The list of national projects SAS

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Institute: Biomedical Research Center SAS

Expression analysis of miRNA genes regulating the biology of cancer stem cells in breast cancer patients
Analýza expresie génov pre miRNA regulujúcich biológiu nádorových kmeňových buniek u pacientok s karcinómom prsníka
Program: VEGA
Project leader: Mgr. Zmetáková Iveta PhD.
Annotation:The high mortality rate for malignant tumors, breast cancer included, is mainly due to their ability to metastasize. A key regulator of hematogenous metastasizing is the process of epithelial-mesenchymal transition (EMT), which allows the epithelial cells to acquire a mesenchymal phenotype and become circulating tumor cells (CTCs). Cancer stem cells (CSCs) are a subpopulation of CTCs, with acquired properties of stem cells responsible for tumor progression, metastases and relapse of cancer. MiRNAs are small non-coding RNAs, which regulate via various mechanisms the amount of physiological cell processes. The deregulation of their expression plays an important role in carcinogenesis. In the present project, we will analyze the expression of 84 miRNAs involved in the biology of CSCs in CTCs enriched population of peripheral blood cells in breast cancer patients. Our goal is to identify potentially clinically relevant miRNAs with possible use for monitoring the risk of metastasis development.
Duration: 1.1.2017 - 31.12.2020

Prognostic biomarker for colorectal carcinoma based on miRNA analysis and characterization of selected proteins in the circadian context
Analýza mikroRNA a charakterizácia expresie vybraných proteínov v cirkadiánnom kontexte ako prognostický biomarker pre kolorektálny karcinóm
Program: SRDA
Project leader: RNDr. Sedlák Ján DrSc.
Annotation:The project will analyze the miRNA profiles of peripheral blood exosomes and immunoscore of tumor tissue for their correlation with clinico-pathological data for the assessment of potential biomarker. miRNA profiling will be focused to identification of miRNA expression patterns that have the potential to regulate epigenetic gene regulation and circadian rhythm.
Duration: 1.7.2015 - 30.6.2019

Antioxidative, anticarcinogen and photoprotective effects of the essential oil from lavender in vitro.
Antioxidačné, antikarcinogénne a fotoprotektívne účinky levanduľového oleja in vitro.
Program: VEGA
Project leader: RNDr. Kozics Katarína PhD.
Annotation:Chemoprotective and photoprotective effect of the essential oil from lavender (Lavandula angustifolia), as well as the knowledge about mechanism of its action is not yet sufficiently described in literature. The project is focused on complex evaluation of antioxidant properties of the essential oil from lavender (LO) with specific interest on protective properties against UV radiation. UV radiation is considered to be the key risk factor in the etiology of skin cancer which incidence has increasing trend line worldwide. Chemo- and photoprotective properties effects of LO will be studied using in vitro models of healthy normal skin (human keratinocytes HaCaT, primary murine keratinocytes) and on melanoma cell line HMB-2. Using comprehensive approaches from biochemistry, biology, molecular biology and genetics will enable us to confirm possible protective effects of LO on normal and cancer skin cells, plus to help to understand the mechanism of action of LO.
Duration: 1.1.2016 - 31.12.2019

Biochips and biosensors for glycorecognition, their development, prepararion and application in cancer research
Biočipy a biosenzory pre glykorozpoznávanie, ich vývoj, príprava a využitie pri výskume rakoviny
Program: SRDA
Project leader: Mgr. Švastová Eliška PhD.
Annotation:Due to the rapid development of new technologies is placed a considerable emphasis on their use for improving the quality of life. The most important areas here include the care of human health, such as the fight against cancer. Here is a keen interest in new sensitive diagnostic approaches and technologies to help increase the effectiveness of therapy and cancer research. Development and application of new diagnostic procedures and methods is based in no small measure on the knowledge gained in the basic research in the field of analytical tools based on the biochips and biosensors. The aim of the project is the development and preparation of new analytical glyco-recognizing biochip and biosensor systems based on lectin in different formats in combination with multiple platforms and innovative detection methods, their validation and use in the analysis of real samples in cancer research. The selected design of biochips and used detection platform enable highly sensitive and high-throughput analysis of glycosylation changes, and the involvement of mass spectrometry also accurate identification of glycan structures subject to glycosylation changes. To increase the functionality of biochips will be in the development of analytical systems used also nanotechnology tools, particularly in the preparation of nanostructured surfaces of biochips and for improving the efficiency of detection. Various types of biological samples will be analyzed such as serum, lysates, tissue and isolated glycoproteins from some areas of cancer research (effect of hypoxia, resistance to cytostatics, search of glyco-biomarkers). It is expected that the involvement of the entire spectrum of analytical procedures for glycorecognition developed in this project will help formulate more sophisticated conclusions on the role of glycans in cancer.
Duration: 1.7.2015 - 30.6.2019

Biological and binding properties of clinically significant viral immunomodulators and their immunotherapeutic potential.
Biologické a väzobné vlastnosti klinicky významných vírusových imunomodulátorov a ich imunoterapeutický potenciál.
Program: VEGA
Project leader: Mgr. Nemčovičová Ivana PhD.
Annotation:Characterizing the structural and molecular basis of the host-virus protein interactions is critical to further our understanding of the immune equilibrium that is established during viral infection, and why disease can occur if this balance is disrupted. The ligands and receptors of Ig or TNF molecules are critical for host defense, therefore we have an interest in delineating immunoterapeutic strategies used by virus to modulate immune recognition. This project proposal is intended to facilitate biological and binding properties of clinically significant viral immunomodulators (HCMV and HIV glycoproteins). In this regard, we are planning a preparation, characterization, expression and purification of selected set of recombinant viral and human genes that are associated with cytotoxicity and viroprotectivity processes in the cell. We expect that by this approach we will be able to design and characterize suitable candidates with high immunomodulatory effects.
Duration: 1.1.2015 - 31.12.2017

The biological effects of the environment with reduced deuterium (D) content or increased pH and physical exercise in relation to cancer: implications for tertiary prevention.
Biologické účinky prostredia so zníženým množstvom deutéria alebo zvýšeným pH a fyzického cvičenia vo vzťahu k onkologickým ochoreniam: implikácie pre terciárnu prevenciu.
Program: VEGA
Project leader: RNDr. Hunáková Ľuba CSc.
Annotation:The project deals with the possibility of the extracellular milieu modulation with potential impact on tertiary prevention of cancer. In vitro we want to examine the regulatory effect of the media with lower deuterium (D) content, or increased pH on the proliferation activity and viability of normal and tumor cells. These will be pursued by various culture and imaging techniques. We will also study possible changes in genome stability by monitoring the incidence of micronuclei typical for cells with replication stress, leading to the increased heterogeneity of tumor population, as well as changes in the expression of surface antigens affecting immune responses, changes in the release of exosomes and in migration of tumor cells. At the level of the human body we want to examine the effects of interventions that modulate the internal environment (Pilates exercise, drinking of alkaline water with reduced ORP) to the redox status, immunological and regulatory body's responses supporting protection against cancer
Duration: 1.1.2016 - 31.12.2018

Detailed characterization and further improvement of system for induction of synchronous meiosis at optimal temperature
Bližšia charakterizácia a vylepšenie systému indukcie synchrónnej meiózy pri optimálnej teplote
Program: VEGA
Project leader: RNDr. Kretová Miroslava PhD.
Annotation:The central aspect of sexual reproduction is the generation of haploid gametes from diploid cells in a process called meiosis. Although we understand certain aspects of regulation of meiotic cell division, we are far from a thorough understanding of it. Here, we plan to make a further improvements of newly developed system of pat1-as-induced synchronous meiosis at optimal temperature, with emphasis on increasing the sensitivity and specificity of inhibition of Pat1-as protein kinase by ATP analogs. Additionally, we will study and characterize in more details the molecular mechanisms driving pat1-as-induced meiosis, which are responsible for correction of most of the aberrant events observed in pat1-114-induced meiosis. Developed system of synchronous meiosis at optimal temperature will open the gate to a deeper and more reliable biochemical dissection of mechanisms regulating the processes of meiotic chromosome segregation.
Duration: 1.1.2016 - 31.12.2019

Cellular and molecular traits of human metastasis-initiating cells at different stages of metastasis development.
Bunkové a molekulárne vlastnosti ľudských buniek iniciujúcich rast metastáz v rôznom štádiu metastatického procesu.
Program: VEGA
Project leader: Ing. Poturnajová Martina PhD.
Annotation:Metastatic dissemination is a critical step in malignant progression and major factor contributing to cancer mortality. Colonizing cancer cells must develop resistance to host-tissue defences to survive and retain tumor-initiating capacity, giving rise to overt metastasis. Such metastasis- initiating cells (MetIC) have to infiltrate distant tissue, survive as disseminated seeds, adapt to supporting new niches and initiate tumor. We will use metastatic human colorectal cancer HT-29/EGFP/FUR in comparison to HT-29/EGFP cells and aggressive melanoma human cell line EGFP-A375/Rel3, prepared in our lab. On established metastatic model in vivo we would like to establish tumor cell lines containing MetIC in the different stages of metastases development. Subsequently, we would like to examine the properties of cancer cell population enriched for MetIC by functional and expression analysis and find out if targeting of the selected tumorigenic population by RNA interference can inhibit tumor growth.
Duration: 1.1.2017 - 31.12.2020

Whole exome sequencing in multiplex families with hereditary hearing loss in Slovakia: identification of novel gene variants
Celoexómové sekvenovanie v multiplexných rodinách s hereditránou poruchou sluchu na Slovensku: identifikácia nových génových variantov
Program: VEGA
Project leader: RNDr. Gašperíková Daniela DrSc.
Duration: 1.1.2016 - 31.12.2019

Directed modification of a potyviral protein for analysis of molecular interactions with the host plant
Cielená modifikácia potyvírusového proteínu pre analýzu interakcií s hostiteľskou rastlinou na molekulovej úrovni
Program: VEGA
Project leader: RNDr. Šubr Zdeno CSc.
Annotation:Potyviruses are the largests taxon of plant viruses, they are economically important especially in temperate climatic zones. Details of the infectious process on the level of host cells are still largely unknown. Particular functions of viral proteins have been cleared, roles of some of them remain mysterious. It concerns especially the proteins P1, P3 and 6K1. This project is focused on the P1 protein, its analysis by directed mutagenesis or interspecies exchange, on the detection of potential host partners of P1 in protein-protein interactions in vivo. To achieve these goals, we will apply an infectious cDNA clone of the Plum pox virus, a two-hybrid system and specific pull-down experiments. We will apply the plant transfection by recently optimized biolistic method or by agroinfection for the in vivo analyses. Obtained results could return a new insight on the molecular pathogenesis of potyviral infections and a potential new scheme of efficient antiviral strategy.
Duration: 1.1.2015 - 31.12.2017

Targeting carbonic anhydrase IX and pyruvate dehydrogenase kinase 1 in hypoxic colorectal tumors
Cielený zásah karbonickej anhydrázy IX a pyruvát dehydrogenázy kinázy 1 v hypoxických kolorektálnych nádoroch
Program: SASPRO
Project leader: PharmDr. Goliaš Tereza PhD.
Annotation:Glycolytic tumor cell metabolism fills the requirements for growth in the hypoxic environmental milieu. The ability to respond to changing environmental oxygen tension through the induction of carbonic anhydrase IX (CAIX) and pyruvate dehydrogenase kinase 1 (PDHK1), implicated in pH regulation and glucose metabolism, respectively, appears to be necessary for model tumor growth, and their high level of expression in human tumors predicts for poor patient outcome. These two hypoxia-regulated proteins therefore present promising new targets for the design of novel, non-standard chemotherapies that would negatively influence tumor cell proliferation and survival, and at the same time avoid normal tissue toxicity or increase efficacy of standard treatment regimens. This project examines molecular mechanisms governing regulation of these proteins in the hypoxic tumor microenvironment and attempts to target them in the background of colorectal cancer, and at the same time stratify patients who would benefit from such tumor microenvironment-directed therapy and improve their outcome.
Duration: 1.6.2015 - 31.5.2018

DNA methylation profiles in genes associated with breast cancer metasasising
DNA metylačné profily v génoch asociovaných s metastázovaním karcinómov prsníka
Program: VEGA
Project leader: RNDr. Fridrichová Ivana CSc.
Annotation:More than 25% of breast cancer patients develop metastatic disease that represent the main cause of high mortality. The epigenetic changes in tumorigenesis have been intensively investigated and new knowledge in metastatic process could contribute to the improving of advanced disease management and identifying of the new therapeutic targets. In present project, we will evaluate the DNA methylation levels in genes associated with cell-cell adhesion (ADAM23, CXCL12), degradation of basement membrane and extracellular matrix (uPA) and regulation of the epithelial-mesenchymal transition (TWIST, SNAI1 a SNAI2) in 50 invasive breast cancer patients with metastatic lymph nodes. Quantitative analyses of DNA methylation in peripheral blood samples, tumour tissues, positive lymph nodes and circulating tumour cells allow to evaluate the role of specific methylation profiles in partial processes of invasivity and metastasising and clinical utility for metastatic potential monitoring.
Duration: 1.1.2015 - 31.12.2018

Effective diagnostics of viruses threatening the production of tomato in Slovakia
Efektívna diagnostika vírusov ohrozujúcich produkciu rajčiaka jedlého na Slovensku
Program: SRDA
Project leader: Ing. Glasa Miroslav PhD.
Duration: 1.7.2015 - 30.6.2019

Factors effecting production of cell-free Marek’s disease virus particles in vivo in chicken and in vitro in cell culture
Faktory ovplyvňujúce produkciu bunkovo-neviazaných partikúl vírusu Marekovej choroby in vivo u kurčiat a in vitro v bunkových kultúrach
Program: VEGA
Project leader: RNDr. Zelník Vladimír CSc.
Annotation:During life cycle of Marek’s disease virus after the primary infection developing in lung alveolar macrophages by dust present in chicken animal house there becomes secondary infection of B-lymphocytes. These cells subsequently infect activated T cell. In some of them namely CD4+ there can reach latent infection. For oncogenic transformation by MDV there are T lymphocytes as target cells. Fully productive infection of enveloped MDV particles can be observed only in cells of chicken feather follicles. It is possible to propagate MDV also in vitro in chicken embryonic fibroblasts but their replication is strictly cell-associated. Mechanisms leading to release of infectious MDV to environment from feather follicles, similarly as current inability to produce cell-free virus in vitro remain unclear. Main targets of the project are: 1) characterization of MDV infectious enveloped particles in vivo from feather follicles and 2) identification of factors that might enable production of infectious enveloped MDV particles.
Duration: 1.1.2014 - 31.12.2017

