Projects

Mirjana Gurinović, Marija Glibetić, Jasmina Martačić-Debeljak, Marija Takić

Institut za nuklearne nauke ”Vinča”

Collaborators from IMI were engaged in the areas of research on nutragenomics and gene regulation of cardiovascular diseases.

Marija Takić, Milica Zekovic, Biljana Pokimica, Tamara Popovic, Gordana Petrovic-Oggiano, Jelena Milešević, Jasmina Martačić-Debeljak, Marija Knez, Marija Ranić, Irena Krga, Vuk Stevanovic, Marta Despotović, Nevena Kardum, Mirjana Gurinović, Marija Glibetić, Vesna Vučić, Aleksandra Arsić, Danijela Ristić-Medić, Milica Kojadinović, Marija Paunović

 Institut za Biološka istraživanja „Siniša Stanković“, Medicinski fakultet u Beogradu, Tehnološko-metalurški fakultet u Beogradu, Institut za proučavanje lekovitog bilja „Josif Pančić“ i Ekonomski fakultet u Beogradu

The subject of the project is research on the intake and status of folate and polyunsaturated fatty acids (PUFA) in the population of Serbia, which entails 1. literature review to identify at-risk population groups with low intake of folate and PUFA, 2. establishment and validation of methods for assessing intake and status , 3. interventional studies on an animal model, 4. determination of the etiopathogenetic, therapeutic and prophylactic effect of PUFA and folate intake in chronic non-communicable diseases on a human model, 5. market research, producer and consumer perception towards foods enriched with folates and PUFA, 6. dissemination of results scientific and general population.

In Europe, at least 6 agents of zoonotic vector-borne diseases have been identified in which ticks play an important role in transmission (Rickettsia sp., Anaplasma phagocytophilum, Borrelia burgdorferi sensu lato, Francisella tularensis, Crimean-Congo hemorrhagic fever virus, tick-borne encephalitis virus). Our preliminary investigations indicate the presence of A. phagocytophilum, F. tularensis, Rickettsia sp. and five genospecies of the B. burgdorferi complex in ixodid ticks in Serbia. According to epidemiological data, tick-borne encephalitis and Crimean-Congo hemorrhagic fever viruses are present in natural foci on the territory of Serbia, but no systematic studies on their presence in ticks have been performed so far. Research in this project included regular collection of material (ticks from vegetation and hosts, serum samples and host tissues), molecular detection of pathogens in samples, and cultivation, characterization and genotyping of these microorganisms. The research focused on potential natural hosts of these zoonotic diseases. The research results provided a clearer picture of the distribution, genetic diversity, and pathogenic potential of tick-borne microorganisms.

This project aimed to investigate the cellular and molecular aspects of the biology and function of multipotent adult stem cells, specifically hematopoietic stem cells and mesenchymal stromal cells. At the beginning of the project period, mesenchymal stromal cells were isolated and characterized (phenotypically and functionally) from various tissues of human and animal origin, including bone marrow, adipose tissue, umbilical cord, dental pulp, and periodontal ligament. In the following phase, the role and mode of action of various factors, primarily the inflammatory microenvironment, on the functional properties of adult stem cells were investigated, as well as the interaction of mesenchymal stromal cells with hematopoietic, immune, and tumor cells, with a particular focus on their role in immunoregulation and tumorigenesis. This project resulted in over 60 publications and presentations at scientific conferences (including 35 in JCI-indexed journals).

This interdisciplinary project aimed to develop a new system of cold atmospheric plasma for use in biomedicine, environmental control, and nanotechnology. It consisted of four sub-projects: 1) Atmospheric discharges, 2) Plasma application in biology and medicine, 3) Plasma application in positron diagnostics, nanotechnology, and material functionalization, and 4) Measurements of biogenic volatile organic compounds. Institute for Medical Research participated in the second sub-project, led by Professor Pavle Milenković. Within this sub-project, the impact of cold atmospheric plasma on the regenerative properties of human dental-derived mesenchymal stromal/stem cells was investigated, both in vitro and in vivo (the rabbit calvarial critical-size defect model). The result of this sub-project was the publication of several papers in prestigious scientific journals and presentations at numerous international conferences.

