scale integrating project of the 7th Framework Program of the EC with the acronym LIPIDOMICNET, as well as in 5 projects of the EU Structural Funds: TRANSENDOGENE, ALPHA GENETICA, TRANSMED-1, TRANSMED-2, and COMPETENCE CENTRES IN MOLECULAR MEDICINE.
In 2003, the Institute of Experimental Endocrinology, SAS and the National Institute of Endocrinology and Diabetes in Lubochňa established a joint laboratory – DIABGENE - engaged in genetic studies of monogenic forms of diabetes, obesity and familial hypercholesterolemia, selected thesaurismoses or deafness with metabolic derangement. In the years 2007-2010, the Institute was the leading workplace of a SAS Centre of Excellence (CENDO) researching in neuroendocrine mechanisms of the pathogenesis of selected diseases.
Results and contributions
The number of publications is kept at a high level (approx. 40 publications annually in impact journals) and the same applies to the number of citations (ranging from 700 – 900 per year.). As to the citation rate, the Institute ranks among the top establishments of the Slovak Academy of Sciences.
When looking back, beside of the initiation of higher iodine intake by iodinating the tabel salt, the Institute has elaborated also the screening methodology for identification of inborn disorders of the neonates leading to congenital hypothyroidism. These activities led to launching a nation wide screening of all neonates for the aforementioned desease. Research of the effects exerted by an analogue of the hormone vasopressin – desmopressin (DDAVP) – resulted in the development of a test for fast determination of the concentration capacity of the kidney, which has been recommended for clinical use.
The DIABGENE Laboratory is the only DNA diagnostic and research lab in the field of diabetology and endocrinology in Slovakia. It participates in internationally coordinated projects focused on diagnosis of monogenic forms of diabetes. The most outstanding result achieved was the finding that patients with permanent neonatal diabetes with specific mutations in the genes for the Kir6.2 subunit of the KATP channel of pancreatic B-cells can be switched from the symptomatic insulin therapy to causal treatment with derivatives of sulfonylurea. A further important outcome was the first determination of the prevalence of permanent neonatal diabetes in Slovakia, as based on the National Children Diabetes Registry data.
The Institute participated in the international program investigating the effects of space flight and microgravity on the human and animal body. The Institute supplied experimental animals for space flights of biosputniks of the Kosmos series. Within the scope of international cooperation, changes of endocrine functions were studied in cosmonauts from Russia, France, Austria, and Slovakia. These investigations involved the use of our complex equipment Plasma 01 and 02, which allowed withdraw and process blood directly on board the spacecraft. In 1999, during the flight of the first Slovak cosmonaut, researchers of the Institute completed three projects within the framework of the scientific program ŠTEFÁNIK.
4. International cooperation, international symposia
Appreciation of the scientific achievements of the Institute has been manifested by an abundant international cooperation with institutions abroad (more than 100 institutions in 22 countries). The focus of these cooperations was on neuroendocrine regulations in response to stressors, on the role of lipids, particularly fatty acids, in the origin and development of insulin resistance, on the occurrence of natural goitrogens, on mechanisms of hormone action and expression of genes induced by hormones.
Commissioned by international scientific organisations and/or by the researchers per se, the Institute organized 28 international symposia, several of them with quadrennial periodicity, e.g. on catecholamines in stress (10 symposia), on insulin and lipid metabolism (4 symposia), developmental endocrinology and hormones in milk (6 symposia), on the function of the thyroid gland, goitrogens and iodine metabolism (3 symposia), and one congress of the working group at the European Association of Diabetology (EASD) on Genetics of Diabetes.
Institute of Experimental Endocrinology, SAS, is nowadays trying to focus on the translational medicine, i.e. vertical transfer of data and knowledge from the lab bench to the patients bed side.
Pharmacogenomic results achieved in the DNA diagnostic laboratory DIABGENE are utilized not only to fulfill scientific aims but also for the benefit of the patient. The outcome of research activities is transferred into pharmacogenomic recommendations for the clinical diabetologists to adjust the treatment to the individual requirements of patients with monogenic disorders of the of insulin secretion.