The role of neuropeptides and receptors in regulation of pathogen transfer from ticks to their hosts
Funkcia neuropeptidov and ich receptorov pri regulácii prenosu patogénov z kliešťov na hostiteľa
Program: SRDA
Project leader: Mgr. Špitalská Eva PhD.
Annotation:Ticks are very important vectors of dangerous pathogens, but regulatory mechanisms required for their successful transmission into the host are poorly understood. Likewise, physiological processes controlling function of the salivary glands, gut and gonads during their life cycle have not been elucidated. Our published and preliminary data indicate that several specific peptidergic neurons innervate these organs which are the most important reservoirs of pathogens. Our unpublished experiments suggest that identified neurons control activity of these organs and associated transmission of pathogens during tick feeding on the host. In this project we will use a combination of techniques (immunohistochemistry, molecular biology and bioinformatics) to identify regulatory molecules (neuropeptide and their receptors) and neuronal pathways important for normal function of the salivary glands, digestive system and reproductive organs of the ticks Ixodes ricinus and I. scapularis. We also propose to study the role of specific neuropeptides and their receptors in transmission of pathogens (Rickettsia helvetica and Borrelia burgdorferi) from these tick organs into laboratory mice using RNAi techniques. Expected results may provide tools for effective suppression of pathogen transmission and development of procedures to inhibit reproductive capability of ticks as dangerous ectoparasites of humans and animals.
Duration: 1.7.2015 - 30.6.2019

Fusion activity of influenza A haemagglutinin as a factor of virulence and pathogenicity.
Fuzogénna aktivita hemaglutinínu vírusu chrípky A ako faktor virulencie a patogenity .
Program: VEGA
Project leader: RNDr. Varečková Eva DrSc.
Annotation:Influenza A viruses (IAV) pose a pandemic threat for humans. There is an effort to know their properties on molecular level which allow to predict danger of new emerged IAV in human population. Many factors influencing IAV virulence of both viral and host origin were decribed till now. A potential critical factor is the fusion activity of IAV, which is crucial for the virus entry into the cell and decides about ability of virus to replicate in the host. The role of surface glycoprotein haemagglutinin (HA), in addition to receptor binding, is to mediate fusion of virus and endosomal membranes. Following endocytosis, fusion potential of native HA trimer is activated by low pH in endosomes resulting in HA refolding into the fusion active form. The HA activation is determined by its 3-Dstructure, is pH-dependent, irreversible and virus specific. Aim of our project is to study the correlation between fusion properties of HA and IAV pathogenicity of various subtype, which has not yet been characterized.
Duration: 1.1.2015 - 31.12.2018

Graphene - based nanoplatform for detection of cancer
Grafénová nanoplatforma na detekciu rakoviny
Program: SRDA
Project leader: prof. RNDr. Pastoreková Silvia DrSc.
Annotation:This project proposal reflects current technological progress and new opportunities in biomedical applications of graphene - based sensors. Our main goals include the design and development of a graphene oxide multifunctional nanoplatform (GO - MFN ) for the detection of tumor cells. In the first step, the development of graphene oxide nanoflakes of appropriate size functionalized by monoclonal antibody is planned. For sensing the tumor cells, GO - MFN of 100 nm size able to interact with a single cell will be prepared. Magnetic nanoparticles added to GO - MFN will enable the inspection of deep tissues by nuclear magnetic resonance. The degree of oxidation of GO, type of the functional groups, optimal functionalization with covalently bound monoclonal ant ibodies and magnetic nanoparticles, are the most important technological steps. The analysis of the basic interactions related to tumor sensing will be conducted in vitro on 2D and 3D cell models up to the proof - of - principle stage that will be directly app licable to laboratory and preclinical testing. The GO - MFN interaction with the cell membrane and with the cell interior will be analysed with subcellular resolution. Such an approach will bring original knowledge and a detailed understanding of the tumor s ensing process that is important for the optimization of the sensor sensitivity. Detection of biomolecules bound to GO - MFN will be addressed in real time by several techniques. The project is based on a complex multidisciplinary approach, ranging from phys ics and chemistry up to biomedicine and combining excellent science and the most sophisticated nano and bio - engineering. The involved partners possess key skills, infrastructure, antibodies and tumor models, and are highly motivated to reach the project go als.
Duration: 1.7.2015 - 30.6.2019

Hantaviruses and crossing of the species barriers
Hantavírusy a prekračovanie druhových bariér
Program: VEGA
Project leader: RNDr. Klempa Boris DrSc.
Duration: 1.1.2015 - 31.12.2017

Characterization of transport pathways of CA IX in tumor cells via real-time analysis
Charakterizácia transportných dráh CA IX v nádorových bunkách pomocou analýzy v reálnom čase
Program: VEGA
Project leader: RNDr. Csáderová Lucia PhD.
Annotation:CA IX is a protein associated with tumors of bad prognosis and molecules that are able to induce its endocytosis (antibodies or hormones) can become efficient therapeutic tools. Endocytosis of the protein and its recycling back to a plasma membrane can effectively regulate the abundance of CA IX at the cell surface, and hence, its activity in pH regulation and migration. The aim of this project is, using our unique instrumental equipment, to study in detail a complex network of transport pathways of CA IX molecule inside the cell in real time, not only after its endocytosis by antibody, but also after the endocytosis induced by intracellular contacts disturbance in hypoxia and by extracellular factors, and to analyze its influence on biological characteristics of tumor cells.
Duration: 1.1.2014 - 31.12.2017

Study of repair of chemotherapy-induced DNA damage using Saccharomyces cerevisiae as a model suystem
Chemoterapiou indukované poškodenia DNA a štúdium ich opravy v modelovom organizme Saccharomyces cerevisiae
Program: SRDA
Project leader: Mgr. Chovanec Miroslav PhD.
Annotation:Many anticancer regimes manifest toxicity against cancer cells via induction of DNA damage. Even though this toxicity cannot be targeted exclusively to cancer cells yet, nevertheless chemotherapy or radiotherapy kills cancer cells more efficiently than normal cells. To better understand mechanism(s) of action of anticancer therapy as well as to improve its efficiency, deeper knowledge on DNA damage response and repair processes is essential. Upon DNA damage induction, an attempt to repair DNA damage is one of the main downstream events. Not surprisingly, DNA damage detection, signaling and repair mechanisms interfere with efficiency of anticancer therapy. Here, we plan to use the budding yeast Saccharomyces cerevisiae to better understand molecular mechanisms of repair of those DNA lesions that are considered to be the most severe in clinical oncology. We intend to further characterize S phase specific arm of interstrand cross-link repair in yeast that has recently been discovered in our laboratory. This repair pathway shares significant similarity with, and is likely evolutionary counterpart of, DNA damage response and repair pathway that is defective in patients suffering from Fanconi anemia. In addition, this project is aimed at uncovering further details of newly discovered regulatory mechanism that is involved in DNA double-strand break repair pathway choice and that is based on physical interaction between the key components of homologous recombination and non-homologous end-joining (NHEJ). Also, the role SUMOylation of components of the DNA ligase IV complex in this regulation as well as in regulation of NHEJ process by itself will be examined. Finally, we wish to delineate a role of proteins that are called alkyltrasferase-like proteins because they share homology with O6-alkylguanine DNA alkyltransferase, a protein that is involved in removal of alkylation damage from DNA and that plays a crucial role in resistance of tumor cells against therapy inducing such DNA damage types. Our main focus here is to reveal a possibility of cross-talk between them and other DNA repair pathways dealing with alkylated DNA, particularly nucleotide excision repair and mismatch repair pathways.
Duration: 1.7.2015 - 30.6.2018

Identification and validation of signalling pathways associated with circulating tumor cells in breast cancer
Identifikácia a validácia signálnych dráh asociovaných s cirkulujúcimi nádorovými bunkami pri karcinóme prsníka.
Program: SRDA
Project leader: Mgr. Kučerová Lucia PhD.
Annotation:Circulating tumor cells (CTC) are indepent prognostic factor in primary as well as in metastatic breast cancer. CTC are heterogenous population of tumor cells and play crucial role in metastatic cascade and tumor progression in process termed self-seeding. Presence of CTC in peripheral blood is a surrogate marker of tumor metastatic ability. Identification of signalling pathways associated with presense of CTC in peripheral blood could help to identifify new therapeutic targets in breast cancer. This project is aimed to identify biomarkers and subsequently signalling pathways in primary tumor associated with different subsets of CTC using using highthroughput technologies of genomics and biostatistcs through translational research involving the analysis of biological material from patients followed by their prospective validation.
Duration: 1.7.2017 - 30.6.2021

Identification of biomarkers associated with late toxicity of chemotherapy in testicular germ cell tumors.
Identifikácia biomarkerov asociovaných s neskorou toxicitou chemoterapie u germinatívnych nádorov testes
Program: SRDA
Project leader: RNDr. Gronesová Paulína PhD.
Annotation:Testicular germ-cell tumor (TGCTs) survivors are men cured from TGCTs with multimodality treatment including cisplatin based chemotherapy. Extraordinary survival with duration for several decades is often stigmatised by morbidity associated with late toxicity of chemotherapy. Number of studies report secondary malignancies, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, infertility, psychological, behavioral and cognitive disorders. These late toxicities negatively influence quality of survivors lives and may be contributing factor on increasing mortality in this population. The data suggest that further research in this area is needed and associations with clinical, biochemical and genetic biomarkers need to be identified. Systematic physical activity is shown to have positive effects on cardiopulmonary and muscle function in general population but effects in TGCT survivors remain to be explored. This is first translational study with excersise-intervention program conducted in TGCT survivorship research and strongly benefical clinical outcome is expected.
Duration: 1.7.2016 - 30.6.2020

Identification of biomarkers associated with late toxicity of chemotherapy in testicular germ cell tumors
Identifikácia biomarkerov asociovaných s neskorou toxicitou chemoterapie u germinatívnych nádorov testis
Program: SRDA
Project leader: Mgr. Ukropec Jozef DrSc.
Duration: 1.7.2016 - 30.6.2020

Identifikacion of a molecular mechanism inducing appearance of dormant cell population in multiple myeloma
Identifikácia molekulárneho mechanizmu indukujúceho vznik dormantnej bunkovej populácie u mnohopočetného myelómu.
Program: VEGA
Project leader: RNDr. Bízik Jozef DrSc.
Annotation:Cancer research provided clear evidences that stroma plays a crucial role in progression of hematological malignancies. Recent studies performed by our team showed that the interactions between stromal cells derived from skin and the leukemic cells are reciprocal and very complex. Remarkably, we observed that diverse types of leukemic cells are capable to modulate a reactivity of the stromal microenvironment, e.g. inflammation. However, we have also found out that certain human multiple myeloma cells responded by growth arrest and phenotypic shift to sterile inflammation induced in a three dimensional structure composed of skin stromal cells. Clinical significance of our observation outlines a fact that we have detected in a preliminary study a subclone of cells exhibiting a novel phenotype in >60% of myeloma patients. Therefore, we plan in the proposed project to perform precise analysis and molecular characterization of a phenomenon of multiple myeloma dormancy and its role in manifestation of the disease.
Duration: 1.1.2016 - 31.12.2018

Identification of novel gene variants of hereditary hearing loss based on nationwide screening
Identifikácia nových génových variantov dedičných porúch sluchu na báze celonárodného skríningu
Program: SRDA
Project leader: RNDr. Gašperíková Daniela DrSc.
Duration: 1.7.2016 - 30.6.2020

Identification of substrates of essential protein kinases using shokat mutants
Identifikácia substrátov esenciálnych proteínkináz využitím shokat mutantov
Program: SASPRO
Project leader: Ing. Čipák Ľuboš PhD.
Annotation:Genomic instability is defined as a process prone to genomic changes or an increased propensity for genomic alterations. The ultimate goal of cell division for most cells is to accurately duplicate the genome and then evenly divide the duplicated genome into the daughter cells or into the germ cells. Alterations or abnormally high-frequency of errors during processes involved in cell division, such as splicing, sister chromatid cohesion, kinetochore assembly and attachment, chromosome segregation or cytokinesis would cause missegregation of chromatids and chromosomal instability. The complexity of cell division is pointing out that this process is controlled by multi-level regulatory network. Several lines of evidence demonstrated that posttranslational modifications of proteins by phosphorylation play important role in regulation of protein functions. However, we still have little clue which protein kinases regulate proteins involved in processes of cell division. So, identification of relevant protein kinases and characterization of biological significance of their activities is highly desirable. Proposed project is aimed to identify direct targets of essential protein kinases and characterize functional relevance of phosphorylation of target proteins for regulation of splicing and fidelity of chromosome segregation by combining the power of analog-sensitive alleles of essential protein kinases with affinity purification and mass spectrometry approaches. The project will provide a new framework for our understanding of how are splicing and chromosome segregation regulated by phosphorylation and will lay the groundwork for future studies. Since the basic cell cycle machinery is highly conserved from yeast to man, it is likely that processes governing in yeast will guide the way for studies of these processes in higher eukaryotes, including humans.
Duration: 1.4.2015 - 31.3.2018

The identification of EBHS virus and selected pathogens as possible cause of the European brown hare (Lepus europaeus) population decline in Slovakia
Identifikácia vírusu EBHS a vybraných patogénov ako možnej príčiny poklesu početnosti zajaca poľného (Lepus europaeus) na Slovensku
Program: SRDA
Project leader: RNDr. Kúdelová Marcela DrSc.
Annotation:European brown hare is one of our most traditional game animals. Since 1975, rapid decline of hare population in Slovakia is registered. It is known that hares suffer from several diseases as tularaemia, leptospirosis, Q-fever, brucellosis, toxoplasmosis, chlamydiosis and others, including coccidiosis and helminthoses as well as European brown hare syndrome (caused by viral infection with EBHSV) which might be the reasons of hare population decline. Slovakia exports hares into some European countries and it is necessary to avoid undesirable transmission of pathogens. The main aim of project is the identification of epidemiologic status of EBHSV and other diseases of brown hares mentioned in Slovakia with emphasis on correlation between health status and population dynamics. Further aims are phylogenetic analysis of Slovakian EBHSV isolates and introducing of methodologies allowing determination of antibodies against pathogens useable for monitoring of epidemiologic situation within free-living hare´s population in Slovakia. The implementation of the project gives the possibility of applying the most recent modern biotechnologies developed by basic research in solving recent tasks of applied research.
Duration: 1.7.2016 - 30.6.2020

