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Projects / Programmes source: ARIS

Proteolysis and its regulation

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Periods
January 1, 2015 - December 31, 2021
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
B000  Biomedical sciences   

Code Science Field
1.06  Natural Sciences  Biological sciences 
Keywords
proteases, cathepsins, caspases, legumain, inhibitors, activity-based probes, targeted-delivery systems, inflammation-associated diseases, cancer, arthritis, immunity, proteomics, chemogenomics
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 (55)
no. Code Name and surname Research area Role Period No. of publications
1.  36326  Teja Bajt  Natural sciences and mathematics  Junior researcher  2015  0 
2.  39130  PhD Monika Biasizzo  Natural sciences and mathematics  Junior researcher  2016 - 2021  23 
3.  32149  PhD Katja Bidovec  Natural sciences and mathematics  Junior researcher  2015 - 2016  12 
4.  37546  PhD Janja Božič  Medical sciences  Researcher  2015 - 2021  30 
5.  33315  PhD Miha Butinar  Natural sciences and mathematics  Researcher  2015 - 2019  60 
6.  08327  PhD Kristina Djinovic Carugo  Natural sciences and mathematics  Researcher  2015 - 2021  344 
7.  00449  PhD Iztok Dolenc  Natural sciences and mathematics  Researcher  2015 - 2021  110 
8.  33160  PhD Sara Drmota Prebil  Natural sciences and mathematics  Junior researcher  2015  12 
9.  54714  Ana Ercegovič Rot  Natural sciences and mathematics  Junior researcher  2020 - 2021  3 
10.  18801  PhD Marko Fonović  Natural sciences and mathematics  Researcher  2015 - 2021  173 
11.  36808  PhD Aljaž Gaber  Natural sciences and mathematics  Researcher  2019 - 2021  69 
12.  39078  PhD Tjaša Goričan  Natural sciences and mathematics  Junior researcher  2016 - 2021  17 
13.  38199  Marija Grozdanić  Natural sciences and mathematics  Junior researcher  2015 - 2019  9 
14.  30872  PhD Maruša Hafner Česen  Natural sciences and mathematics  Researcher  2015 - 2017  31 
15.  36335  PhD Katarina Hočevar  Natural sciences and mathematics  Junior researcher  2015 - 2017  9 
16.  50500  Urban Javoršek  Medical sciences  Junior researcher  2017 - 2021  9 
17.  50310  PhD Nežka Kavčič  Natural sciences and mathematics  Researcher  2017 - 2021  37 
18.  54695  Matej Kolarič  Natural sciences and mathematics  Junior researcher  2020 - 2021  7 
19.  10502  PhD Nataša Kopitar Jerala  Natural sciences and mathematics  Researcher  2015 - 2021  235 
20.  38198  PhD Andreja Kozak  Medical sciences  Researcher  2015 - 2021  21 
21.  37474  Aleksander Krajnc  Natural sciences and mathematics  Junior researcher  2015 - 2018  11 
22.  37408  PhD Anja Krajnc  Natural sciences and mathematics  Junior researcher  2015 - 2016  7 
23.  35467  PhD Lovro Kramer  Natural sciences and mathematics  Researcher  2015 - 2017  40 
24.  03422  PhD Brigita Lenarčič  Natural sciences and mathematics  Researcher  2015 - 2021  336 
25.  53032  Petra Matjan Štefin  Natural sciences and mathematics  Junior researcher  2019 - 2021  7 
26.  37797  PhD Georgy Mikhaylov  Natural sciences and mathematics  Researcher  2015 - 2021  53 
27.  26028  PhD Marko Novinec  Natural sciences and mathematics  Researcher  2015 - 2021  205 
28.  35318  Maja Orehek    Technical associate  2020 - 2021  0 
29.  37465  PhD Sabina Ott Rutar  Natural sciences and mathematics  Junior researcher  2015 - 2016  11 
30.  23575  PhD Miha Pavšič  Natural sciences and mathematics  Researcher  2021  182 
31.  29470  PhD Katarina Pegan  Natural sciences and mathematics  Researcher  2015 - 2016  44 
32.  29966  Dejan Pelko    Technical associate  2015 - 2021  0 
33.  09091  PhD Vida Puizdar  Natural sciences and mathematics  Researcher  2015 - 2020  55 
