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Projects / Programmes source: ARRS

Toxins and Biomembranes

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Periods
January 1, 2009 - December 31, 2014
Research activity

Code Science Field Subfield
1.05.00  Natural sciences and mathematics  Biochemistry and molecular biology   

Code Science Field
P4   Natural sciences and mathematics  P4  
P310  Natural sciences and mathematics  Proteins, enzymology 
P320  Natural sciences and mathematics  Nucleic acids, protein synthesis 
P340  Natural sciences and mathematics  Lipids, steroids, membranes 

Code Science Field
1.06  Natural Sciences  Biological sciences 
Keywords
neurotoxic secretory phospholipase A2 (sPLA2), ammodytoxin (Atx), Atx-receptor, membrane pore formers are: equinatoxin, perforin, ostreolysin, parborlysin, alkylpyridinium polymeres, biomembrane, liposome, lipid monolayer, cancer, neuronal system, receptor, synapsa, cytolysis, hemolysis, protein engineering, molecular evolution, retroposon, functional and comparative genomics, yeast.
Evaluation (rules)
source: COBISS
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Researchers (46)
no. Code Name and surname Research area Role Period No. of publications
1.  15686  PhD Gregor Anderluh  Biochemistry and molecular biology  Researcher  2009 - 2014  935 
2.  27539  PhD Biserka Bakrač Bremec  Biochemistry and molecular biology  Junior researcher  2009 - 2011  29 
3.  34328  Špela Bordon  Biochemistry and molecular biology  Junior researcher  2011 - 2014  9 
4.  33313  PhD Vesna Brglez  Biochemistry and molecular biology  Junior researcher  2010 - 2014  34 
5.  24290  PhD Matej Butala  Biochemistry and molecular biology  Researcher  2011 - 2014  224 
6.  25518  PhD Miha Črnigoj  Pharmacy  Researcher  2012 - 2014  42 
7.  15639  PhD Gregor Gunčar  Biochemistry and molecular biology  Researcher  2012 - 2014  249 
8.  26231  PhD Borut Jerman  Biochemistry and molecular biology  Junior researcher  2009 - 2011  23 
9.  29992  Petra Kaferle  Biochemistry and molecular biology  Technician  2009  21 
10.  34435  Minca Klobčar  Biology  Junior researcher  2011 - 2014  5 
11.  30876  PhD Janez Kokošar  Biochemistry and molecular biology  Researcher  2009 - 2014  31 
12.  15587  Igor Koprivec    Technician  2009 - 2014  0 
13.  07673  PhD Dušan Kordiš  Biochemistry and molecular biology  Researcher  2009 - 2014  214 
14.  25628  PhD Lidija Kovačič  Biochemistry and molecular biology  Researcher  2009 - 2013  82 
15.  00412  PhD Igor Križaj  Biochemistry and molecular biology  Principal Researcher  2009 - 2014  696 
16.  18802  PhD Adrijana Leonardi  Biochemistry and molecular biology  Researcher  2009 - 2014  139 
17.  31952  PhD Nataša Lindič  Biochemistry and molecular biology  Junior researcher  2009 - 2013  22 
18.  19649  PhD Marija Nika Lovšin  Microbiology and immunology  Researcher  2009 - 2011  99 
19.  06994  PhD Peter Maček  Biochemistry and molecular biology  Researcher  2009 - 2014  524 
20.  26460  PhD Mojca Mattiazzi Ušaj  Biochemistry and molecular biology  Researcher  2009 - 2014  62 
21.  33136  PhD Miha Mikelj  Pharmacy  Junior researcher  2010 - 2014  18 
22.  34329  PhD Omar Naneh  Biochemistry and molecular biology  Junior researcher  2011 - 2012  22 
23.  35371  PhD Maruša Novak  Biotechnology  Junior researcher  2013 - 2014  34 
24.  33324  PhD Jernej Oberčkal  Biochemistry and molecular biology  Junior researcher  2010 - 2014  36 
25.  35372  PhD Davor Obradović  Natural sciences and mathematics  Junior researcher  2012 - 2014  14 
26.  35319  PhD Mojca Ogrizović  Biochemistry and molecular biology  Technician  2014  35 
27.  33683  Nina Orehar    Technician  2011 - 2014  5 
28.  31914  PhD Katja Ota  Geology  Junior researcher  2009 - 2013  23 
29.  17422  Irena Pavešič    Technician  2009 - 2010  1 
30.  23575  PhD Miha Pavšič  Biochemistry and molecular biology  Researcher  2012 - 2014  177 
31.  20213  PhD Toni Petan  Biochemistry and molecular biology  Researcher  2009 - 2014  161 
32.  20653  PhD Uroš Petrovič  Biochemistry and molecular biology  Researcher  2009 - 2014  274 
33.  29424  PhD Tilen Praper  Biochemistry and molecular biology  Researcher  2009 - 2011  24 
34.  19648  PhD Petra Prijatelj Žnidaršič  Biochemistry and molecular biology  Researcher  2009 - 2011  37 
35.  30887  PhD Anja Pucer Janež  Pharmacy  Junior researcher  2009 - 2013  55 
36.  04570  PhD Jože Pungerčar  Biochemistry and molecular biology  Researcher  2009 - 2014  318 
37.  27541  PhD Andrej Razpotnik  Natural sciences and mathematics  Junior researcher  2009  18 
38.  24291  PhD Katja Rebolj  Neurobiology  Junior researcher  2009  56 
39.  31915  PhD Nejc Rojko  Biochemistry and molecular biology  Junior researcher  2009 - 2013  29 
40.  30888  PhD Tamara Sajevic  Pharmacy  Junior researcher  2009 - 2013  24 
41.  15328  PhD Kristina Sepčić  Biochemistry and molecular biology  Researcher  2009 - 2014  698 
42.  33137  PhD Matej Skočaj  Biochemistry and molecular biology  Junior researcher  2010 - 2013  95 
43.  21553  PhD Jernej Šribar  Biochemistry and molecular biology  Researcher  2009 - 2014  106 
44.  06905  PhD Tom Turk  Biochemistry and molecular biology  Researcher  2009 - 2014  602 
45.  29601  PhD Ana Zovko  Biochemistry and molecular biology  Researcher  2009 - 2013  17 
46.  15640  PhD Vera Župunski  Biochemistry and molecular biology  Researcher  2009 - 2014  167 
Organisations (3)
no. Code Research organisation City Registration number No. of publications
1.  0103  University of Ljubljana, Faculty of Chemistry and Chemical Technology  Ljubljana  1626990  21,898 