IMMUNOVIROLOGICS: Immune modulation by HCMV and its immunotherapeutic potential.
IMUNOVIROLOGIKÁ: Imunomodulácia HCMV a jej imunoterapeutický potenciál.
Program: SASPRO
Project leader: Mgr. Nemčovičová Ivana PhD.
Annotation:Characterizing the structural and molecular basis of the host-virus protein interactions is critical to further our understanding of the immune equilibrium that is established during viral infection, and why disease can occur if this balance is disrupted. The ligands and receptors of Immunoglobulin (Ig) or Tumour Necrosis Factor (TNF) families are critical for host defence; therefore we have an interest in delineating evasion strategies used by virus to modulate immune recognition. Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that persistently infects the majority of the world’s population. HCMV is a paradigm for viral immune evasion that maintains a number of immunomodulatory genes that act to suppress Natural Killer (NK) cell function. In this regard, we are planning a preparation and molecular characterization of selected set of recombinant viral and human genes that are associated with cytotoxicity and viroprotectivity processes in the cell while these events will also be monitored. We expect by using this cross-disciplinary approach we will able to design and characterize suitable candidates with high immunomodulatory activity. In summary, project aims to examine the targets and mechanisms by which HCMV immunomodulation is achieved, and therefore discuss the development of immunomodulatory biologics for the treatment of HCMV infection. In addition, the understanding of mechanism by which HCMV modulates immune effector pathways highlights its possibility being used as a vaccine vector for the treatment of cancer or other autoimmune diseases.
Duration: 1.7.2015 - 31.12.2018

Induction of apoptosis by betulinic acid coupled to magnetite nanoparticles in human colorectal cell lines
Indukcia apoptózy kyselinou betulínovou naviazanou na magnetické nanočastice v ľudských nádorových bunkách hrubého čreva
Program: VEGA
Project leader: RNDr. Šramková Monika PhD.
Annotation:The incidence of colorectal cancer has still alarming trend worldwide with the frequent occurrence of resistance towards chemotherapy, especially in metastasis. Therefore, the development of drugs that can bypass the chemoresistance and/or augment the cytotoxicity of conventional chemotherapeutics can be the strategy. Betulinic acid (BA) is such a compound. Despite the number of studies describing the biological effect of BA, characterization of its coupling to magnetite nanoparticles (MNP-BA) used as nanovectors still remains to be addressed. Our project is aimed at a comprehensive assessment of properties of MNP-BA with specific regard to its cytotoxic, cytostatic and genotoxic effects in colorectal cell lines sensitive/resistant to chemotherapeutics. A complex approach from biochemistry, biology, and molecular biology will enable us to show whether MNP-BA is able to act as an anticancer drug by inducing the apoptosis in resistant cancer cells.
Duration: 1.1.2017 - 31.12.2020

Interaction of hypoxia with the signaling pathways implicated in differentiation, tumor progression and metastasis.
Interakcia medzi hypoxiou a signálnymi dráhami zapojenými v diferenciácii, nádorovej progresii a metastázovaní.
Program: VEGA
Project leader: RNDr. Takáčová Martina PhD.
Annotation:Hypoxia is an important aspect of the tumor microenvironment, which along with other components (stromal cells, extracellular matrix proteins, growth factors, etc.) plays a crucial role in influencing tumor and stem cell behavior. Through the interaction with autocrine/paracrine oncogenic signaling pathways, such as Wnt, Notch, TGFb, and receptor tyrosine kinases (c-Met, EGF, PDGF), hypoxia has the potential to inhibit tumor cell differentiation and to maintain tumor cells in an undifferentiated stem cell-like state. This project will focus on the interaction between hypoxia and previously mentioned signaling pathways in the control of carbonic anhydrase IX expression and function (both in pH regulation and migration). Understanding of this interplay is critical for rational application of CA IX as diagnostic and therapeutic target. Therefore, we will use both cell cultures and tissue samples from different carcinomas to elucidate the role of CA IX as indicator of differentiation, progression and metastasis.
Duration: 1.1.2016 - 31.12.2019

Interaction of nitrergic, neurotrophic and endocrine signaling in the etiopathogenesis of schizophrenia
Interakcia nitrergickej, neurotrofickej a endokrinnej signalizácie v etiopatogenéze schizofrénie
Program: SRDA
Project leader: prof. PharmDr. Ježová Daniela DrSc.
Duration: 1.7.2015 - 30.6.2019

The clinical significance of the relationship between aldosterone and depression and the regulatory mechanisms involved
Klinický význam vzťahu aldosterónu k depresii a zúčastnené regulačné mechanizmy
Program: VEGA
Project leader: prof. PharmDr. Ježová Daniela DrSc.
Duration: 1.1.2015 - 31.12.2018

Clonal dynamics of multiple myeloma
Klonálna dynamika mnohopočetného myelómu
Program: SASPRO
Project leader: RNDr. Jakubíková Jana PhD.
Duration: 1.9.2015 - 31.8.2018

Constitutive and induced DNA damage in hematopoietic cells for assessment of risk and optimizing treatment of childhood leukemia
Konštitutívne a indukované poškodenie DNA v hematopoetických bunkách pre posúdenie rizika a optimalizáciu liečby detskej leukémie
Program: VEGA
Project leader: doc. Ing. Beliaev Igor DrSc.
Annotation:Childhood leukemia arises from hematopoietic stem cells (HSC). Usually, characteristic preleukemic gene fusions (PGF) arise prenatally in HSC as a first key event in multistage process of leukemogenesis. DNA double-strand breaks (DSB) are critical DNA damage resulting in PFG. Ionizing radiation at high doses is known to induce leukemia. While radiosensitivity of stem cells to high doses has been investigated, the data on low dose effects in stem cells are very limited. Exposure to non-ionizing radiation has also been related to increased risk of childhood leukemia. No experimental data are available regarding possible effects of non-ionizing radiation in HSC. We will study DSB and most frequent PGF in HSC from umbilical cord blood induced by low-dose ionizing and non-ionizing radiation. We will also analyze DSB and apoptosis in hematopoietic cells of leukemia patients with various immunophenotype and PGF. The data will be correlated with clinical outcome what may result in improvement of therapy.
Duration: 1.1.2015 - 31.12.2017

Mechanism of the mesenchymal stromal cell-induced tolerance to antitumor treatment and targeted therapeutic intervention in the breast cancer cells
Mechanizmus tolerancie indukovanej mezenchýmovými stromálnymi bunkami voči protinádorovej liečbe a cielená terapeutická intervencia v nádorových bunkách karcinómu prsníka
Program: SRDA
Project leader: Mgr. Kučerová Lucia PhD.
Annotation:Chemoresistance to conventional cytotoxic drugs used in breast cancer patients results in disease relapse, progression and dissemination. There are many intrinsic mechanisms in breast cancer cells contributing to refractoriness to chemotherapeutic agents. Tumor microenvironment surrounding the tumor cells, which is composed of many types of non-malignant cells and extracellular proteins, significantly affects drug responses by soluble-factor mediated and cell adhesion-mediated drug resistance. The interactions between the tumor cells and TME blunt the cytotoxic effect of genotoxic drugs thus substantially negatively affecting treatment efficiency. Mesenchymal stromal cells as one of the TME components represent relatively resistant cell population actively recruited and engrafted in the TME. The exposure to chemotherapeutic drug alters their phenotype thus substantially affecting tumor cell behavior. The project is focused on unraveling the molecular mechanism by which MSC blunt the response to chemotherapeutic agents and induce tolerance in otherwise intrinsically sensitive tumor cells. The project is focused on unraveling the point of therapeutic intervention to abrogate this MSC-mediated tolerance.
Duration: 1.7.2017 - 30.6.2021

Immune modulation by cytomegalovirus and its immunotherapeutic potential.
Modulácia imunitnej odpovede cytomegalovírusom a jej imunoterapeutický potenciál.
Program: SRDA
Project leader: Mgr. Nemčovičová Ivana PhD.
Annotation:Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that persistently infects the majority of the world’s population (more than 80% infected of Slovak adult population). HCMV is a paradigm for viral immune evasion that maintains a number of immunomodulatory genes that act to suppress Natural Killer (NK) as well as T cell functions. Characterizing the structural and molecular basis of the host-virus protein interactions is critical to further our understanding of the immune equilibrium that is established during viral infection, and why disease can occur if this balance is disrupted. The ligands and receptors of Immunoglobulin (Ig) or Tumour Necrosis Factor (TNF) families are critical for host defence; therefore we have an interest in delineating evasion strategies used by virus to modulate immune recognition. In this regard, we are planning a preparation and molecular characterization of selected set of recombinant viral and human genes that are associated with cytotoxicity and viroprotectivity processes in the cell while these events will also be monitored. We expect by using this cross-disciplinary approach we will able to design and characterize suitable candidates with high immunomodulatory activity. In summary, project aims to examine the targets and mechanisms by which HCMV immunomodulation is achieved, and therefore discuss the development of immunomodulatory biologics for the treatment of HCMV infection. In addition, the understanding of mechanism by which HCMV modulates immune effector pathways highlights its possibility being used as a vaccine vector for the treatment of cancer or other autoimmune diseases.
Duration: 1.7.2015 - 30.6.2019

Modulation of immunogenicity of HA2 immunogen as potential candidate for preparation of cross-protective influenza vaccine.
Modulácia imunogenicity HA2 imunogénu ako potenciálneho kandidáta na prípravu krížovo-protektívnej chrípkovej vakcíny
Program: VEGA
Project leader: RNDr. Bobišová Zuzana PhD.
Annotation:Current vaccines against influenza have a narrow specificty to the vaccine strains and to their antigenically similar variants. To broaden spectrum of vaccine efficacy we focused on the conserved part of HA, HA2 glycopolypeptide (gp) as a candidate for preparation of cross-protective influenza vaccine. We showed that immunization with HA2gp in the presence of adjuvant or after conjugation to a carrier protect mice against lethal infection with homologous but only partially against infection with heterologous influenza virus. The enhanced cross-protection was achieved after the insertion of HA2gp into the detoxified adenylate cyclase toxin that enables the stimulation humoral and also T cell immunity. The aim of the project is the preparation of deletion variants of HA with removed variable part of HA and monitor their cross-protective potential in vivo. Another objective is the use of streptavidin system as a new tool to deliver conserved antigens to immune cells and induction of heterosubtypic immunity.
Duration: 1.1.2014 - 31.12.2017

Molecular epidemiology of viruses of fruit trees and grapevines across the agroecological interface
Molekulárna epidemiológia vírusov ovocných drevín a viniča hroznorodého naprieč agroekologickým rozhraním
Program: VEGA
Project leader: Ing. Glasa Miroslav PhD.
Annotation:The project focused on identification and characterisation of the diversity and distribution of viruses of fruit trees and grapevine in its entirety across agroecological interface, which represents a dynamic border between wild and agricultural communities, at the same time a potential reservoir of new and emerging viral pathogens and an outbreak spot of fast epidemics. Besides the standard methods, the nonspecific next generation sequence (NGS) tools will be used for the molecular characterisation of pathogens, with a possibility to detect new viruses or their highly divergent forms. Molecular variability will be assessed in relation to the virus pathogenicity and etiology. In case of the identification of new or up to now undetected viruses, the obtained sequence data will be used for development of detection methods applicable in a routine diagnostic. The results acquired will provide the original data for establishment or optimisation of phytosanitary and control measures.
Duration: 1.1.2016 - 31.12.2019

Molecular mediators of physical exercise and carnosine induced effects in patients with preclinical and early stage neurodegenerative disease
Molekulárne mediátory účinkov fyzickej aktivity a karnozínu u pacientov s preklinickými a včasnými štádiami neurodegeneratívnych ochorení
Program: SRDA
Project leader: doc. MUDr. Ukropcová Barbara PhD.
Duration: 1.7.2016 - 30.6.2020

Experimental approaches in vitro and in vivo to inovative therapy of rheumatoid arthritis based on molecular-pharmacological principles
Molekulárno-farmakologické prístupy k inovatívnej terapii reumatoidnej artritídy hodnotenej v experimentálnych podmienkach in vivo a in vitro
Program: SRDA
Project leader: Ing. Zorad Štefan CSc.
Annotation:The project is based on the study of the therapeutic potential of selected compounds for the therapy of rheumatoid arthritis (RA), and especially, for the combined therapy with methotrexate. The substances studied will be natural and synthetic low molecular weight compounds and their derivatives (glutathione, meso-2,3- dimercaptosuccinic acid, N-butyldeoxynojirimycin); immunomodulators of bacterial origin (different probiotic strains of Lactobacillus); the substances of plant origin isolated from plants, their derivatives and complexes (astaxanthin, complex quercetin- phosphatidylcholine (phytosome), carnosic acid, carnosol, sulphoraphane, diplacone, glabridin, ginkolides, bilobalide, feruloyl aldehyde and mono- and digalactosyldiacyl glycerol, epigallocatechin gallate, gallic acid, quinic acid, ellagic acid, fatsiflogin and robinin) and their corresponding standardized extracts; polysaccharides with different molecular weight and their derivatives (chitosan-glucan and chitosan isolated from the mycelium of Schizophyllum commune and their derivatives, sodium salt of hyaluronan of bacterial origin). The adjuvant arthritis model (AA) induced in Lewis rats will be used. We will characterize the development of AA and its pharmacological influence by parameters describing immunological, oxidative and inflammatory processes. The compounds evaluated will be applied in a preventive-therapeutic and therapeutic design. Subchronic AA will be completed also by the acute carrageenan-induced inflammation model. The therapeutic value of selected substances will be verified in collagen model of arthritis at the end of the project. With the aim to analyze their molecular mechanism of action, along with in vivo evaluation of the compounds studied, experiments on chemical systems and cell cultures will be performed. Pharmacological modulation of the cardiovascular complications in arthritis will be also analyzed using functional parameters of isolated hearts in ischemia-reperfusion.
Duration: 1.7.2016 - 30.6.2020

Molecular pathways influenced by CA IX in hypoxic cancer cell lines
Molekulové dráhy regulované karbonickou anhydrázou IX v hypoxických nádorových bunkách
Program: VEGA
Project leader: MVDr. Kopáček Juraj DrSc.
Annotation:The main object of our study, carbonic anhydrase IX (CA IX) is a transmembrane enzyme expressed predominantly in tumors derived from various tissues and organs. CA IX is markedly induced by hypoxia and its pH regulating activity contributes to overall cancer phenotype. Thus, CA IX can be seen as a marker of hypoxia, a very common feature of solid tumors, as well as a promising therapeutic target in particular carcinomas. Our goal is to uncover signaling pathways and events which contribute to CA IX related cancer outcome and can be seen as putative vulnerabilities. To gain even better comprehension of processes taking place behind we want to harness CRISPR/Cas9 genome editing tool as well. Because of targeted modifications to genes in their natural genomic context, novel systems like CRISPR/Cas9 editing in vivo can lead to establishment of more natural models of cancer and hypoxia and thus, generally can bring deeper understanding of studied phenomena.
Duration: 1.1.2015 - 31.12.2018

