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Projects / Programmes source: ARIS

Proteolysis and its regulation

Periods
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
P004  Natural sciences and mathematics  Biochemistry, Metabolism 
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
Researchers (42)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  23572  PhD Lea Bojič  Pharmacy  Researcher  2004 - 2008  35 
2.  23573  PhD Dejan Caglič  Biochemistry and molecular biology  Researcher  2004 - 2008  53 
3.  19331  PhD Tina Cirman  Microbiology and immunology  Researcher  2004  52 
4.  24259  PhD Slavko Čeru  Biochemistry and molecular biology  Junior researcher  2005 - 2008  55 
5.  00449  PhD Iztok Dolenc  Biochemistry and molecular biology  Researcher  2004 - 2008  110 
6.  18801  PhD Marko Fonović  Biochemistry and molecular biology  Researcher  2005 - 2008  189 
7.  20211  PhD Uroš Gregorc  Biotechnology  Researcher  2004  31 
8.  24261  PhD Saška Ivanova  Biochemistry and molecular biology  Researcher  2005 - 2008  35 
9.  26451  Martina Klarić  Biochemistry and molecular biology  Junior researcher  2007 - 2008  12 
10.  25653  PhD Špela Konjar  Chemistry  Junior researcher  2005 - 2008  59 
11.  10502  PhD Nataša Kopitar Jerala  Biochemistry and molecular biology  Researcher  2004 - 2008  239 
12.  22312  PhD Gregor Kosec  Biotechnology  Researcher  2004 - 2007  129 
13.  17110  Louisa Johanna Kroon Žitko    Technical associate  2004 - 2008  22 
14.  23574  PhD Tomaž Langerholc  Biotechnology  Junior researcher  2004 - 2007  289 
15.  03422  PhD Brigita Lenarčič  Biochemistry and molecular biology  Researcher  2004 - 2008  338 
16.  22318  PhD Primož Meh  Pharmacy  Junior researcher  2004 - 2006  14 
17.  26028  PhD Marko Novinec  Biochemistry and molecular biology  Junior researcher  2005 - 2008  221 
18.  26243  PhD Kristina Orešić  Biochemistry and molecular biology  Researcher  2007 - 2008  32 
19.  23575  PhD Miha Pavšič  Biochemistry and molecular biology  Junior researcher  2004 - 2007  204 
20.  24764  PhD Ana Petelin  Cardiovascular system  Technical associate  2007 - 2008  234 
21.  25642  PhD Urška Požgan  Pharmacy  Junior researcher  2005 - 2008  24 
22.  19366  PhD Aleš Premzl  Pharmacy  Researcher  2004 - 2007  81 
23.  09091  PhD Vida Puizdar  Biochemistry and molecular biology  Technical associate  2004 - 2008  55 
24.  22321  PhD Sabina Rabzelj  Biochemistry and molecular biology  Junior researcher  2004 - 2006  43 
25.  06056  PhD Metka Renko  Biochemistry and molecular biology  Researcher  2004 - 2008  99 
26.  21560  PhD Urška Repnik  Microbiology and immunology  Researcher  2008  149 
27.  16411  PhD Jerica Rozman Pungerčar  Biochemistry and molecular biology  Researcher  2004 - 2007  61 
28.  17096  Andreja Sekirnik  Biochemistry and molecular biology  Technical associate  2004 - 2008  31 
29.  29542  PhD Barbara Sobotič  Biochemistry and molecular biology  Junior researcher  2008  62 
30.  14829  PhD Veronika Stoka  Biochemistry and molecular biology  Researcher  2004 - 2008  237 
31.  28484  PhD Dejan Suban  Animal production  Junior researcher  2007 - 2008  17 
32.  25623  PhD Katja Škerget  Pharmacy  Junior researcher  2005 - 2008  35 
33.  28485  PhD Aleš Špes  Biochemistry and molecular biology  Junior researcher  2007 - 2008  24 
34.  15969  Ivica Štefe  Biochemistry and molecular biology  Technical associate  2007 - 2008  36 
35.  29544  PhD Ajda Taler Verčič  Biochemistry and molecular biology  Junior researcher  2008  80 
36.  05234  Mojca Trstenjak Prebanda  Biochemistry and molecular biology  Technical associate  2007 - 2008  64 
37.  07561  PhD Boris Turk  Biochemistry and molecular biology  Researcher  2004 - 2008  1,038 
38.  01085  PhD Vito Turk  Biochemistry and molecular biology  Head  2004 - 2008  1,492 
39.  21557  PhD Tjaša Urbič  Chemistry  Researcher  2004 
40.  21619  PhD Olga Vasiljeva  Oncology  Researcher  2004 - 2008  183 
41.  18286  PhD Tina Zavašnik Bergant  Biochemistry and molecular biology  Researcher  2004 - 2008  138 
42.  03368  PhD Eva Žerovnik  Biochemistry and molecular biology  Researcher  2004 - 2008  391 
Organisations (2)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0103  University of Ljubljana, Faculty of Chemistry and Chemical Technology  Ljubljana  1626990  23,454 
2.  0106  Jožef Stefan Institute  Ljubljana  5051606000  91,961 
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