In the field of translational medicine, 10 papers were published in extenso over the last five years. They appeared in journals with high impact factor, including the paper published in 2006 in the New Engl J Med (with the second highest impact factor in the field of biomedicine, i.e. IF = 51.296).
PRESENT-DAY RESEARCH TRENDS OF THE INSTITUTE
Laboratory of Cellular Endocrinology (LCE)
Mechanisms of action of endocrine disruptors are studied at cellular and molecular level. Substances mimicking the action of hormones while polluting the life environment are in the focus of research. Using cell cultures of different tissues, the aim is to reveal the effects of various industrially used plasticizers with estrogenic activity, of derivatives of phenols and phthalates and of their combination with natural hormones on cell proliferation, metabolic processes and on genomic and non-genomic mechanisms of action. Exposure to these chemical substances involves a serious health risk not only for humans but also for farm animals and wild-type animals.
Laboratory of Developmental Genetics (LDG)
Hormonally controlled ontogenetic processes, particularly metamorphosis, are studied on the ideal genetic model of the fruit fly Drosophila melanogaster. The main research targets include: (1) hormonally responsive genes operative in initiation and regulation of cell differentiation and morphogenesis, (2) genes participating in hormonally controlled programmed cell death, (3) identification and analysis of the function of genes coding for basal metabolism and post-translational modifications which perform cell- or time-specific functions in the course of postembryonal developmental phases of Drosophila melanogaster.
Laboratory of Diabetes and Metabolic Derangements (LDaMD)
Research is focused on genetics of monogenic forms of diabetes and on molecular mechanisms of obesity and insulin resistance development. The aim is to provide genetic diagnosis of different forms of monogenic diabetes for the patients with diabetes and their families throughout Slovakia. Subjects with different subtypes of monogenic diabetes are actively searched, and their DNA stored in the DNA repository. In newly identified mutations, the pathomechanism of diabetes development has been studied. In clinical studies, research is focused on the endocrine role of adipose tissue in relation to molecular mechanisms involved to the development of insulin resistance, obesity and diabetes. Metabolic pathways are investigated in patients with different tolerance of glucose and in patients with growth hormone deficit. Molecular biology processes of patients with obesity and/or diabetes are investigated by the most up-to-date methods of genomics, transcriptomics, and lipidomics.
Laboratory of Functional Neuromorphology (LFnM)
Study of the complexity of the vagus nerve is the central aim of the Laboratory. The role of the central nervous system in the etiopathogenesis of diseases of peripheral tissues is investigated with focus on the involvement of the vagus nerve monitoring and modulating tumour growth. Further research areas concern the participation of the vagus nerve in inflammatory processes accompanying ischemia–reperfusion-induced liver damage and depression, as well as its share in controlling the activity of the sympatho-adrenal system in stress response.
Laboratory of Human Endocrinology (LHE)
The centre of research activities concerns physiological processes in healthy subjects as well as pathophysiological mechanisms and the role hormones play in metabolism and chronic inflammation both in selected endocrine and nonendocrine diseases (diabetes mellitus type 2, hypertension, metabolic syndrome, rheumatoid arthritis, systemic sclerosis). Examination procedures applied in the Laboratory include: the technique of insulin clamps, biopsy of adipose tissue, microdialysis of adipose tissue, insulin hypoglycemia, orthostatic tests, pharmacological tests, analysis of heart rate variability, etc.
Laboratory of Metabolic Regulations (LMR)
The Laboratory studies the participation of hormones in controlling metabolism with particular focus on adipose tissue. The main target of investigation is the regulatory role of angiotensin II and of oxytocin in adipogenesis and the responsiveness of the tissue to insulin. In light of the results obtained so far it can be assumed that angiotensin II inhibits adipogenesis and contributes to the hypertrophy and insulin resistance of adipose tissue. Oxytocin, on the other hand, stimulates the genesis of new adipocytes and increases the expression of markers of insulin sensitivity. Animal models of obesity and insulin resistance are used to study proteins presumably possessing protective and compensatory functions in the early phases of metabolic disorder. Further, in rats, experimental models of rheumatoid arthritis, adjuvant arthritis, are employed in investigating immuno-endocrine relationships.