Molecular bases of depressive disorders in children and adolescents, effect of omega-3 fatty acids and oxidative stress
Molekulové základy depresívnej poruchy u detí a adolescentov, vplyv omega-3 mastných kyselín a oxidačný stres
Program: SRDA
Project leader: prof. PharmDr. Ježová Daniela DrSc.
Annotation:Mood disorders is a serious global problem of child psychiatry. Pathophysiology of depressive and anxiety disorders (DD) are not fully known. DD patients were found to have activated the inflammatory response through increased production of cytokines, a failure in the metabolism of serotonin (ratio tryptophan/kynurenine) and other neurotransmitters (release of pterins).In patients with DD reduced levels of omega-3 fatty acids (FA) were found, which can be involved in modulation of membrane fluidity and transmission of neurotransmitters. The consequence may be increased lipid peroxidation of FA, which can influence cell signaling, synthesis of eicosanoids, inflammation, shorten the length of telomeres, and oxidative stress. Our goal is to study the relationship between the level of unsaturated FA, depressive symptoms, selected biochemical parameters focused on lipid profile, subfractions of LDL and HDL lipoproteins, cholesterol in membranes, nonspecific inflammation and oxidative stress, to monitor the participation of neurohormonal regulation in pathophysiology of DD. To assess the influence of 3-month administration of omega-3 fatty acids - eicosapenthaenoic (EPA) and docosahexaenoic (DHA) acids - on the observed clinical and biochemical parameters in a placebo controlled study (60 patients, 6-18 yrs.) and from our results to deduce mutual interactions at the molecular level.
Duration: 1.7.2016 - 30.6.2020

Possible dual function of P-glycoprotein in leukemia cells: efflux pump and regulatory protein
Možná duálna funkcia P-glykoproteínu pri viacliekovej rezistencii leukemických buniek: efluxná pumpa a regulačný proteín
Program: SRDA
Project leader: Ing. Brtko Július DrSc.
Duration: 1.7.2015 - 31.12.2018

Multivalent morpholino-based antisense system for CML
Multivalentný morpholino-based antisense systém pre CML
Program: SRDA
Project leader: RNDr. Gábelová Alena CSc.
Annotation:The proposed MOR4CML project is dedicated to an innovative, morpholino-based antisense concept for BCR-ABL silencing in patients with chronic myelogenous leukemia (CML). Due to its original design and mechanism of action, the suggested concept allows to significantly enhance both selectivity towards CML cells and sequence-mediated specificity towards BCR-ABL mRNA. It is expected that the presented interdisciplinary effort will overcome the main issues that have so far hindered introduction of BCR-ABL antisense-therapeutics into clinical practice. If successful, the proposed concept is also expected to provide a tremendous curative potential not only in CML but also in all diseases with known molecular basis, where a particular protein plays a causal role in disease pathophysiology.
Duration: 1.7.2016 - 30.6.2020

Neuroendocrine effects on synaptogenesis during the brain development
Neuroendokrinné vplyvy na synaptogenézu v priebehu vývinu mozgu
Program: VEGA
Project leader: RNDr. Bakoš Ján PhD.
Annotation:Although there is no consensus on description and explanation of the mechanisms how synaptic connections are formed, several families of synaptic proteins have been identified bridging a space between presynaptic and postsynaptic neuron membranes. Development of the brain and formation of synapses is under control of many factors, among them hormones – neuropeptides and steroids. Particularly. oxytocin deficit, or alterations in oxytocin signaling might be involved in the pathogenesis of the neurodevelopmental disorder. Therefore, there is urgent need to understand how oxytocin and steroids interact to affect synaptogenesis and expression of synaptic proteins. In the present project, we focus on analyzes of the morphology of the neurons and visualization of the synaptic proteins in response to oxytocin, testosterone or estradiol treatment. Systematic approach to research of regulation of synaptic proteins may bring important data for understanding of the brain development at the molecular level.
Duration: 1.1.2016 - 31.12.2018

New regulatory effects of nitric oxide and their role in the development of essential hypertension
Nové regulačné účinky oxidu dusnatého a ich úloha v rozvoji esenciálnej hypertezie
Program: SRDA
Project leader: Ing. Zorad Štefan CSc.
Annotation:High blood pressure is a main risk factor in sustained increased morbidity and mortality of humans suffering cardiovascular diseases. Understanding of causes leading to hypertension enable to reveal new preventive and therapeutic decisions. A new regulatory system involved in vessel tree regulation seems to be neuronal NO-synthase (nNOS) and its interactions with other regulatory systems. On the level of the kidney nNOS signal pathway interferes with renin-angiotensin system (RAS) and sulfide signalization (H2S), and the interactions among them are the unexplored area of regulatory mechanisms. nNOS in macula densa stimulate renin syntesis and via it influences RAS and sympathetic nerve system, on the other hand, H2S inhibits renin synthesis. Moreover, the regulatory pathways of nNOS and also endothelial eNOS could interact with endogenous NOS inhibitor, asymmetric dimetylarginine ADMA, on local as well as systemic level. The aim of the project is to study the effect of interactions of NO/nNOS/eNOS signalization with mentioned regulatory pathways (RAS, H2S, ADMA) on cardiovascular system and to find out their role in the specificity of nNOS and/or eNOS action in the conditions of essential hypertension. The availability of the results will be reached via using complex approach (functional, molecular, morphological). Moreover, on the level of acute experiments, we will confront selected biochemical markers of perivascular adipose tissue (plasma/serum) as well as vasoactive responses of arteries isolated from normotensive and hypertensive rats with biochemical markers and reactivity of vessels isolated after nephrectomy from normotensive patients and patients with essential hypertension.
Duration: 1.7.2016 - 30.6.2020

Novel synergistic antitumour properties ofnuclear retinoid X receptor (RXR) agonists as a consequence of the conditional RXR-RAR heterodimer formation in human breast cancer cells
Nové synergické protinádorové vlastnosti agonistov nukleárnych retinoidných X receptorov (RXR) ako následok vzniku "conditional" RXR-RAR heterodiméru v ľudských nádorových bunkách prsníka
Program: SRDA
Project leader: Ing. Brtko Július DrSc.
Duration: 1.7.2016 - 30.6.2020

Unravelling the mechanisms of post-translational regulation of RNA splicing factors in maintenance of genome integrity
Objasnenie mechanizmov posttranslačnej regulácie faktorov zostrihu RNA pri udržiavaní stability genómu
Program: SRDA
Project leader: Ing. Čipák Ľuboš PhD.
Annotation:Several mutations in RNA biogenesis factors have been implicated in human cancers. Early studies linked RNA processing defects with genome instability phenotypes such as hyper-mutation and hyper-recombination. Since then, recent functional genomic studies have implicated several more aspects of RNA processing in genome instability and revealed that virtually every major aspect of RNA processing is potentially mutable to a genome instability phenotype and in some cases are coupling RNA processing defects to increased RNA:DNA hybrid mediated R-loop formation, which in turn constitute a major source of genome instability across species. Despite it is now clear that RNA processing defects could destabilize genomes, the molecular mechanism of post-translational regulations of RNA processing and its connections to genome instability are not clear. Our project is aimed at a detailed analysis of the regulatory role of phosphorylation for functions of splicing factors that co-purified with the recently identified spliceosome-associated Nrl1 protein of fission yeast S. pombe. We showed Nrl1 protein be involved in suppression of accumulation of genome threating RNA:DNA hybrids, structures formed during RNA processing. The experimental approaches include protein purifications and phospho proteomics analysis, which will help us to identify post-translational modifications of splicing factors. Analysis of phenotypes of phospho mutants of splicing factors employ fluorescence/live-cell microscopy, analysis of splicing defects of these mutants using RT-qPCR or transcriptome sequencing, followed by analysis of their sensitivity to DNA damaging agents and analysis of their defects in DNA repair pathways. The obtained data should bring especially completely new information concerning the regulatory roles of post-translational modifications associated with the defects of RNA processing leading to genome instability that may be important as possible targets for anti-cancer therapy.
Duration: 1.7.2017 - 30.6.2021

Elucidation of novel pro-metastatic functions of tumor-associated carbonic anhydrase IX and its cross-talk with pro-inflammatory response.
Objasnenie nových prometastatických funkcií nádorovoasociovanej karbonickej anhydrázy IX a jej interakcie so zápalovou odpoveďou.
Program: SRDA
Project leader: Mgr. Švastová Eliška PhD.
Annotation:Tumor microenvironment is a complex ecosystem consisting from components influencing each other - tumor cells, stromal cells, extracellular matrix and many soluble factors and cytokines. Characteristic feature of the tumor microenvironment-hypoxia is considered as indicator of bad prognosis. Among the most hypoxia-induced proteins is carbonic anhydrase IX (CA IX) whose increased expression in tissues is often correlated with high malignity and the main task of which is to maintain intracellular pH homeostasis linked with acidification of the extracellular space. It is known that many processes in cells are tightly controlled by the values of intracellular and extracellular pH. Such process is also the formation of invasive structures, so-called invadopodia, which represents an important step in tumor cells metastasizing. Intriguingly, CA IX protein can markedly affect their formation by its enzymatic activity. Our most recent results indicate that another mechanism by which CA IX could participate in the invasion process is its cross-talk with proteins such as Arp2/3, WASP and mDia, responsible for actin polymerization. The molecular mechanism of this interplay will be the subject of our research. Moreover, from the point of view of migration and invasion, the proteoglycan domain of CA IX has an interesting ability to bind ECM proteins, and hence promote dissemination of tumor cells. It was also proved that certain inflammatory mediators, such as COX-2 and IL-6, increase the expression of CA IX. Hypoxia, necrosis and inflammatory reaction are closely connected during malignant progression. Despite this fact it has not been elucidated yet how necrosis-related signaling modulates hypoxia at the molecular level. Therefore, by a detailed study of CA IX we would like to identify a functional link between necrosis-induced signaling molecules, hypoxia and invasive potential of tumor cells, and subsequently to search for possibilities of their influencing or inhibition.
Duration: 1.7.2015 - 30.6.2019

DNA damage REsponse and preleukemic Clones in hematopoietic stem cells in diagnOstics, Risk estimation and treatment of peDiatric leukemia
Odpoveď na poškodenia DNA a preleukemické klony v hematopoetických kmeňových bunkách v diagnostike, v stanovení rizika a v liečbe detskej leukémie
Program: SRDA
Project leader: doc. Ing. Beliaev Igor DrSc.
Annotation:A chromosomal translocation resulting in an in-frame preleukemic gene fusion (PGF) is often a primary genetic abnormality in the origination of acute childhood lymphoblastic/myeloid leukemia (ALL/AML). PGF arise in hematopoietic stem/progenitor cells (HSPC), often in utero. According to our results, which confirmed the data on UK and US newborns, about 1% of Slovak newborns harbor most frequent TEL-AML PGF in their umbilical cord blood (UCB). Our data have also suggested that only PGF arisen relatively early during embryonic/fetal development in specific HSPC population may facilitate overt leukemia. Using a bank of UCB cells, we will study FACS-sorted HSPC subpopulations from PGF positive UCB samples by PCR, DNA sequencing, and FISH. The obtained data may be used for early diagnostics of predisposition to ALL/AML and exclusion of UCB PGF positive samples from transplantation. DNA damage response (DDR) and apoptosis are crucial for origination and persistence of PGF and may be impaired in HSPC of subjects predisposed to leukemia. Ionizing radiation at high doses is known to induce leukemia. Exposure to electromagnetic fields (EMF) has also been related to increased risk of childhood leukemia. However, no data are available whether ionizing radiation at low doses and EMF, to which significant part of general public is exposed in modern society, are able to induce PGF in HSPC and whether PGF may be used for assessment of risks for ALL/AML. Induction of PGF, DDR and apoptosis will be studied in HSPC subpopulations using state-of-the-art techniques. Preleukemic HSPC are considered to be a cellular reservoir for relapses. We will study diagnostically relevant PGF in HSPC subpopulations from PGF positive ALL/AML patients at diagnoses, remission, and relapse and in their backtracked UCB. All data will be correlated with clinical outcome to the aim of validation this approach for minimal residual disease (MRD), adjustment of treatment, and prevention of relapses.
Duration: 1.7.2016 - 30.6.2019

Polyphasic analysis of molecular data obtained by examining of the Rickettsiae, Coxiella burnetii and similar microorganisms.
Polyfázický prístup k analýze molekulárnych dát získaných skúmaním rickettsií, Coxiella burnetii a im podobných mikroorganizmov.
Program: VEGA
Project leader: RNDr. Sekeyová Zuzana PhD.
Annotation:Aims and results shared in this project will provide a number of theoretical knowledge in the field of molecular analysis of rickettsiae and a like microorganisms, with similar direct intrusions into medical practice, means such interferences that will predict and affect an analytical accuracy of diagnoses of rickettsioses, Q fever, and similar, biologically active intracellular bacteria. We will provide a specific picture of the course of the diseases caused by them, and will try to transfer this knowledge to determination of the specific laboratory indicators of studied pathogens at the molecular level. Reliable diagnoses, vigilance, preparedness, and the availability of efficacious vaccines and antibiotics are dependent on assignation of precise biomarkers that will enhance diagnostic capabilities and reduce delayed identification or misdiagnosis of infectious agent.
Duration: 1.1.2015 - 30.12.2017

Mechanisms of gold and magnetic nanoparticle effects on renal cells
Porovnanie mechanizmov účinku nanočastíc zlata a magnetitu na jednotlivé typy renálnych buniek
Program: VEGA
Project leader: Mgr. Bábelová Andrea PhD.
Annotation:Kidney is a unique organ characteristic by the high degree of heterogenity. Each cell type in the kidney has a distinct gene expression pattern and changes in the cellular composition largely impact on gene expression that is closely linked to the cell function. Different types of kidney cells have varying sensitivities to toxic substances that may accumulate in kidneys, including nanoparticles. Prolonged residency of nanoparticles in the kidney has been shown to induce toxicity with hallmarks similar to glomerulonephritis affecting all types of renal glomerular cells as mesangial cells, fibroblasts, or podocytes what may form a basis for reduced glomerular filtration capacityin nephrotic kidneys. Similarly, nanoparticle accumulation in the tubular basement membrane can be detrimental to tubular epithelial cells and so alter the ability of solute reabsorption by the kidney. Considering expansion of nanoparticles into biomedicine the type of renal toxicity studies are required to avoid potential health risks.
Duration: 1.1.2015 - 31.12.2018