Protein processing and degradation, which can be intra- or extracellular, is one of the most important physiological processes with a key role of proteolytic enzymes. 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. (Lopez-Otin in Overall, 2002; Turk, 2006). In the past, our research group has contributed significantly to the development of the field with the following discoveries: discoveries of cathepsins S, X, discoveries of endogenous inhibitors cystatin C, the stefins (A, B, C and D), kininogens and later thyropins. The studies of characterization of cysteine cathepsins and their inhibitors, understanding of their mechanism of action and their ineraction with inhibitors, their 3-D structure determination (in collaboration with group of Nobel laureate dr. R. Huber and later dr. D. Turk), and the studies of the physiological roles of cysteine protease including our pioneering work on the connections between the lysosomal proteases and the caspases during apoptosis (Stoka et al., 2001; Cirman et al., 2004; Droga-Mazovec et al., 2008) and their role during autophagy in parasites (Alvarez et al., 2008), classify our reasearch at the cuting edge in this area of research. This is reflected also in high citation of our works in this competitive field. The proposed research program offers new possibilities for further understanding of protease regulation, physiological processes involving proteases investigated in normal and pathological conditions (cancer, neurodegeneration, inflammation, etc.), as well as possibilities for rational drug design. Therefore, we have good arguments to expect that the proposed research will be accomplished succesfully also in the next six year period. A major interest of the pharmacuetical companies for proteases and among them also the cathepsins are supporting the idea that this problematics is extremely important. Moreover, the research topics are among the topics of FP6 and FP7 research programmes. It can be concluded that the proposed research topics belong among the most attractive areas of research in the fields of biomedicine, agricultura 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 12 publications in the journals with IF ) 10.0 since 1990 and consequently the high citation of the works of the programme leader Prof. Dr. V. Turk (over 11000 citations total, H-index 51; the most cited Slovene scientist after 1991) and the new programme leader Prof. Dr. B. Turk (~3000 citations total; H-index 27), as well as of the other researchers. Moreover, this is evident also from the list of interantional collaborations with a number of top class researchers worldwide.
Significance for the country
Programme team performs basic research and contributes to the world treasure knowledge by numerous excellent publications. Research of protein processing is of major importance for the understanding of physiological processes in living organisms in helath and disease. There is almost no disease, which would not be associated with proteolytic enzymes and their increased and/or uncontrolled activity. Because of their importance and excellent achievements the research results enable immediate usage in modern industrial laboratories and inclinical laboratories. Similarly, studies are important for defense e.g. in bioterrorism, and for the development of biosensors and diagnostics. Reseacrh within this programme lead to over 200 finished BSc theses, over 40 MSc theses and over 30 PhD theses. After finishing their studies, numerous researchers left the group and went to other institutes and universities. At the University of Ljubljana (UL) researchers from this programme form the core of the biochemistry program and chair of biochemistry at FKKT UL. A number of the researchers went to pharmaceutical industry, including the three PhD's who got employed in Lek in the new facility for recombinant protein production. As a result of previous investigations, a new diagnostic program for early cancer diagnosis was developed on the basis of monoclonal antibodies against cysteine cathepsins and cystatins together with the resesrchers from Krka pharmaceuticals. This research also resulted in several patents. With Lek d.d. we have been collaborating on antibiotics development and other programmes. Both Krka and Lek have financially supported establishment of our new laboratories for cell biology, which enable research at the highest standard (GLP). It can be concluded that the proposed application is very up-to-date, competitive and interdisciplinary. Investigations like this combining biochemistry, and molecular and cell biology are critically important for the development of modern biotechnology. 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. With our achievements we contribute also to the cultural rise of Slovenia as both science and arts are indispensable for that. 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. Dr. Vito Turk was so 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. Dr. Boris Turk is currently Secretary General of European Cell Death Organization (ECDO), he was councilor of the International Proteolysis Society (IPS, 2001-2005), he is an EMBO member (2007-) and was awarded Zois amendment for the important achievements in the field of Biochemistry of proteolytic enzymes. In addition, other group members received various awards and amendments.
Most important scientific results Final report, complete report on dLib.si
Most important socioeconomically and culturally relevant results Final report, complete report on dLib.si
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