2.  0106  Jožef Stefan Institute  Ljubljana  5051606000  85,573 
3.  0481  University of Ljubljana, Biotechnical Faculty  Ljubljana  1626914  64,490 
Abstract
Several pharmacologically active proteins are already used in biomedicine as a research tool, as a diagnostic or therapeutic resource, and unfortunately also in bio-terrorism. Exact understanding of the mechanism of action of such proteins is a preliminary condition for their useful application and also for defence from them. Secretory phospholipases A2 (sPLA2) are enzymes that have a number of physiological and pathological effects like inflammatory processes, degradation of lipids, cell to cell signalling, defence of organism, they play also an important role in in some cancers. We are particularly interested in ammodytoxin (Atx) a presynaptically neurotoxic sPLA2 of long nosed viper (Vipera ammodytes) venom. Nerve endings exposed to Atx have heavily damaged mitochondria. In plasmalema, omega shaped vesicles are seen that cannot be endocytosed and synaptic vesicles are markedly decreased in number. We are isolating and characterising proteins that bind Atx in neural and other tissues. Our aim is to explain the role of these proteins in neurotoxicity and other (patho)physiological properties. The role of related (endogenic) sPLA2 could be tested for binding to proteins that bind Atx, and may help to explain their still unknown role in the cell. The study of the evolution of the superfamily of phospholipases A2 in eukaryotes will facilitate the understanding of this large group of proteins. The study of adaptive evolution will be continued in several multigene protein families like metalloproteases, inhibitors of serine proteases, perforins and tionins, proteins responsible for defence of different organisms. The research on the evolution of transposable elements (TE) in eukaryots will be continued by searching TE in different genomic sequence data bases that are mostly unexamined ("in silico" approach). Together with evolutionary analyses we will obtain a global insight into the source, evolution and heterogeneity of TE in eukaryots, which is still only fragmentary. Pore forming proteins that have no enzymatic activity to affect biomembranes are among the most wide spread toxins. Cnidarian equinatoxin , human perforin, ostreolysin from mushroom, nemertine's parborlysin and alkylpyridinium polymers from sponge have in common formation of permanent or temporary pores in the lipid part of the membrane. This causes in the cell a series of uncontrolled processes and finally necrotic or apoptotic cell death. Alkylpyridinium polymers from sponge Reniera sarai were found to be inhibitors of acetylcholinesterase and efficient non-detergent pore formers in biological membranes. We shall investigate the possible use of this polymer to protect the underwater surfaces from settling of organisms (so called antifouling).
Significance for science
Our research activities can broadly be classified as 1) toxinology-related research, 2) studies of mammalian sPLA2s, 3) pore forming proteins research, 4) yeast phenomics and 5) genome analysis – these are complementary and interwoven topics that together build a coherent and powerful research programme. In the field of toxinology our research is focused on the mechanism of action of different components of animal venoms with the aim of developing new molecular tools for physiology and medical research, innovative biological drugs (antithrombics, cytostatics, analgetics, immunotoxins), and for new anti-envenomation approaches (both in terms of detection and prevention/therapy) for medical or anti-bioterrorism applications. The toxins that we study have different modes of action and target different cells. We are focused on the mechanism of action of presynaptically neurotoxic sPLA2s, cytolysins (especially pore-forming proteins and myotoxic sPLA2s), and the venom components affecting haemostasis. The findings on their action on the molecular level are expected to provide an important contribution also in the more basic research of the structure and dynamics of biomembranes (e.g. regulated exocytosis and endocytosis) and protein targeting. They will also contribute to finding new ways to treat thrombo-embolic diseases such as acute heart failure, pulmonary embolism, stroke, and peripheral arterial occlusion. In addition, our research will be aimed at understanding and treating of neurological disorders which result as a consequence of abnormal synaptic vesicle cycling, and regulation of haemostasis. Secreted PLA2s are triggers of signalling cascades (lipid-mediated signalling) and one of the key factors in lipid metabolism in mammals. Understanding these processes is essential for higher-level complexity understanding of diseases and disorders such as Alzheimer’s and Parkinson’s disease, Zellweger syndrome, cardiovascular diseases, atherosclerosis, type 2 diabetes and obesity. Membrane rafts participate in numerous biological processes where they serve as platforms for biochemical signaling pathways. Their defects can lead to different pathological states and diseases. Membrane rafts have been shown to be involved in neurological (Alzheimer, Parkinson, and prion diseases) and cardiovascular diseases, in carcinogenesis, in immune diseases like systemic lupus erythematosus, and in various virus infections (e.g. HIV), which proposes these membrane domains as interesting targets for pharmacological approaches to cure these diseases. Within the programme, we developed a non-toxic recombinant fluorescently labeled