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Projects / Programmes source: ARIS

Proteolysis and its regulation

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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   
4.06.00  Biotechnical sciences  Biotechnology   

Code Science Field
P4   Natural sciences and mathematics  P4  

Code Science Field
1.07  Natural Sciences  Other natural sciences 
Keywords
Proteolysis, degradomics, proteases, inhibitors, lysosomes, cathepsins, caspases, cystatins, stefins, thyropins, structure-function relationship, physiology, immunology, cancer, apoptosis, neurodegeneration, bioinformatics, proteomics, protein folding, protein expression, biotechnology, biochemistry
Evaluation (rules)
source: COBISS
Evaluation of bibliographic research performance indicators according to ARIS methodology
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Researchers (53)
no. Code Name and surname Research area Role Period No. of publications
1.  36326  Teja Bajt  Biochemistry and molecular biology  Junior researcher  2013 - 2014  0 
2.  32149  PhD Katja Bidovec  Biochemistry and molecular biology  Junior researcher  2009 - 2014  12 
3.  37546  PhD Janja Božič  Medical sciences  Junior researcher  2014  30 
4.  33315  PhD Miha Butinar  Biology  Researcher  2010 - 2014  60 
5.  23573  PhD Dejan Caglič  Biochemistry and molecular biology  Researcher  2009 - 2010  53 
6.  00449  PhD Iztok Dolenc  Biochemistry and molecular biology  Researcher  2009 - 2014  110 
7.  33160  PhD Sara Drmota Prebil  Biochemistry and molecular biology  Junior researcher  2014  12 
8.  34090  PhD Gabriele Droga Mazovec  Biochemistry and molecular biology  Researcher  2011 - 2013  38 
9.  18801  PhD Marko Fonović  Biochemistry and molecular biology  Researcher  2009 - 2014  187 
10.  30872  PhD Maruša Hafner Česen  Biochemistry and molecular biology  Beginner researcher  2009 - 2014  31 
11.  36335  PhD Katarina Hočevar  Biochemistry and molecular biology  Junior researcher  2013 - 2014  9 
12.  24261  PhD Saška Ivanova  Biochemistry and molecular biology  Researcher  2009 - 2012  35 
13.  33349  PhD Barbara Jerič Kokelj  Biotechnology  Junior researcher  2010 - 2014  38 
14.  26451  Martina Klarić  Biochemistry and molecular biology  Junior researcher  2009  12 
15.  25653  PhD Špela Konjar  Chemistry  Junior researcher  2009  59 
16.  10502  PhD Nataša Kopitar Jerala  Biochemistry and molecular biology  Researcher  2009 - 2014  239 
17.  37474  Aleksander Krajnc  Biochemistry and molecular biology  Junior researcher  2014  12 
18.  35467  PhD Lovro Kramer  Biochemistry and molecular biology  Junior researcher  2012 - 2014  42 
19.  17110  Louisa Johanna Kroon Žitko    Technical associate  2009 - 2014  22 
20.  03422  PhD Brigita Lenarčič  Biochemistry and molecular biology  Researcher  2009 - 2014  338 
21.  30882  PhD Katarina Maher  Biochemistry and molecular biology  Junior researcher  2009 - 2013  38 
22.  29598  PhD Petra Nikolić  Biochemistry and molecular biology  Researcher  2012 - 2014  64 
23.  26028  PhD Marko Novinec  Biochemistry and molecular biology  Researcher  2009 - 2014  218 
24.  37465  PhD Sabina Ott Rutar  Biochemistry and molecular biology  Junior researcher  2014  11 
25.  29470  PhD Katarina Pegan  Biochemistry and molecular biology  Researcher  2011 - 2014  44 
26.  29966  Dejan Pelko    Technical associate  2010 - 2014  0 
27.  24764  PhD Ana Petelin  Cardiovascular system  Researcher  2009 - 2011  231 
28.  32162  PhD Mira Polajnar  Biochemistry and molecular biology  Junior researcher  2009 - 2013  34 
29.  35024  PhD Michal Piotr Potempa  Biochemistry and molecular biology  Researcher  2012 - 2013  0 
30.  25642  PhD Urška Požgan  Pharmacy  Researcher  2009 - 2010  24 
31.  09091  PhD Vida Puizdar  Biochemistry and molecular biology  Technical associate  2009 - 2014  55 
32.  35337  PhD Vid Puž  Pharmacy  Junior researcher  2014  15 
33.  06056  PhD Metka Renko  Biochemistry and molecular biology  Researcher  2009  99 
34.  21560  PhD Urška Repnik  Microbiology and immunology  Researcher  2009 - 2014  149 
35.  17096  Andreja Sekirnik  Biochemistry and molecular biology  Technical associate  2009 - 2014  30 
36.  29542  PhD Barbara Sobotič  Biochemistry and molecular biology  Technical associate  2009 - 2014  62 
37.  14829  PhD Veronika Stoka  Biochemistry and molecular biology  Researcher  2009 - 2014  237 
38.  28484  PhD Dejan Suban  Animal production  Junior researcher  2009 - 2012  17 
39.  06688  PhD Andrej Šali  Biochemistry and molecular biology  Researcher  2011 - 2014  57 
40.  25623  PhD Katja Škerget  Pharmacy  Junior researcher  2009 - 2010  35 
41.  28485  PhD Aleš Špes  Biochemistry and molecular biology  Junior researcher  2009 - 2012  24 
42.  15969  Ivica Štefe  Biochemistry and molecular biology  Technical associate  2009 - 2014  36 
43.  29544  PhD Ajda Taler Verčič  Biochemistry and molecular biology  Junior researcher  2009 - 2014  79 
44.  05234  Mojca Trstenjak Prebanda  Biochemistry and molecular biology  Technical associate  2009 - 2014  64 
45.  07561  PhD Boris Turk  Biochemistry and molecular biology  Head  2009 - 2014  1,037 
46.  01085  PhD Vito Turk  Biochemistry and molecular biology  Researcher  2009 - 2014  1,490 
47.  21619  PhD Olga Vasiljeva  Oncology  Researcher  2009 - 2014  183 
48.  33762  PhD Robert Vidmar  Biochemistry and molecular biology  Technical associate  2011 - 2014  148 
49.  33162  PhD Tilen Vidmar  Chemistry  Junior researcher  2010 - 2014  13 
