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The role of NETosis in the etiopathogenesis of rheumatoid arthritis, APVV-18-0366, 2019-2023; principal investigator

Pathogenesis of rheumatoid arthritis (RA) is relatively well known and the currently available anti-inflammatory treatment is more effective than ever, but that does not mean that nothing can be improved. The etiology of RA is largely unknown, and therefore even the most modern treatment cannot be causal. One of the mechanisms that neutrophils use to fight microorganisms is the formation of extracellular traps, so called NETs in the process of NETosis. In NETosis, DNA, histones and specific enzymes are released into the extracellular space. NETs are immunogenic and can induce inflammation, which could explain the circulus vitiosus of chronic inflammation in various diseases including RA. In particular, if the presence of autoantibodies against citrullinated peptides formed during NETosis are one of the early markers of RA. Our previous research has highlighted the importance of extracellular DNA not only as a marker of tissue damage, but also as a pathogenetic factor in liver and kidney diseases or sepsis. Removal of extracellular DNA produced during NETosis or prevention of NETosis induction could be interesting therapeutic or preventive approaches in RA. The aims of this project are to: 1. Investigate and quantify NETosis markers including extracellular DNA in RA patients in an observational clinical study; 2. Describe mechanisms leading to NETosis using in vitro neutrophil functional tests and using monitoring of changes induced by biological anti-inflammatory therapy and 3. To test in animal models of RA the therapeutic or preventive effects of modulating the consequences of NETosis including the removal of extracellular DNA.

Deoxyribonuclease - role in the physiology and pathophysiology of pregnancy, VEGA 1/0742/21, principal investigator

Extracellular DNA (ecDNA) of fetal and maternal origin is very important for non-invasive prenatal diagnosis, but it is also recognized by the immune system and induces inflammation. Mechanisms that remove ecDNA include deoxyribonuclease (DNase). Little is known about its role in physiology and pathophysiology and even less in relation to pregnancy. In previously unpublished studies, we confirmed in 3 independent studies that ecDNA is higher in women with preeclampsia. However, the assumption that lower DNase activity may be the cause has not been confirmed. On the contrary, we surprisingly found that DNase activity is higher in preeclampsia. The aim of the project is 1) to describe the variability of DNase activity during physiological pregnancy, 2) to analyze DNase activity in relation to the amount, fragmentation and immunogenicity of ecDNA in preeclampsia, intrauterine infection and preterm birth, 3. to investigate the effect of change of DNase activity on pregnancy with pharmacological and genetic tools.

The role of NETosis in the pathogenesis of preeclampsia, VEGA 1/0156/17; 2017-2019; principal investigator

Preeclampsia is common pregnancy-specific disorder with increasing incidence. Abnormalities in placental development and inflammation are basic concepts in pathogenesis of preeclampsia, although etiology remains unknown. Several studies have shown elevated levels of extracellular DNA in maternal circulation during preeclampsia. This DNA is recognized by maternal immune system causing the inflammation. In our clinical study, we will examine the levels of extracellular DNA, amount of NETs, nucleosomes and activity of DNases. In animal models of preeclampsia, we will analyze the same parameters and try to reveal effects of inhibition of activity of neutrophils, inhibition of inflammatory response as well as impact of DNase on preeclampsia-like symptoms. Our aim is to confirm the hypothesis that extracellular DNA produced during activation of NETs contributes to inflammation since this DNA is oxidized in a form of nucleosomes in maternal circulation what further protects DNA from the activity of DNases.