Potential risk of metal and metal oxide nanoparticles used for biomedical applications: focus on reproductive and immune systems and brain
Potenciálne riziko nanočastíc kovov a oxidov kovov používaných v nanomedicíne: vplyv na reprodukčný a imunitný systém a mozog
Program: SRDA
Project leader: Mgr. Scsuková Soňa CSc.
Annotation:The development of nanomaterials (NMs)/ nanoparticles (NPs) for biomedical applications, including medical imaging and drug delivery, is currently undergoing a dramatic expansion. The same properties that make the NMs beneficial for their applications may also affect their interactions with biological systems and have unintended consequences on human health. NMs in dependence on their physicochemical properties, composition, and functionalization are able to cross biological barriers and enter the central nervous system (CNS) and peripheral organs. Current data support the notion that different types of NPs are capable of altering the physiological activity of endocrine system. Moreover, it has been shown that NMs with potential use for diagnostic and therapeutic purposes might induce neurotoxic effects resulting in neurodegeneration in different CNS regions. Despite the studies carried out in recent years, current knowledge of underlying molecular mechanisms of NPs action on endocrine, especially reproductive system and CNS, and immune systems and oxidative status is still limited. In the present project, potential adverse effects of metal (gold, silver) and metal oxide (titanium and silicon dioxide) NPs on selected parameters of reproductive, neuroendocrine and immune system, and oxidative status will be assessed by series of in vitro and in vivo model systems. Natural plant substances with antioxidant and anti-inflammatory properties will be tested to overcome possible negative impact of NPs on the studied processes. Early identification of potential negative features of NMs using interdisciplinary research approaches (biological, toxicological, clinical, engineering) could minimize the risk of newly designed/developed NMs for biomedical applications.
Duration: 1.7.2016 - 30.6.2020

Preleukemic gene fusions and DNA repair in umbilical cord blood cells
Preleukemické génové fúzie a oprava DNA v bunkách pupočníkovej krvi
Program: VEGA
Project leader: RNDr. Škorvaga Milan CSc.
Annotation:One way how to determine the susceptibility to childhood leukemia is to search for preleukemic gene fusions (PGF) in umbilical cord blood (UCB) of newborns. In this study, we aim to backtrack the UCB of pediatric patients diagnosed for acute leukemia for pathological PGF. The presence of these PGF in positive UCB samples will be verified by sequencing of PCR products. Hematopoietic stem cells and lymphocytes will be explored for DSB repair foci. The presence of causative chromosomal translocations in CD34+ cells from previously tested positive newborns will be explored with long-distance inverse PCR. High-dose ionizing irradiation of UCB CD34+ cells will serve as a model to study a selective induction of leukemia-associated PGF. Finally, a B-cell precursor leukemia cell line carrying specific gene fusion will be used to assess the sensitivity of RT qPCR and the impact of freeze/thaw cycle on the stability of studied fusion transcripts, thus affecting the suitability of UCB for clinical use.
Duration: 1.1.2015 - 31.12.2017

Prenatal and postnatal effects of delta and mu opioid receptor ligands on the hippocampal development and function.
Prenatálne a postnatálne účinky ligandov delta a mí opioidných receptorov na vývoj a funkciu hipokampu.
Program: SRDA
Project leader: RNDr. Hlaváčová Nataša PhD.
Annotation:Ligands of opioid receptors δ (DOR) and μ opioid receptors (MOR) are commonly used in treatment of severe acute and chronic pain. DORs are involved also in mood disorders like depression and anxiety, which are related to the hippocampal function. Treatment with DOR ligands does not result in adverse effects including addiction, which are common with MOR ligands. However, much less is known about DOR – activated signaling pathways than about MOR – activated pathways. We will analyze the effect of acute (seconds to minutes) and chronic (hours to days) in in vitro and in vivo (prenatal and postnatal) administration of DOR ligands on the morphological and electrophysiological properties of rat hippocampal neurons and compare them with effects of MOR ligands and with effects of ligands specific for MOR-DOR heteromers. Further, involvement of calcium transporting proteins in signal transduction pathways activated by DORs and MORs ligands will be addressed by molecular biology methods. Possible remodeling of the dendritic spines will be investigated using transmission electron microscopy. Effect of DOR ligands on hippocampal plasticity in control and stressed rats will beexamined using behavioral tests and molecular neuroscience techniques. Excitability will be investigated in primary culture of hippocampal neurons by patch clamp and in situ by in vivo electrophysiology. Both models enable to follow effects of acute and chronic drug application as well as possible receptor desensitization and offer complementary advantages. Primary neuronal culture is the possibility to visually identify neurons, characterize in details both action potentials and underlying ionic currents and to correlate electrophysiology and molecular biology on the same batch of neurons. In vivo electrophysiology offers the possibility to measure neuronal activity within its normal environment including all interactions with other brain parts.
Duration: 1.7.2016 - 30.6.2020

Drug repurposing as a novel approach to therapy of colorectal carcinoma: molecular mechanisms and potential applications
Presmerovanie liekov na protinádorovú liečbu ako nový prístup k terapii kolorektálnych karcinómov: molekulárne mechanizmy a potenciálne aplikácie.
Program: VEGA
Project leader: RNDr. Baráthová Monika PhD.
Annotation:Drug repurposing is the identification of new therapeutic applications for drugs that have received approval for another purpose. B-blockers have the potential to be repurposed in therapy of colorectal cancers (CRC), which are the third most frequent cancer in men and the second most frequent cancer in women in the world. Many studies have supported the observation that ß-blockers produced an anticancer effect and improved survival of cancer patients. The main project objective is to elucidate effect of ß-blockers on hypoxia-regulated pathways in the process of tumor progression, to identify molecular pathways of interplay between stress hormones,ß-blockers and CAIX. Resistance to therapy of CRC occurs in most cases and allows cancer progression. This project can help to understand correlation between ß-blockers, drugs used in the chemotherapy of CRC, to elucidate interactions between comorbidities treatment and effectiveness of anticancer therapy and to reveal possible chemopreventive effect of ß-blockers.
Duration: 1.1.2016 - 31.12.2019

Preparation of erythropoietin a therapeutic hormone affecting the production of red blood cells by expression in eukaryotic cell system and its further purification
Príprava erytropoetínu, terapeutického hormónu ovplyvňujúceho tvorbu červených krviniek, expresiou v eukaryotickom bunkovom systéme a jeho ďalšia purifikácia
Program: SRDA
Project leader: Ing. Škultéty Ľudovít DrSc.
Duration: 1.7.2015 - 31.12.2018

Proteomic analyses of the interaction of host with pathogenic bacterium Coxiella burnetii
Proteomická analýza interakcie hostiteľa s patogénnou baktériou Coxiella burnetii
Program: VEGA
Project leader: Ing. Škultéty Ľudovít DrSc.
Duration: 1.1.2015 - 31.12.2018

Proteomic analysis of the plum pox virus (PPV) / Prunus avium (cherry) interaction and factors of the virus adaptation to the host.
Proteomická analýza interakcie vírus šarky slivky (PPV)/čerešňa (Prunus avium) a faktorov adaptácie vírusu na hostiteľa.
Program: VEGA
Project leader: Ing. Nováková Slavomíra PhD.
Duration: 1.1.2015 - 31.12.2017

Regulation of the ligation step of non-homologous end-joining
Regulácia ligačného kroku spájania nehomologických koncov DNA
Program: VEGA
Project leader: Mgr. Chovanec Miroslav PhD.
Annotation:As DNA double-strand breaks (DSB) are the most toxic DNA lesion, their repair is essential to maintain genome stability and cell viability. Non-homologous end-joining (NHEJ) is one of the two main pathways that have evolved to repair DSB. Central to NHEJ is the DNA ligase IV complex, which catalyzes the ligation step of the process and involves the Lif1 protein in yeast. We have revealed the SUMOylation of Lif1 and identified lysine 301 as the major conjugation site. We suggest that Lif1 SUMOylation represents a new regulatory mechanism that regulates NHEJ. Moreover, Lif1 undergoes cyclin-dependent kinase-dependent phosphorylation at serine 261 and this modification also controls NHEJ. Thus, Lif1 undergoes both SUMOylation and phosphorylation, the two modifications that regulate NHEJ. Here, we intent to verify a possibility of cross-talk between Lif1 SUMOylation and phosphorylation during the regulation of NHEJ using the Lif1 substituted alleles and various biochemical and genetic methods.
Duration: 1.1.2014 - 31.12.2017

Multiple sclerosis - The role of mitochondrial dysfunction in insulin resistance.
Sclerosis multiplex - Úloha mitochondriálnej dysfunkcie v inzulinovej rezistencii
Program: SRDA
Project leader: MUDr. Imrich Richard DrSc.
Annotation:Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) and is one of the most common neurological diseases, often leading to disability of the patients. The MS pathogenesis includes vascular and inflammatory components, however recently also the role of mitochondrial dysfunction being a hot topic in neurodegeneration. Current project is based on our previous project results, where we found signs of insulin resistance (IR) with hyperinsulinemia in patients with MS, which seems not to be related to chronic inflammation or low physical activity. Therefore aim of present project is to elucidate impact of mitochondrial dysfunction in the pathogenesis of impaired insulin action and its role in the neurodegenerative process. To test our hypothesis we will assess mitochondrial function, endothelial function, changes in membrane proteins and function of autonomic nervous system. Those parameters will be measured non-invasively and in samples of blood, cerebrospinal fluid and skeletal muscle. MS patients will be examined at the time of diagnosis and after 12 months of treatment, healthy subjects will be used as controls. We expect elucidation of insulin resistance cause and the role of mitochondrial dysfunction in pathogenesis of thedisease.
Duration: 1.7.2016 - 30.6.2020

Early molecular markers of myocardial infarction.
Skoré markery akútneho infarktu myokardu
Program: VEGA
Project leader: MUDr., Mgr. Hodosy Július PhD., MPH.
Duration: 1.1.2015 - 31.12.2017

Investigation of effect of acute and repeated asenapine (ASE) treatment on activity of neurons in extrastriatal brain, identification of activated neurons phenotype, and revealing whether chronic mild stress preconditioning may alter the effect of ASE
Skúmanie akútneho a chronického účinku azenapínu (AZE) na aktivitu neurónov v mimostriatálnych oblastiach mozgu, identifikovanie fenotypového charakteru aktivovaných neurónov a zistenie či účinok AZE je ovplyvniteľný chronickým predstresovaním zvierat.
Program: VEGA
Project leader: RNDr. Kiss Alexander DrSc.
Annotation:Antipsychotics (APs) are drugs used in the treatment of mental illnesses. The majority of morphological studies deals with the impact of APs in forebrain structures and only little is known about their effect in extrastriatal areas, whereas they act also extrastriatally and the extent of their action considerably differs one from another. Asenapine (ASE) is an atypical AP with low affinity to D2 and high affinity to serotoninergic (5-HT2A) receptors. We have described, as the first, the impact of ASE on the activity forebrain structures. This project will bring a new knowledge about acute and repeated effect of ASE in the extrastriatal areas, reveal the phenotype character of activated neurons, and disclose whether ASE impact may be modifiable by a stress preconditioning. The data obtained in this project might be perspectively helpful in the developing of new APs with reduced negative side effects and to lead to more integrated understanding of the neurobiology of serious mental illnesses.
Duration: 1.1.2016 - 31.12.2018

Monitoring of the APC gene and its product functions in familial adenomatous polyposis (FAP) patients.
Sledovanie funkcie APC génu a jeho produktu u pacientov s familiálnou adenomatóznou polypózou (FAP).
Program: VEGA
Project leader: Mgr. Adamčíková Zuzana PhD.
Annotation:Familial adenomatous polyposis ( FAP ), as one of the most common hereditary forms of colon cancer represents a suitable model to study tumorigenesis. Germline mutations are induced up to 90 % in the APC gene. The second allele mutation of the tumor-suppressor gene (TSG) resulst in the induction of malignancy. The aim of project is study the APC gene causes and monitor enormous number of mutations in the MCR 15 exon. To this purpose has been elaraborated original model, according to the primary structure of some TSG assumed that the basis should be bacterial genes that gradually adding new genetic information was developed for genes essential for higher organisms. APC -like sequences will be monitored in intestinal bacteria FAP patients. The APC gene expression in bacteria will be analysed using specific antibodies against the APC gene. Elimination of potentially pathogenic bacteria with APC -like sequences can be carried out prospectively applying symbiotics.
Duration: 1.1.2015 - 31.12.2018

Analysis of matrix metalloproteinase induction in association with expression of HLA-G molecules
Sledovanie indukcie matrixových metaloproteináz v asociácii s expresiou HLA-G molekúl
Program: VEGA
Project leader: RNDr. Poláková Katarína DrSc.
Annotation:HLA-G molecules are non-classical HLA class I antigens induced in tumors. HLA-G have immuno-suppressive properties thefore significantly contribute to tumor growth, invasion and formation of metastasis. It was demonstrated that matrix metalloproteinases (MMPs) play an important role in the tumor progression. There is indication that expression of HLA-G may lead to the induction of some MMPs. The main goal of this project is to learn whether in cells originally negative in expression of HLA-G following their transfection with HLA-G also expression of some MMPs is induced. Synthesis of HLA-G can be also induced epigenetically. Therefore cell lines expressing HLA-G following DNA hypomethylation will be also analyzed for expression of MMPs. Finally we will examine whether HLA-G molecules on the cell surface or released during tumor progression are affected for example by necrosis (common process during invasion of solid tumors). We expect that obtained results will be basis for new diagnostic approaches.
Duration: 1.1.2015 - 31.12.2017

Effect of salivary gland extracts derived from different tick species on induction and biological activity of interferon-lambda 1.
Sledovanie vplyvu extraktov slinných žliaz (SGE) z rôznych druhov kliešťov na indukciu a na biologickú aktivitu IFN-lambda 1.
Program: VEGA
Project leader: Mgr. Bartíková Pavlína PhD.
Annotation:During bloodfeeding, tick salivary glands secrete into the damage area a broad spectrum of pharmacologically active substances interacting with host innate and adaptive immune systems. This manipulation of host defense reactions is important not only to successful ticks surviving also to facilitate transmission and replication pathogen into the host (SAT phenomenon). Interferons (IFNs), innate immune cytokines, contribute the first line of antiviral defence. Recently, IFNs lambda was found as new family of interferons, type III. Type III IFNs are structurally closed to interleukin 10(IL-10) and IL10–related cytokines, functionally are closely related to type I IFNs. Probably, IFN l1 could be important innate immunity activator, particularly at the site of viral infection, such as tick’s feeding site could be. Elucidation of the mode of action of tick bioactive molecules on the cell processes connected with interferons can provide new tools for understanding the mechanisms contribute on SAT phenomenon.
Duration: 1.1.2015 - 31.12.2018