protein, ostreolysin A. This protein was shown to bind to cholesterol- and sphingomyelin-enriched membrane domains. It enabled us to prove the existence of these domains in cells, and to study their dynamics in cells. The developed molecule could serve as a crucial, and the only current tool in basic and applicative biomedical researches for the estimation of overall biological role of membrane rafts, and their involvement in several pathologies. Studying of mechanisms of action of aegerolysin-like proteins that are proposed as putative virulence factors of opportunistically pathogenic moulds might lead to better understanding of the pathogenesis, and to its prevention and therapy. Studying the genes encoding long-nosed viper’s venom toxins is also important for explaining the mechanism of enhanced and adaptive evolution of various animal venom protein families. Our research will, among other, show which regions of the toxin molecules are amenable for development of new functions, without disrupting their 3D structure. Based on these data it will be possible to design proteins with new characteristics, which is crucial for the development of new biologically active molecules. The research topics of our program group are very relevant and up to date. The results published are internationally recognized for their importance.
Significance for the country
Our investigations not only contribute into the world`s treasury of knowledge, but have also practical values. We develop procedures for production of more efficient and safer antivenoms, novel tumour chemotherapeutics, anticoagulant substances and antithrombotics as well as new tools for intracellular delivery of DNA (alkylpyridinium salts). With the same substances (alkylpyridinium salts) we develop non-toxic antifouling agents for the protection of the submerged surfaces. Very important aspect of our investigations is introducing and applying the latest research technologies, such as DNA microarrays, technology of systematic determination of genetic interactions (SGA), latest bioinformatics methods and proteomics. We actively participate in the development of new research methods. In collaboration with the Slovenian high-tech company we developed a manipulator for the automatic replica plating of ordered yeast colonies that will enable us technological advantage and competitiveness at the European level in the analysis of protein toxins and other bioactive substances at the genome level. We participate actively in the development of new bioinformatics tools for the analysis of the results of the genome research activities. We also develop new SPR-based methods for the study of interactions between proteins and lipid membranes. Our research group therefore represents innovative milieu, producing young researchers that are well trained with the latest research techniques in biochemistry, pharmacology, molecular biology and genomics. In such a manner the sphere of activity of our research group is very important for Slovenian economy in the form of setting up modern, biotechnology-based companies and laboratories. Therefore our largest pharmaceutical company Lek-Novartis collaborates intensively with our program group. Our research activity is important also for health and defence – in the later we had NATO support for part of our research connected with the war against bioterrorism. Very important is our participation in the education of young researchers and in the transfer of research-based knowledge to the Slovenian students. Majority of members of our research group is strongly involved into the teaching activities at undergraduate and postgraduate levels, at the Universities of Ljubljana, Maribor and Nova Gorica as well as at the Jožef Stefan International Postgraduate School. Some members of our research group are holders of Bologna reform-based renovation of faculty programs. A number of young researchers have been raised in our group, by making their BS, MSc and PhD theses, and moved later into the research labs of diverse research institutes and universities, medical clinical laboratories and to the pharmaceutical companies. By numerous publications in high-impact scientific journals, invited talks at international conferences, in academic institutions and in industry as well as with the organization of international scientific meetings our research group contributes to the international reinforcement of the reputation of Slovenian science (important part of national culture and originality). Our research group established numerous international collaborations with respectable investigators and institutions around the world. Members of our research group performed and perform some of the leading functions in the committees of European and international professional societies (at the moment Dr. Igor Križaj has a function of a secretary of the European section of IST and is the member of the board of IST), which helps in the international recognition of Slovenian science and in strengthening our national identity. A part of our investigations contributes to the preservation of the richness of our national heritage (of our autochtonic fauna) and to the understanding of our large biodiversity, one of the important characteristics of small Slovenia.
Most important scientific results Annual report 2009, 2010, 2011, 2012, 2013, final report, complete report on dLib.si
Most important socioeconomically and culturally relevant results Annual report 2009, 2010, 2011, 2012, 2013, final report, complete report on dLib.si
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