50.  32171  PhD Matej Vizovišek  Biochemistry and molecular biology  Researcher  2009 - 2014  142 
51.  18286  PhD Tina Zavašnik Bergant  Biochemistry and molecular biology  Researcher  2009 - 2014  138 
52.  34458  PhD Janja Završnik  Biochemistry and molecular biology  Junior researcher  2011 - 2014  51 
53.  03368  PhD Eva Žerovnik  Biochemistry and molecular biology  Researcher  2009 - 2014  389 
Organisations (2)
no. Code Research organisation City Registration number No. of publications
1.  0103  University of Ljubljana, Faculty of Chemistry and Chemical Technology  Ljubljana  1626990  23,083 
2.  0106  Jožef Stefan Institute  Ljubljana  5051606000  90,682 
Abstract
Research in the area of proteolytic enzymes with an emphasis on explaining their functioning and regulation has largely expanded. Knowledge of the entire human genome has opened up new possibilities in discovering new proteins and their role in normal and pathological processes. Cysteine proteases, including lysosomal papain-like cathepsins and the caspases, can be found not only in animals and humans, but also in plants and micro organisms. At the moment we know 11 human cysteine cathepsins and 12 human caspases. Generally speaking, cathepsins make an important contribution in processes such as intracellular protein degradation, peptide degradation, antigen presentation, bone growth, and processing other proteins, whereas caspases play a key role in removing damaged, infected or excessive cells (proapoptotic) and in inflammatory processes where they play a key role in processing numerous cytokines (proinflammatory). Both cathepsins and caspases have a very important role in various pathologies such as cancer, osteoporosis, neurodegenerative disorders, inflammatory processes and autoimmune diseases, which makes them very interesting to the entire pharmaceutical industry as drug targets. Studies demand preparation of sufficient amount of proteins by means of recombinant DNA technology using heterologous expression systems. To date, we have been able to successfully express cathepsins B, H, L, S, K, F and X and we plan to obtain the other cathepsins as well and to include some mice cathepsins (B, L, S, K) in the programme for use in animal models. In addition, we intend to increase the number of expressed caspases (caspases-3, -6, -7, -8) and include at least caspase-1 and possibly mouse caspases-1 and -11 for the studies of physiological role. We will search for new potential cysteine cathepsins and their endogenous protein inhibitors (cystatins, thyropins) in the human genome by bioinformatic methods. New proteins will be biochemically characterised and we will attempt to explain their physiological role. For an understanding of the physiological role of proteases knowledge of their degradome, i.e. physiological ligands (substrates, inhibitors, ) is essential. With the help of proteomics and classic methods in biochemistry, molecular biology and cell biology we will try to identify new ligands for the individual cathepsins. Our work will also involve using transgenic mice and individual cathepsins knock-out mice and their cells. Understanding processing and activation of cathepsins is important in understanding their physiological role, especially in pathology. We will continue our study of activation of cathepsins B and S as model enzymes and the influence of glycosaminoglycans in extracellular conditions as in, for example, osteoarthritis, rheumatoid arthritis and cancer. We will continue studies aimed at understanding the molecular mechanism of triggering apoptosis with cathepsins in various in vitro and cellular models. We will primarily study ways to trigger apoptosis directly and through caspase activation. This research will be expanded to the role of lysosomes and cathepsins in neurodegenerative processes and ageing, characterised by excessive dying of neurons. We will continue the research of the role of cathepsins and their inhibitors in various types of cancer, with the focus mainly on cathepsins B, H, L, S and X and their inhibitors cystatins and thyropins. In the area of endogenous inhibitors research will be directed primarily towards new inhibitors of the thyropin family. We will study inhibitory action of some other proteins containing tyroglobulin domains of type 1 (TROP, SMOC), and try to evaluate their physiological role as protease inhibitors. We will also continue the research on cystatins in the area of understanding the fibril formation by stefins A and B as model systems for various amyloidoses. Other proteases will be include in the programme if needed (cathepsin D, metalloproteases,).The
Significance for science