Soluble and/or exosome-associated Carbonic anhydrase IX as a biologically active molecule.
Solubilná a/alebo exozómovo-viazaná karbonická anhydráza IX ako biologicky aktívna molekula.
Program: VEGA
Project leader: RNDr. Zaťovičová Miriam CSc.
Annotation:Many transmembrane proteins involved in signal transduction or other regulatory processes exist also in soluble single-molecule form and/or as extracellularly released complex structures called exosomes. Extracellular forms regulate the fate and physical location of membrane anchored proteins and have a significant impact on their biological functions. The proposed project is aimed at understanding the mechanisms of release of soluble and exosomal forms of the tumor associated protein carbonic anhydrase IX (CA IX) and their implications in cellular processes such as tumor cell adhesion, migration, and metastasis. In the project we will use not only latest in vitro methods of cell biology including measurements of cell parameters in real time but also in vivo experiments. Results of this project are expected to extend our knowledge on function of soluble CA IX ectodomain and exosomal CA IX as important intercellular messengers as well as potential non-invasive clinical biomarkers.
Duration: 1.1.2016 - 31.12.2019

Activity Assay of Transfer Factor, Immunostimulatory Drug from Leukocytes Extract And Its Preparation Standardization
Stanovenie aktivity transfer faktora, imunostimulačného preparátu z extraktu leukocytov a štandardizácia jeho prípravy
Program: SRDA
Project leader: MVDr. Kopáček Juraj DrSc.
Annotation:Transfer factor (TF) is dialyzable leukocyte extract from peripheral blood of healthy donors that clearly demonstrates immunostimulatory effect in treatment of infectious diseases, allergies, some oncogenic disorders and immunodeficiencies. TF represent mixture of low molecular weight molecules (up to 10 KDa) predominantly of peptide origin that affect cell mediated immune response. Currently we are lacking information on molecular nature and composition of TF that hampered standardization of TF preparation, determination of its composition and efficacy and, consequently, its acceptance by drug control authorities. The main objectives of the project are analysis of TF treatment impact and characterization of its main components at molecular level; development and standardization of innovative methods of TF preparation and determination of its activity in vitro. For analytical separation of TF active components there will be used methods of HPLC and after demonstration of their biological activity they will be further characterized by proteomics methods. Concurrently there will be innovated methods for TF biological activity assays with focus of TF ability to modulate signal pathways of immune response in cells that will be studied by protein- and micro-array methods. The main goal of these studies will be development of simple quantitative method(s) for determination of TF biological activity. On basis of gained knowledge of main TF active components and innovative methods of their activity assay it will be possible to progress to TF preparation optimization with intention to improve therapeutic properties of current TF formulations. Data that will be obtained during the project will contribute to knowledge of TF biological effect; will open opportunities for its better, acceptable characterization and efficacy determination. The results could be transferred to TF production innovation for therapeutic purposes.
Duration: 1.7.2016 - 30.6.2020

Sulfide signaling as a potential mechanism in tumor´s treatment
Sulfidová signalizácia ako potenciálny mechanizmus pri liečbe nádorov
Program: SRDA
Project leader: RNDr. Hudecová Soňa CSc.
Annotation:Hydogen sulfide, which was previously accounted as a toxic gas, is currently considered as a third gassotransmitter, playing a crucial role in a cell physiology and patophysiology. Changes in the metabolism of hydrogen sulfide lead to the development of pathophysiological states, e.g. hypertension, diabetes, inflammation, sepsis, neurodegenerative disases etc. This project is appointed to determine a role of the endogenous (formed by a cell) and also exogenous (added) H2S in selected types of cancer cells (pheochromocytomas, ovarial and kidney cells). We expect that by the H2S donors we will be able to modulate proliferation by these cells and also induction of the apoptosis (possibly through the calcium fluxes). Understanding the mechanism might contribute to development of new therapeutics based on the H2S release.
Duration: 1.7.2015 - 30.6.2019

Investigation of anatomical-functional differences between the effects of aripiprazole and quetiapine, atypical antipsychotics with simiral terapeutic indications, but different impact on brain dopaminergic receptors, in experimental animals
Štúdium anatomicko-funkčných rozdielov v účinkoch aripiprazolu a kvetiapínu, atypických antipsychotík s podobnými terapeutickými vlastnosťami, ale rozdielnym vplyvom na dopaminergické receptory v mozgu, u experimentálnych zvierat
Program: SRDA
Project leader: RNDr. Kiss Alexander DrSc.
Annotation:Antipsychotics (ATs) represent a group of drugs used in the treatment of psychotic and depressive disorders. However, the frequency of ATs treatment is rather increasing than decreasing and the number of new atypical AP drugs have been emerged over the last few years. In addition, APs treatment is connected with a number of unwanted side effects, such as extrapyramidal syndrome, akathisia, body mass increase, agranulocytosis, tardive dyskinesia, somnolencia, etc. Anatomical-functional investigations are incessantly bringing information about the effects of APs on the activity of neurons and their spatial distribution over the whole brain, which allows more precisely to define and predict the consequences of the APs treatments. The aim of the present study is to reveal the effects of the acute and repeated treatment of two, relatively new atypical APS, aripiprazole (ARI) and quetiapine (QUE), on the activity of neurons in the forebrain and extra-forebrain areas of the brain, to identify the phenotype (chemical) character of the targeted neurons, to investigate their impact on the behaviour, and to compare their impact on the activity of signaling pathways, expression of signaling molecules, and secretion of selected neuropeptides in anatomically precisely defined brain structures. The data of the present project will be new and helpful for the deeper understanding of the biology of mental disorders. They also will bring new impulses to the drug developing procedures to make drugs with more directed and beneficial therapeutic efficacy.
Duration: 1.7.2016 - 30.6.2020

Study of biological effects of H2S/NO products and molecular mechanism of their actions
Štúdium biologických účinkov produktov H2S/NO interakcie a molekulárne mechanizmy ich pôsobenia
Program: SRDA
Project leader: RNDr. Ondriaš Karol DrSc.
Annotation:Now it is well acknowledged that endogenously produced H2S affects and is involved in regulation of many physiological and pathological functions of living organisms. It is suggested that biological effects of H2S might not result from actions of H2S alone, but from its oxidation products, which come from e.g. interaction of H2S with NO. Last four years, our “international” group indentified the following products of H2S and NO interaction: nitrosopersulfide (SSNO−), polysulfides (HSn−) and dinitrososulfite [N-nitrosohydroxylamine-N-sulfonate (SULFI/NO) (Proc Natl Acad Sci U S A. 112, 2015, E4651-E4660). Biological effects and molecular mechanisms of these products are not completely understood Therefore the aim of our project is to explore biological effects of the products of H2S/NO interactions and to study their molecular mechanism of their actions. Particularly, as a continuation of our research, we will study their effects on rat blood pressure and aortic rings relaxation. To elucidate molecular mechanisms of their biological effects, we will study their influence on expression of enzymes that endogenously produce H2S (CBS, CSE and 3-MST), on intracellular membrane channels, concentration of intracellular calcium, lipid peroxidation and their antioxidant properties. Goal of the project is also to find out, if studied compounds could provide us with information leading to a drug design based on their molecular structure, what could be an object for next application studies and lead to implementation in medical praxis.
Duration: 1.7.2016 - 30.6.2020

Study of selected endocrine disruptors with phytochemicals on in vitro models of ovarian intrafollicular processess and hormone-sensitive cancer cell lines
Štúdium interakcií vybraných endokrinných disruptorov s fytochemikáliami na in vitro modeloch ovariálnych intrafolikulárnych procesov a hormón-senzitívnych nádorových bunkových líniách
Program: VEGA
Project leader: Mgr. Bujňáková Mlynarčíková Alžbeta PhD.
Duration: 1.1.2015 - 31.12.2017

Study of the mechanisms blocking tumorigenicity of cancer cells overexpressing human tumor necrosis factor alpha.
Štúdium mechanizmov, ktoré eliminujú tumorigenitu nádorových buniek vplyvom nadexpresie ľudského faktoru nádorovej nekrózy.
Program: VEGA
Project leader: RNDr. Tyčiaková Silvia PhD.
Annotation:Tumor necrosis factor alpha (TNFa), a pleiotropic cytokine, can induce apoptosis of tumor cells, modulate expression profile, secretome and can have tumor destructive capacity. As showed our recent studies, engineered human melanoma and colon carcinoma cell lines overexpressing TNFa fail to form tumors in xenografted mice, conferring 100% protection against tumorigenesis. These results gave us an impulse to study mechanisms of TNFa induced blocking of tumorigenicity and its influence on tumor heterogeneity. We will focus on alternation in expression and secretion profile of the tumor cells, especially markers of the stemness/pluripotency and epithelial-mesenchymal transition. We will monitor the impact of TNFa transgene expression on the proportion of subpopulation of CD133+/ALDH+ positive tumor initiating cells (TISc), which are responsible for tumorigenesis, therapy resistance and relapse. Detailed study of the process of TNFa- induced tumor resistance can offer a new therapeutic strategy to eliminate TICs.
Duration: 1.1.2017 - 31.12.2020

The study of gut microbiome in patients with colorectal cancer.
Štúdium mikrobiómu u pacientov s kolorektálnym karcinómom.
Program: VEGA
Project leader: RNDr. Čierniková Soňa PhD.
Annotation:Colorectal cancer is the most frequent malignancy of the digestive tract in Slovakia with the highest incidence worldwide. Therefore, the studies on the causes, risk factors and new possibilities for screening and treatment is highly actual issue. The project aims to characterize bacteria from colorectal adenomas and carcinomas, rectal swabs of cancer patients and compared with the intestinal microflora from healthy people biopsies. To identify differences in the bacterial composition, ENTEROtest will be used. The presence of intracellular bacteria will be monitored by Gentamicin protection assay. Molecular analysis for the genes associated with pathogenicity and adhesion will be done by PCR. Identification and analysis of certain types of microbiota,which are not presented in healthy intestinal tract, but in the precancerous tissue and would correlate with the results obtained from rectal swabs, could provide a simple,non-invasive tool for the assessment of increased risk of colorectal cancer development.
Duration: 1.1.2017 - 31.12.2020

Studies on molecular mechanisms of cold and exercise-induced metabolic activation of brown and beige adipose tissue in humans with respect to obesity and type 2. diabetes
Štúdium molekulárnych mechanizmov cvičením a chladom indukovanej metabolickej aktivácie hnedého/béžového tuku u človeka vo vzťahu k obezite a diabetu 2. typu
Program: VEGA
Project leader: Mgr. Kurdiová Timea PhD.
Duration: 1.1.2015 - 31.12.2017

Study of the potential role of selected genes in molecular pathogenesis of myotonic dystrophy
Štúdium možnej úlohy vybraných génov v molekulárnej patogenéze myotonickej dystrofie
Program: VEGA
Project leader: RNDr. Radvánszky Ján PhD.
Annotation:Myotonic dystrophy (DM) comprises at least two genetically distinct forms. DM1 is caused by expansion of a CTG repeat in the DMPK gene, while expansion of a CCTG repeat in the CNBP gene causes DM2. Both expansions cause misregulation of several splicing events in the cells, mediated by the mutated RNA molecules through upregulation and/or depletion of splicing regulating proteins. According to our hypothesis, if the presently accepted pathogenic pathways of DM are valid, there is a possibility of existence of genes, mutations of which can cause symptoms highly resembling DM even without the presence of the known expansions or can modify the disease phenotype in DM1 or DM2 patients. Our project is aimed to test our hypothesis using simultaneous massively parallel resequencing of a number of selected genes in DM suspected patients with or without identified DM1/DM2 causing expansions. Results of our project will have a potential to contribute to a more detailed characterisation of DM causing pathogenic pathways
Duration: 1.1.2015 - 31.12.2017

Study of protective potential of synthesized phenylethanoid glycosides in the systems of mammalian cells and plasmid DNA
Štúdium protektívneho potenciálu syntetizovaných fenyletanoidných glykozidov v systémoch cicavčích buniek a plazmidovej DNA
Program: VEGA
Project leader: Mgr. Horváthová Eva PhD.
Annotation:DNA damage associated with different changes at the genetic level of the cell is generally considered as the most important stimulus for the initiation of the multistage process of carcinogenesis. The study of protective effects of natural compounds and their analogs, which are frequently used in health protection and prevention, is therefore of great importance. In the proposed project we plan: 1. to prepare phenylethanoid glycosides and their analogues using chemical or less conventional enzymatic procedures; 2. to determine their antioxidant, chelating and reducing capacity using biochemical methods; 3. in experimental systems utilizing mammalian cells, primary rat hepatocytes and plasmid DNA to evaluate their protective potential against lesions induced by model mutagens and carcinogens; 4. to monitor the activity of important cellular enzymatic and nonenzymatic antioxidants. Compounds studied could be a part of preventive and therapeutic strategies aimed at fighting the civilization diseases.
Duration: 1.1.2016 - 31.12.2019

Study of products of H2S/oxidized glutathione interaction on membrane channels and molecular mechanism of their actions
Štúdium účinkov produktov interakcie H2S/oxidovaný glutatión na membránové kanály a molekulárny mechanizmus ich pôsobenia
Program: VEGA
Project leader: RNDr. Ondriaš Karol DrSc.
Duration: 1.1.2017 - 31.12.2020

Effects of acute and regular exercise on myokines and microRNAs in circulation and cerebrospinal fluid in relation to cognitive functions and metabolism of patients with neurodegenerative disease
Účinky akútneho a pravidelného cvičenia na profil myokínov a mikroRNA v cirkulácii a v cerebrospinálnom likvore vo vzťahu ku kognitívnym funkciám a metabolizmu pacientov s neurodegeneratívnym ochorením
Program: VEGA
Project leader: doc. MUDr. Ukropcová Barbara PhD.
Duration: 1.1.2015 - 31.12.2017