Vladan Čokić, Olivera Mitrović Ajtić, Dragoslava Đikić, Teodora Dragojević, Tijana Subotički, Milica Vukotić

Institute for Medical Research, National Institute for Medical Research, University of Belgrade

In order to discover the mechanism underlying frequent thrombosis in hematologic malignancies, it will be initiated the inflammation dependent activation and interplay of endothelial cells, platelets, and leukocytes with subsequent formation of microparticles and nitric oxide (NO) linked to thrombus generation by induction of coagulation and fibrinolysis. Cancer-associated thrombosis (CAT) is the second leading cause of death in cancer patients including both venous and arterial thromboembolism. While CAT can be treated with anticoagulants, benefits of therapy must be balanced with the increased bleeding risks. The coagulation related cells and biomarkers will be analyzed and selected by flow cytometry from the following hematologic malignancies: multiple myeloma, lymphoma, acute myeloid leukemia, and transplanted patients with graft-versus-host disease (GvHD). Besides clinical follow-up of the patients, extensive preclinical studies will be performed using in vitro cell cultures (hypoxia chamber, RT-qPCR, immunoassays), in vivo mouse models (NO analyzer), and in silico profiling. Activation of the coagulation factors will be observed through the prothrombotic properties of endothelium (microchip flow-chamber system), neutrophil extracellular traps (NETs, spectrophotometry) and anticancer treatments. The proposed study will show inflammatory stimulation of hypercoagulability, chemotaxis of immune response, and NET formation as well as modulation of fibrinolytic system and miRNA regulated platelet activation. In addition, the equilibrium between NO production and oxygen tension will largely influence the inflammation-dependent thrombus formation, with a prognostic significance of hypoxia related gene signature. Understanding the principal mechanisms may allow the development of new therapies to safely prevent CAT in the hematologic malignancies and GvHD, while determination of the specific biomarkers in each malignancy can be used as predictors of thrombosis.

PI Vladan Čokić, P2 Juan F. Santibanez, P3 Olivera Mitrović Ajtić, P4 Milica Vukotić, P5 Dragoslava Đikić, P6 Tijana Subotički, P7 Teodora Dragojević

Severe acute coronavirus virus syndrome 2 (SARS-CoV-2)-induced hyperinflammation is a major reason for severe clinical outcome of coronavirus disease 19 (COVID-19), principally in male patients. Cell entry of SARS-CoV-2 depends on binding to angiotensin-converting enzyme 2 (ACE2) and androgen-regulated transmembrane serine protease 2 (TMPRSS2). We propose a novel androgen-dependent mechanism of ACE2 activation by SARS-CoV-2 in endothelial and immune cells; as well as endothelial dysfunction and hyperinflammation stimulated immune response predispose to thrombus formation in COVID-19. SARS-CoV-2 will be isolated, in vitro expanded, and used to monitor cell signaling and cytokine storm by immune assays and viral load by RT-qPCR. Related androgen pathways will be pharmacologically targeted. Immune-endothelial cell co-cultures will be performed for thrombosis development. We expect androgen-dependent SARS-CoV-2 host cell infection and mediated inflammation in thrombotic complications. This translational research will reveal androgen pathways implication in SARS-CoV-2 infection and therapeutic strategies to speed up patient recovery.

Dr Snežana Tomanović, Dr Darko Mihaljica, Dr Ratko Sukara, Dr Gorana Veinović, and Dr Dragana Marković

In Europe, at least 6 agents of zoonotic vector-borne diseases have been identified in which ticks play an important role in transmission (Rickettsia sp., Anaplasma phagocytophilum, Borrelia burgdorferi sensu lato, Francisella tularensis, Crimean-Congo hemorrhagic fever virus, tick-borne encephalitis virus). Our preliminary investigations indicate the presence of A. phagocytophilum, F. tularensis, Rickettsia sp. and five genospecies of the B. burgdorferi complex in ixodid ticks in Serbia. According to epidemiological data, tick-borne encephalitis and Crimean-Congo hemorrhagic fever viruses are present in natural foci on the territory of Serbia, but no systematic studies on their presence in ticks have been performed so far. Research in this project included regular collection of material (ticks from vegetation and hosts, serum samples and host tissues), molecular detection of pathogens in samples, and cultivation, characterization and genotyping of these microorganisms. The research focused on potential natural hosts of these zoonotic diseases. The research results provided a clearer picture of the distribution, genetic diversity, and pathogenic potential of tick-borne microorganisms.