Laboratory of Molecular Endocrinology (LME)
The research focus is on elucidating the mechanisms of action of analogues of retinoic acid and vitamin D3 with regard to their corresponding nuclear receptors, coregulators, and selected target genes and in view of endogenous and exogenous factors which may affect the expression of corresponding transcription factors that canbe induced by biologically active ligands. The feasibility of therapeutic intervention in tumour growth is studied on the model of chemically induced carcinogenesis of the mammary gland in the rat and on human tumour cells. Research outcomes are transposed into clinical studies to reveal the role of nuclear receptors in the therapy of tumours of the thyroid gland, mammary gland, and kidney.
Laboratory of Neurobiology (LNb)
To study the role of the nervous system in ethiopathogenesis of the peripheral diseases (tumors, metabolic). We are focusing on investigation of the mechanisms and neuronal pathways involved in the signaling related to the pathological processes in the peripheral tissues, processing of the signals in the brain and on the adaptive/compensatory responses of central nervous system to the pathological processes at the periphery.
To study the role of signals transmitted by afferent neuronal pathways to the brain on the neuroendocrine stress response of the organism: role of the vagus nerve in the regulation of sympathoadrenal activity during the stress reaction, role of the feedback mechanism of the vagus nerve afferent pathways on the activity of catecholaminergic neurons and adrenal medulla in the rat.
To study the potential of therapeutic application of stem cells in treatment of experimental glioblastoma.
Laboratory of Neurohumoral Regulations (LNhR)
Humoral mechanisms and their role in controlling the secretion of neuropeptides in the pancreas, brain, and heart are studied in vivo and in vitro. The primary issue under study is the mechanism of secretion brought on by changes of the cell volume, as an unconventional mode of inducing exocytosis. So far, the signalling pathway of this stimulation remains unclear. Particular attention is given to the study of secretory reactions of tumour cell lines and to the role Ca2+ plays in the mechanism of their response. A further field of research concerns encapsulation of pancreatic islets by a polymer which would provide their protection, thus broadening the possibilities of their transplantation without immunosuppression.
Laboratory of Pharmacological Neuroendocrinology (LPNe)
Research is oriented on regulatory mechanisms operative in stress response, on negative consequences of stress and on possibilities of their pharmacological modulation. Animal models of depression, selective enhancement of stress hormones, and of increased brain plasticity have been developed. Main attention is given to selected mechanisms present in the brain and peripheral tissues (e.g. markers of brain plasticity and neurogenesis, gene expression), evaluation of neuroendocrine activation, of anxiety and depression-like behaviour. Non-traditional effects of hormones are studied, particularly of aldosterone and oxytocin. In healthy volunteers, noninvasive examination methods have been developed to assess the ability to cope with stress situations.
Laboratory of Stress Research (LSR)
The laboratory investigates the mechanisms of activation of the sympatho-adrenal system (SAS) in stress and during adaptation of the organism to chronic or intermittent exposure to different stressors. The main targets are processes of catecholamine (CA) biosynthesis, the levels of mRNA enzymes involved in CA biosynthesis in the adrenal medulla, sympathetic ganglia, heart, and various brain regions, while special focus lies on processes controlling the expression of genes coding for enzymes of CA biosynthesis. Mechanisms involved in the effects of stress on SAS are studied in mice with knocked-out genes for the synthesis of CA enzymes, corticoliberin synthesis, or the c-fos gene. Activity of SAS is studied also in animals exposed to hypergravitation in the centrifuge as a model of aircraft take-off or the launching of spacecraft. The mechanisms of action of chronic stress on the origin and development of Alzheimer’s disease represent a further target of research of the Laboratory.