The role of ALDH1 in chemoresistance of cancer cells
Úloha ALDH1 v chemorezistencii nádorových buniek
Program: VEGA
Project leader: RNDr. Kozovská Zuzana PhD.
Annotation:The project will be focused on the study of the role of aldehyde dehydrogenase 1 (ALDH1) in chemoresistance and stemness of tumour cells. We will use cell lines derived from human colorectal adenocarcinoma, their chemoresistant derivatives as well as primocultures derived from patients’ tissues. The subject of the study will be cancer stem cells (CSC) which are characterised with higher chemoresistance, and are believed to be the main cause of chemotherapy failure. They represent 0.1-10 % of cancer cell population, depending on cell type and cultivation conditions. We will use the immunomagnetic separation and fluorescently activated cell sorting (FACS) for separation of particular cell population in which we will analyse the expression profile and we will compare it with the expression profile of the rest population. The part of the project will be focused on siRNA and/or shRNA methods by which we will specifically inhibit the expression of genes ALDH1A1 or ALDH1A3 involved in the resistance of CSC.
Duration: 1.1.2017 - 31.12.2020

The role of CA IX in adaptation to tumor microenvironment and in resistance to anticancer therapy: molecular mechanisms and clinical implications
Úloha CA IX v adaptácii na nádorové mikroprostredie a v rezistencii na protinádorovú terapiu: molekulárne mechanizmy a klinické implikácie
Program: SRDA
Project leader: prof. RNDr. Pastoreková Silvia DrSc.
Annotation:The project is based on the most recent understanding of tumor microenvironment as a key factor driving cancer progression and therapy resistance through physiological stresses, such as hypoxia and acidosis, and via paracrine signaling from cells of tumor stroma. In this context, we intend to focus on carbonic anhydrase IX (CA IX), a cancer-associated protein induced by hypoxia and functionally implicated in tumor biology. CA IX has been correlated with aggressive tumor phenotype, poor outcome and unfavorable prognosis of cancer patients, and is considered as a clinically relevant biomarker and promising target for anticancer therapy. The main project goal is to elucidate the role of CA IX in the adaptation of tumor cells to microenvironmental stresses, in the crosstalk between cancer and stromal cells, as well as in the resistance to chemotherapy. Our efforts will be aimed at decoding molecular mechanisms of the anticipated pro-survival and pro-metastatic effects of CA IX in response to drugs and stresses (i.e. involvement in autophagy, senescence or multidrug resistance). We also intend to evaluate immunotherapeutic strategies of targeting CA IX in tumor xenografts by our domain-specific monoclonal antibodies using diverse cell models (acid-adapted, chemotherapy-adapted, expressing CA IX mutants or siRNA). Moreover, we want to shed more light on responses of mesenchymal stromal cells to hypoxia, acidosis and to CA IX ectodomain cleaved from cancer cells. We expect that the project can bring original data contributing to improvement of basic knowledge on tumor biology and to further development of rational diagnostic and therapeutic strategies. Existing research infrastructure, including expertise of participating teams, modern equipment, and unique in-house reagents and models, represent solid prerequisites for the successful accomplishment of the project objectives.
Duration: 1.7.2016 - 30.6.2020

The role of cytokines/chemokines in the immune response to influenza A infection
Úloha cytokínov/chemokínov v imunitnej odpovedi na infekciu vírusom chrípky typu A
Program: VEGA
Project leader: RNDr. Betáková Tatiana DrSc.
Annotation:Multiple factors are likely to influence immune response to influenza A virus (IAV) infection, including the rate of virus replication, its ability to actively antagonise IFN induction and also factors conferred by the host. Innate immune response results in the production of cytokines/chemokines and activation of immune-signaling pathways. NS1 protein of IAV counteracts the induction of antiviral response. Influenza virus NS1 deletion mutants pose great tool for studying innate immune response against influenza virus, especially stimulation individual genes involved in individual cytokines elicit by influenza virus infection. Proteome profiler array and qPCR will allow as study expression more than 40 cytokines and 25 chemokines and their pathways depending of the time after infection. At present, type III IFNs are the least well characterized IFN types. There is some evidence that type III IFNs not only activates the same IFN-signaling pathways as type I IFNs but it also contributes to transcriptional regulation of other genes which are not stimulated by type I IFN. Our preliminary data show that IFN-lambda trigger IFN-signaling pathway without increasing expression of RIG-1 and stimulate induction of type I IFN. Thereby, expression of receptor proteins specific for type I and type III IFNs and activation of RIG-1/MDA5-MAVS-IRF3/7 pathway will be studying in the cells induced by individual IFNs as well as in the cells infected with NS1 deletion mutants, human or avian influenza viruses.
Duration: 1.1.2016 - 31.12.2019

The role of endogenous catecholamines in modulation of neuro-immuno-endocrine response to stress in mesenteric adipose tissue
Úloha endogénnych katecholamínov v mezenterickom tukovom tkanive pri modulácii neuroimunoendokrinnej odpovede na stres
Program: VEGA
Project leader: Ing. Vargovič Peter PhD.
Duration: 1.1.2014 - 31.12.2017

The role of exosomes in the process of chemoresistence of ovarian carcinoma
Úloha exozómov pri vzniku rezistencie na chemoterapiu pri karcinóme ovária
Program: VEGA
Project leader: RNDr. Sedlák Ján DrSc.
Annotation:Ovarian cancer is the leading cause of women’s death for gynecologic malignancy in developed countries. The rapid development of the tumor and the impossibility of proper screening cause the disease diagnoses in the high stages in more than 75% of cases. The treatment consists of debulking surgery and chemotherapy. The disease, in most cases, despite chemosensitive primary tumor, relapses in average 18 months after the treatment with progressive development of chemoresistance. 5-year survival rate is 25-35 %. It is therefore necessary to identify new prognostic and predictive biomarkers that would allow earlier diagnosis of the disease and reveal resistance to chemotherapy. Exosomes, small 30-100 nm big vesicles, are involved in physiological and pathological processes, e.g. tumor growth, the development of metastases, immune system stimulation and intercellular transfer of miRNA. Exosomes in the peripheral blood, its miRNA composition, present a potential biomarker for better diagnosis of ovarian cancer.
Duration: 1.1.2016 - 31.12.2018

The role of hypoxia-induced carbonic anhydrase IX in invasion processes of tumor cells.
Úloha hypoxiou-indukovanej karbonickej anhydrázy IX v invazivite nádorových buniek
Program: VEGA
Project leader: Mgr. Švastová Eliška PhD.
Annotation:Carbonic anhydrase IX (CA IX) is hypoxia inducible protein whose expression is associated with tumors with bad prognosis. Hence, these cells have a high invasive potential. Formation of invasive structures, i.e. invadopodia is an essential step in tumor cell penetration into ECM. This process is strictly controlled by intracellular and extracellular pH. By its enzymatic activity CA IX acidifies pHe and, at the same time, neutralizes pHi, which could significantly influence invadopodia formation. Our microarray data indicate that CA IX level also affects the expression of proteins, such as Arp2/3 or WASP which form a signaling complex important for actin polymerization in invadopodia. Besides its pH regulatory function CA IX could have an impact on the formation of signalozome regulating the growth of these invasive structures, Moreover, proteoglycan domain of CA IX could facilitate intravasation and extravasation and in such way support tumor cells dissemination by its ability to bind ECM proteins.
Duration: 1.1.2015 - 31.12.2018

Role of IL-6/NF-κB /HIF-1 axis in adipose tissue mesenchymal stromal cells-mediated breast cancer cells stemness
Úloha IL-6/NF-κB/HIF-1 signálnej dráhy v kmeňovosti prsníkových nádorových buniek sprostredkovanej mezenchýmovými stromálnymi bunkami izolovanými z tukového tkaniva
Program: SRDA
Project leader: Mgr. Kučerová Lucia PhD.
Annotation:Adipose tissue mesenchymal stromal cells (AT-MSC) are an important component of breast cancer microenvironment and though secretion of different molecules are able to influence many features of tumor cells. Our previous results have shown increased dediferentiation and chemoresistance (stem cell-like properties) of breast cancer cells (BCC) after cultivation with ATMSC or their secreted factors. We propose, that AT-MSC-secreted IL-6 activates NF-κB/HIF-1 axis, which is responsible for maintenance of stemness properties of tumor cells. We will analyze cell cycle progression/quiescence, mammosphere formation and expression of pluripotency markers in breast cancer cells cultivated in the presence of AT-MSC and/or their secreted factors. Also, to confirm existence of NF-κB/HIF-1 axis and its role in stemness of BCC, we will determine HIF-1 activation and localization in NF-κB and/or HIF-1–suppressed BCC.
Duration: 1.1.2017 - 31.12.2018

The role of carbonic anhydrase IX in tumor metabolism: regulation, function and clinical significance
Úloha karbonickej anhydrázy IX v nádorovom metabolizme: regulácia, funkcia a klinický význam
Program: VEGA
Project leader: RNDr. Gibadulinová Adriana CSc.
Annotation:Tumor cells are capable to adapt their metabolism to the tumor tissue microenvironment stress, as is lack of oxygen and nutrients. They become less dependent on oxidative phosphorylation and use glycolysis to receive not only the energy required for survival, but also the biomass needed for proliferation. Such tumor metabolism promote an aggressive phenotype and progression of cancer. Based on our preliminary proteomic data, in this project we will stydy the role of hypoxia - induced carbonic anhydrase IX ( CA IX ) in tumor metabolism and its cooperation with the metabolic pathways and signaling. In addition to the experimental 2D and 3D cell models, the results will be validated on clinical tissue samples and sera from patients with breast tumors . In the project we will use the latest methods of molecular and cell biology ( including cultivation cells in hypoxia and measurements of cell parameters in real time), immunodetection methods as well as unique reagents available in our laboratory.
Duration: 1.1.2015 - 31.12.2018

The role of the nervous system in etiopathogenesis of experimental melanoma
Úloha nervového systému v etiopatogenéze experimentálneho melanómu
Program: VEGA
Project leader: Mgr. Horváthová Ľubica PhD.
Annotation:Malignant melanoma represents a serious tumor disease. The incidence and mortality caused by this disease annually significantly increases. Explanation of the mechanisms associated with the development and progression of malignant melanoma requires research not only on the level of malignant cells transformation, but also on the level of processes running in its micro and macro environment, this includes also components of the nervous system. Several experimental and clinical studies have shown involvement of the nervous system in the etiopathogenesis of cancer. It is proved that nervous system may affect tumor proliferation and metastasis formation via modulation of cellular immune reactions, regulation of neuroendocrine stress reaction, as well as via other pathways including parasympathetic and sensitive nerves. The aim of the proposed project is to examine the role of the nervous system in etiopathogenesis of experimental melanoma using various experimental approaches.
Duration: 1.1.2016 - 31.12.2018

Role of polysulfides in regulation of chloride channels and respiration of mitochondria
Úloha polysulfidov v regulácii chloridových kanálov a dýchania mitochondrií
Program: VEGA
Project leader: Mgr. Grman Marián PhD.
Annotation:Endogenously produced hydrogen sulfide (H2S) influences many physiological functions. Molecular mechanism of H2S mediated protein modification – persulfidation and a role of polysulfides in this mechanism are not fully understood yet. Mitochondria as the energetic centre of the cell is the main site of H2S oxidation, that leads to polysulfide generation. The main aim of this project is to study the effect of polysulfides effect on activity of mitochondrial chloride channels, which are involved in mitochondrial transmembrane potential regulation, mainly under oxidative stress conditions. For this purpose we will use method of incorporation of ion channels into bilayer lipid membrane. We will also investigate effect of polysulfides on respiration and oxidative phoshorylation of mitochondria using the oxygen electrode. These results could contribute to better understanding of the role of polysulfides in mitochondrial redox regulation and their possible involvement in pathological states formation.
Duration: 1.1.2016 - 31.12.2018

Posttranslation modifications of the influenza A virus proteins and its role during the infection cycle
Úloha posttranslačných modifikácií proteínov vírusu chrípky typu A a ich vplyv na infekčný cyklus
Program: VEGA
Project leader: RNDr. Košík Ivan PhD.
Duration: 1.1.2014 - 31.12.2017

Role of protein kinases in regulation of chromosome segregation
Úloha proteínkináz v regulácii segregácie chromozómov
Program: VEGA
Project leader: Ing. Čipák Ľuboš PhD.
Annotation:Meiosis is a specialized cell cycle that reduces the chromosome number by half to allow sexual reproduction. Complexity of chromosome segregation is pointing out the importance of the regulatory mechanisms that ensure the correct functions of all proteins involved in this process. The project is aimed to analyze in depth the role of protein kinases required for proper segregation of chromosomes during meiosis and to understand the underlying molecular mechanisms of its regulation. Specifically, we will use created knock-out and conditional analog-sensitive alleles of protein kinases to study their role in regulation of meiotic processes. We will elucidate role of protein kinases in meiotic recombination, mono-orientation of sister kinetochores and protection of centromeric cohesion. Obtained results could reveal much about the mechanism of gamete development and sexual reproduction with possible implications for diagnostics and treatment of infertility, certain cancers and genetic diseases.
Duration: 1.1.2014 - 31.12.2017

Role of Stress Response Induced in Mesenchymal Stromal Cells in Extrinsic Drug Resistance of Human Tumor Cells
Úloha stresovej odpovede mezenchýmových stromálnych buniek v rezistencii ľudských nádorových buniek na liečbu
Program: VEGA
Project leader: Mgr. Kučerová Lucia PhD.
Annotation:Cells of the tumor microenvironment are recognized as major determinants of the tumor biology. The adjacent non-malignant cells regulate drug responses of the cancer cells by the secreted paracrine factors and interactions. Human mesenchymal stromal cells (MSC) actively contribute to many aspects of tumor biology including extrinsic effects on the drug responses in tumors. MSC were proven to exhibit increased drug resistance. The idea of the project is to examine the intracellular signaling pathways activated upon cytotoxic stimulus in human MSC because these were not described in detail. Moreover the stress response activated upon drug exposure may activate the cellular program preventing damage and promoting the tissue regeneration, and thus contribute to altered drug responses. We intend to evaluate the MSC-exerted effect on the drug responses in tumor cells, verify these effect on animal models and identify options for therapeutic augmentation based on the tumor microenvironment targeting.
Duration: 1.1.2015 - 31.12.2018

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Úloha vápnikovej signalizácie cez IP3 receptory v nádorových bunkách svetlobunkových karcinómov.
Program: VEGA
Project leader: prof. Ing. Križanová Oľga DrSc.
Duration: 1.1.2016 - 31.12.2018