Proteolytic enzymes play a key role in intra- and extracellular protein processing and degradation, which are among the most important physiological processes. Under normal conditions proteolysis is a highly regulated process, where protease activities are largely controlled by activation of inactive zymogens and through inhibition by endogenous inhibitors. However, when regulation fails, proteases can be extremely harmfull for the organism, leading to numerous diseases (Turk 2006; Drag and Salvesen, 2010; Turk et al., 2012). In the past, our research group has contributed significantly to the development of the field with the discoveries of several cathepsins and their endogenous inhibitors cystatin C, stefins A and B, kininogens and thyropins, lysosomal pathway to apoptosis, , understanding the role of autophagy in T. cruzi, as well as pioneering efforts in the fields of development of novel nanoparticle-based targeted drug delivery systems, allosteric protease inhibitors and novel activity-based probes for proteases which classify our research at the cutting edge in the field. This is reflected also in high citation of our works in this competitive field. A major interest of the pharmaceutical companies for proteases including the cathepsins (the first cathepsin targeting drug odanacatib for osteoporosis treatment is expected to be filed to FDA soon) is supporting the idea that this problematics is extremely important. Moreover, the research topics are also among the topics of Horizon2020 research programmes. It can be concluded that the research topics belong among the most attractive areas of research in the fields of biomedicine, agriculture and farmacy, to list just some of them. A further confirmation for the high level of scientific achievements of the group is evident from numerous publications in the most important international journals, including several publications in the journals with IF ) 9.0 in the programme (2009-2014) and consequently the high citation of the works of the programme leader (over 7700 citations total, H-index 45), as well as of the other researchers. Moreover, this is evident also from the numerous awards received by research group members as well as from the list of international collaborations with a number of top class researchers worldwide.
Significance for the country
Although the proposed research is basic research, it also has its applied component and can be classified as strategic basic research. Members of the group have extensively collaborated with Slovene (Lek, Krka, Medis, Acies Bio, …) and foreign industry (Sanofi), which resulted in a substantial amount of contract-based research and FP7 projects, as well as extensive collaborations within the Center of Excellence CIPKEBIP and the Competence Center Brin, which have been both financed by European Structural Funds. Moreover, as a result several international patents have been filed and/or granted. The work also offers great opportunity for students to be trained in the most advanced methods and areas, such as proteomics (the only proteomics facility in Slovenia), chemogenomics, targeted drug delivery and in vivo imaging (the only in vivo imaging system in Slovenia). All these fields have namely high international priority as they are of extreme importance in modern drug discovery and early diagnostics, and combining them should help translate the findings into clinics and bring the personal medicine to a new level. It is therefore not suprising that research within this programme since its beginning lead to over 250 finished BSc theses, over 40 MSc theses and over 40 PhD theses, including 12 in the last programme call since 2009. After finishing their studies, numerous researchers left the group and went to other institutes and universities. A number of the researchers from the programme also went to pharmaceutical industry (over 10 in last 7-8 years). At the University of Ljubljana (UL) researchers from this programme form the core of the biochemistry program and chair of biochemistry at FKKT UL. In addition to graduate teaching, programme members also have major role in undergraduate education programmes as they are responsible for a number of courses, whereas Pro. Brigita Lenarčič is currently also vice-dean for Investigations like this combining biochemistry, chemogenomics, proteomics and molecular and cell biology are critically important for the development of modern biotechnology and biomedical research. Excellent and up-to-date science and its transfer to modern technology are of major importance for the sustainable socio-economic development and competitiveness of Slovenia and its classification among the developed members of EC. In addition, members of the project team have received wide-spread international recognition, which is very important for the world-wide promotion of Slovenia and as such also for preservation of national identity of Slovenia. The group organized a number of international meetings with participation of numerous excellent foreign researchers from academia and industry, including several Nobel laureates. A number of international collaborations have been established, which all contributes to the international reputation of Slovenia. Group members also served important functions in governing bodies of various International organizations. Dr. Boris Turk is currently Secretary General of European Cell Death Organization (ECDO), he was councilor of the International Proteolysis Society (IPS, 2001-2005; 2009-2013) andt its Secretary (2009-2011) and President (2011-2013), he is an EMBO member and member of Academia Europea (London) and was awarded Zois award for outstanding achievements in the field of Protease signaling in 2011. Dr. Vito Turk was performing leading functions in the Federation of European Biochemical Societies (FEBS) and in IUBMB, he is a member of Slovene Academy of Sciences and Arts, EMBO, European Academy (London), etc. In addition, other group members also received various awards and amendments. Furthermore, several group members serve as Editors or Editorial board members of various international journals, which additionally contribute to international recognition of 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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