The role of vitamin D and interferons type III in gammaherpesvirus oncogenesis
Úloha vitamínu D a interferónov tretieho typu v gamaherpesvírusovej onkogenéze
Program: VEGA
Project leader: RNDr. Režuchová Ingeborg PhD.
Annotation:Human gammaherpesviruses, namely Epstein-Barr virus and Kaposi´s sarcoma-associated herpesvirus, establish life-long latent infection in B cells and are known as causative agents of several malignancies and lymphoproliferative disorders. We have identified that interferons type III (IFNs-III) could play an important role in establishment, maintenance and regulation of gammaherpesvirus latency. Moreover, it is known that vitamin D deficiency is a critical factor in development of several cancers. In our project we hypothesize that a lack of vitamin D in a combination with suppressed immune system could contribute to cell transformation and tumorigenesis. Our ambition is to explore the antiproliferative, antiviral and preventive effect of vitamin D and IFNs-III in gammaherpesvirus-associated cancer cells. We expect that our results will elucidate relation of vitamin D to innate immune system and can be applied to other types of cancer cells, which are characterized by high expression of receptor for IFNs-III.
Duration: 1.1.2016 - 31.12.2019

Effect of flavonoids and mycotoxins on adipose tissue. The influence of metabolic status, inflammation and oxidative stress
Vplyv flavonoidov a mykotoxínov na tukové tkanivo v závislosti od celkového metabolického stavu, zápalu a oxidačného stresu
Program: SRDA
Project leader: Ing. Zorad Štefan CSc.
Annotation:Adipose tissue is metabolic and endocrine organ. Disorders in its functions result in ectopic accumulation of lipids in muscles, liver, pancreas and brain, elevation in parameters of oxidative injury. Reactive oxygen species (ROS) with hyperglycemia initiate inflammation processes in adipocytes. Published works recommend higher consumption of natural substances to improve antioxidant capacity. There is no comprehensive and relevant clinical study proving positive effect of antioxidants on any disease. New theory (Watson, J.D., 2014) introduces that an initiator of diabetes is incapability of organism to create sufficient amount of ROS. Divergent effect of flavonoids and their role as antioxidants/pro-oxidant is discussed. Actual mechanisms of action of flavonoids in vitro were investigated on 3T3-L1 mouse preadipocytes. In our project we consider as relevant to use primary culture of humanpreadipocytes. Publications concerning in vivo effect of lavonoids on metabolism pointed that the effect of these substances is dependent not only on chemical structure but also on kind of animal model. Therefore in our project we will systematically study the effect of selected flavonoids and mycotoxins in healthy animals, obese animals with low level of oxidative stress and diabetic animals with high level of oxidative stress and inflammation. Main aim is to verify if, in literature describing inhibition effect of flavonoids on adipogenesis depend on metabolic disease, if long-term inhibition of adipogenesis has positive impact on metabolism of adipose tissue and organism. Further we will study the role of oxidative stress in mechanism of actions of flavonoids and mycotoxins on adipose tissue from aspect of regulation of glucose and lipids metabolism by insulin cascade. We believe that results of project specify the role of flavonoids in nutrition of livestock and human.
Duration: 1.7.2016 - 30.6.2020

The effect of chronic inflammation on cardiometabolic parameters
Vplyv chronického zápalu na kardiometabolické parametre
Program: VEGA
Project leader: MUDr. Penesová Adela PhD.
Annotation:Systemic chronic inflammation has been proposed to have an important role in the pathogenesis of obesity-related insulin resistance and atherosclerosis. Aim of present study is to elucidate mechanisms involved in the pathogenesis of impaired insulin action in chronic inflammatory diseases such rheumatoid arthritis (RA) and multiple sclerosis (MS). Several metabolic, immune markers, autonomic nervous system dysfunction, physical fitness, endothelial dysfunction, impaired function of microcirculation will be measured in patients SM at the time of diagnosis and after at least of 12 months treatment with biological therapy or crossectionally in RA. Age, sex and BMI matched healthy subjects will be used as control group. We will look for associations between measured parameters, clinical characteristics and effect of the treatment, which may allow us to identify critical mechanisms of IR and cardiometabolic risk in chronic inflammation
Duration: 1.1.2016 - 31.12.2019

Impact of LCMV infection on the activity of HIF-regulated signal transduction pathways
Vplyv infekcie vírusu lymfocytovej choriomeningitídy na aktivitu signálnych dráh regulovaných transkripčným faktorom HIF-1
Program: VEGA
Project leader: Ing. Tomášková Jana PhD.
Annotation:The outcome of viral infections can be significantly affected by the components of tissue physiology and cellular microenvironment. Low oxygen tension exerts significant effect on the replication of several DNA and RNA viruses in cultured cells. Recently, we have demonstrated that chronic hypoxia enhances lymphocytic choriomeningitis virus (LCMV) replication in hypoxia inducible factor (HIF) -dependent manner, but molecular mechanisms underlying this process are not yet known. Therefore, the main goal of the proposed project is to reveal the biological impact of LCMV infection on the activity of HIF-1-regulated signal transduction pathways in cells cultured under low or atmospheric oxygen tensions. We will examine whether LCMV affects HIF-1α levels by modulating its transcription, translation, or stabilization. Identification of involved components and/or mechanisms will contribute to a more detailed understanding of viral pathogenesis, may reveal new aspects of host regulation and offer potential therapeutic targets.
Duration: 1.1.2015 - 31.12.2018

Effects of oxytocin receptor ligands on differentation of neuronal cells
Vplyv ligandov oxytocínových receptorov na diferenciáciu neuronálnych buniek
Program: VEGA
Project leader: Mgr. Bačová Zuzana PhD.
Annotation:Although oxytocin is considered to be one of the most important neuroendocrine factors involved in the brain development, mechanisms of its local effects on central nervous tissue are not known. Activation of oxytocin receptors may result in specific consequences on different neuronal populations and growth of their cones. Main aim of the project is research of effects of oxytocin receptor ligands on neuronal phenotype (differentiation) changes in vitro. Increased concentrations of oxytocin, oxytocin antagonist and vasopressin will be tested in relation to the changes of number, ratio and morphology of primary neurons and glial cells isolated from various brain areas of neonatal rat. Downregulation of oxytocin receptor with help of siRNA will be used to evaluate intracellular signalization and to measure shape and length of axons, dendrites and dendritic spines. Mechanisms of paracrine effects of oxytocin will be testes using immortalizes neuronal lines as well.
Duration: 1.1.2015 - 31.12.2017

Functional consequences of renal cell activation due to iron oxide and gold nanoparticle uptake
Vplyv nanočastíc oxidu železa a zlata na funkciu renálnych buniek
Program: SASPRO
Project leader: Mgr. Bábelová Andrea PhD.
Annotation:Despite the fact that more than 40 products, so called „nanomedicines” have already been approved for treatment and diagnosis of various diseases, including cancer, with many others in clinical development (phase I and II clinical trials), very limited body of literature links nanoparticles and kidney function, yet. Kidney is a unique organ characteristic by the high degree of heterogenity. Each cell type in the kidney has a distinct gene expression pattern and changes in the cellular composition largely impact on gene expression that is closely linked to the cell function. Different types of kidney cells have varying sensitivities to toxic substances that may accumulate in kidneys, including nanoparticles. Prolonged residency of nanoparticles in the kidney has been shown to induce toxicity with hallmarks similar to glomerulonephritis affecting all types of renal glomerular cells as mesangial cells, fibroblasts, or podocytes what may form a basis for reduced glomerular filtration capacity in nephrotic kidneys. The main objective of the project is to investigate the interactions of nanomaterials (gold and iron oxide nanoparticles) with the contractile mesangial cells which provide support of the whole glomerular structure and postmitotic podocytes, the principal part of renal filter and uncover potential toxic effects of nanoparticles affecting renal function and so the whole body homeostasis. Considering expansion of nanoparticles into biomedicine the renal toxicity studies are required to avoid potential health risks.
Duration: 1.8.2015 - 31.7.2018

The effect of selected natural compounds of plant origin (essential oils) on rickettsiae and ticks
Vplyv vybraných sekundárnych rastlinných metabolitov (esenciálne oleje) na rickettsie a kliešte
Program: VEGA
Project leader: Mgr. Štefanidesová Katarína PhD.
Annotation:I. ricinus and D. reticulatus, belonging among the most important vectors of tick-borne diseases (TBD) in Europe may transmit various pathogens, e. g. rickettsiae, anaplasmae, borreliae, C. burnetii, F. tularensis, and babesiae.The only available prevention of the majority of TBD is to avoid a tick bite. Increasing incidence of TBD,occurence of infected ticks in urban and suburban habitats, and possible adverse health effects of synthetic repellents caused tendency to use „natural repellents“ with unknown efficacy. Proposed project aims to clarify the efficacy of essential oils (EO) against ticks (to evaluate the ability of EO to interfere with the host-seeking behaviour) as well as against transmitted pathogens (to evaluate antirickettsial properties of EO). Project will help to elucidate the inhibitory properties of EO against obligate intracellular bacteria, and to assess which of EO may be used as the prevention of tick bite for the part of the population,that decided not to use commercial repellents.
Duration: 1.1.2016 - 31.12.2019

Evaluation of the protein expression of Coxiella burnetii in response to antibiotic resistance
Vyhodnotenie proteínovej expresie Coxiella burnetii v odpovedi na rezistenciu voči antibiotikám
Program: VEGA
Project leader: Mgr. Flores-Ramírez Gabriela PhD.
Duration: 1.1.2015 - 31.12.2017

Usage of next-generation sequencing for virome analysis of medically and economically relevant organisms.
Využitie sekvenovania novej generácie pre analýzu virómu medicínsky a hospodársky významných organizmov.
Program: SRDA
Project leader: RNDr. Klempa Boris DrSc.
Duration: 1.7.2016 - 30.6.2019

Development of novel diagnostic method for clinical oncology based on the interaction of DNA aptamers with proteins
Vývoj progresívnej diagnostickej metódy pre klinickú onkológiu založenej na interakcii DNA aptamerov s proteínmi
Program: SRDA
Project leader: RNDr. Bízik Jozef DrSc.
Annotation:The project is focused on the development of novel diagnostic method for clinical oncology based on the interaction of DNA aptamers with membrane proteins. For this purpose the extensive basic research will be performed with focus on the study of the mechanisms of interaction DNA aptamers with model proteins incorporated into the supported lipid membranes as well as with tumor markers at the surface of the cell cultures. The progressive biophysical methods will be applied such as acoustic thickness shear mode method, atomic force misroscopy, single molecule force spectroscopy, fluorescence resonance energy transfer and others. The exprienced teams composed of senior scientists, young researchers and PhD students from Faculty of Mathematics, Physics and Informatics of Comenius University in Bratislava and from two Research Institutes of the Slovak Academy of Sciences – Institute of Animal Biochemistry and Genetics and Cancer Research Institute will be involved in the project. We assume that will obtain new knowledge on the mechanisms of interaction of DNA aptamers with membrane proteins depending on the lipid composition as well as with tumor markers at the surface of cell cultures depending on the type of the tumor and the progress of dissease.
Duration: 1.7.2015 - 30.6.2019

Development of Rickettsia antibodies detection system using an enzyme immunological assay
Vývoj systému na detekciu rickettsiálnych protilátok s využitím enzýmovej imunoanalýzy
Program: VEGA
Project leader: Mgr. Quevedo Diaz Marco PhD.
Annotation:Rickettsiae are obligate intracellular bacteria that proliferate within the cytoplasm of eukaryotic cells. In humans, members of the genus Rickettsia can cause diverse human diseases such as epidemic typhus, Mediterranean spotted fever and Tibola, this last one caused by Rickettsia slovaca, one of the most distributed rickettsia in our region. One of the biggest challenges for physicians is diagnose these infections early in their clinical course, when antibiotic therapy is most effective but sometimes they are undiagnosed or misdiagnosed and lead to fatal cases. Although rickettsiae can be isolated from or detected in clinical specimens, serological tests still remain an indispensable tool in the diagnosis of rickettsial diseases. The goal of this proposal is identify specific rickettsial immunogenic proteins (markers) from SFG by proteomics techniques, screening of rickettsial membrane components, generate recombinant proteins and employ them to improve detection in diagnosis of rickettsial infections.
Duration: 1.1.2016 - 31.12.2018

Importance of the Na/Ca exchanger in ovarian tumor cells, its modulation and a role in inducing apoptosis.
Význam Na/Ca výmenníka v ovariálnych nádorových bunkách, jeho modulácia a úloha pri vyvolaní apoptózy.
Program: VEGA
Project leader: Mgr. Lenčešová Ľubomíra PhD.
Annotation:Tumor cells have altered signaling pathways for calcium. These changes depend on many factors, e.g. type of tumor, origin of tumor cells, etc. Alteration in calcium signaling is caused by modification in a function of calcium transporters that are localized on the plasma membrane, but also on an intracellular organelles. One of them, which might significantly contribute to the flow of calcium ions in the tumors, is Na+/Ca2+ exchanger (NCX). NCX can transport calcium into the cell and also out of the cell depending on the state and the condition of the cell. We assume that in tumor cells NCX operates in the reverse mode, therefore NCX transports calcium into the cell and thus affects others intracellular calcium transporters. The project will study the role of NCX in ovarian cancer cells. We will focus on studying the mechanism of operation of NCX, potential partners from among the receptor proteins and the induction of apoptosis in the modulation of NCX function under normal conditions and during hypoxia.
Duration: 1.1.2016 - 31.12.2018

Alterations in neuritogenesis related to neurodevelopment
Zmeny regulácie neuritogenézy vo vzťahu k neurovývinovým ochoreniam
Program: SRDA
Project leader: RNDr. Bakoš Ján PhD.
Annotation:Functional development of social skills, speech and memory is determined by formation of neural circuits under the control of many genes and epigenetic factors. At the cellular and molecular level, they include regulation of neurite outgrowth (axons, dendrites) and changes of neurite direction. Oxytocin production, secretion and receptor activation is frequently associated with neurodevelopmental disorders, including autistic spectrum diseases. Therefore, it is important to understand the role of oxytocin in regulation of neuritogenesis and neurite outgrowth. It is not known, how oxytocin receptor activation is related to the changes of neurite elongation and how oxytocin interacts with other factors, particularly cytoskeletal proteins and GTPases, their disruption suppose to play a role in neurodevelopmental disorders. Central aim of the project is to search for interaction of oxytocin with cytoskeletal proteins MAGEL2 and SHANK3 in relation to neuritogenesis. The main hypothesis represents an assumption, that oxytocin can compensate neuritogenesis disrupted by downregulation/knockout of MAGEL2 and SHANK3 genes. The project includes manipulation of MAGEL2 and SHANK3 genes and their consequences on neuritogenesis. Efforts will be devoted to visualize neurite elongation in real time and to find an association between oxytocin levels and neuritogenesis. Systematic approach to research of regulation of neuronal cell growth and neurite arborisation may bring important data for understanding of brain development at the molecular level and contribute to reveal causes of neurodevelopmental disorders.
Duration: 1.7.2016 - 31.12.2019

The total number of projects: 106