34.  35337  PhD Vid Puž  Natural sciences and mathematics  Junior researcher  2015 - 2016  14 
35.  34212  PhD Jelena Rajković  Natural sciences and mathematics  Researcher  2016 - 2017  21 
36.  21560  PhD Urška Repnik  Medical sciences  Researcher  2015 - 2016  149 
37.  17096  Andreja Sekirnik  Natural sciences and mathematics  Technical associate  2015 - 2017  26 
38.  52063  Tilen Sever  Natural sciences and mathematics  Junior researcher  2018 - 2021  12 
39.  55799  Tea Sinožić  Natural sciences and mathematics  Junior researcher  2021  4 
40.  29542  PhD Barbara Sobotič  Natural sciences and mathematics  Researcher  2015 - 2016  60 
41.  14829  PhD Veronika Stoka  Natural sciences and mathematics  Researcher  2015 - 2021  235 
42.  06688  PhD Andrej Šali  Natural sciences and mathematics  Researcher  2015 - 2021  57 
43.  15969  Ivica Štefe  Natural sciences and mathematics  Technical associate  2015 - 2021  34 
44.  05234  Mojca Trstenjak Prebanda  Natural sciences and mathematics  Technical associate  2015 - 2021  60 
45.  07561  PhD Boris Turk  Natural sciences and mathematics  Head  2015 - 2021  1,019 
46.  01085  PhD Vito Turk  Natural sciences and mathematics  Retired researcher  2015 - 2021  1,487 
47.  21619  PhD Olga Vasiljeva  Medical sciences  Researcher  2015 - 2021  181 
48.  50513  Eva Vidak  Natural sciences and mathematics  Junior researcher  2017 - 2021  15 
49.  33762  PhD Robert Vidmar  Natural sciences and mathematics  Researcher  2015 - 2021  109 
50.  32171  PhD Matej Vizovišek  Natural sciences and mathematics  Researcher  2015 - 2018  118 
51.  52068  Miki Zarić  Natural sciences and mathematics  Junior researcher  2018 - 2021  13 
52.  18286  PhD Tina Zavašnik Bergant  Natural sciences and mathematics  Researcher  2015 - 2018  138 
53.  34458  PhD Janja Završnik  Natural sciences and mathematics  Researcher  2015 - 2018  51 
54.  51998  Tomaž Žagar  Natural sciences and mathematics  Junior researcher  2018 - 2021  7 
55.  03368  PhD Eva Žerovnik  Natural sciences and mathematics  Researcher  2015 - 2021  386 
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  22,621 
2.  0106  Jožef Stefan Institute  Ljubljana  5051606000  87,000 
Abstract
Proteolytic processing is one of the most important irreversible post translational protein modifications. Through processing and/or degradation proteases control a great variety of physiological processes that are critical for life, including the immune response, cell cycle, cell death, wound healing, food digestion, and protein and organelle recycling. Their action is strictly controlled and imbalances in their activities have been found to be critical in a number of pathologies, such as inflammation, cancer and neurodegenerative diseases, thereby suggesting proteases as suitable and valuable drug targets. Especially in inflammation, which plays a major role in disease onset and progression in a vast number of diseases, including various cancers and arthritis, proteases have very important roles. These disease-associated proteases include cysteine cathepsins, metalloproteases, some caspases and aspartic cathepsins that can be found at the sites of inflammation. As in most of these diseases there is an urgent clinical need for improved diagnosis, therapies and patient welfare, the major focus of our program will be on cysteine cathepsins, for which unambiguous evidence for their major roles in diseases, such as cancer, atherosclerosis and rheumatoid arthritis, has been provided using genetic ablation and pharmacological inhibition in animal models. In addition to cathepsins, caspases, legumain, various metalloproteases, autophagins and aspartic cathepsins will be investigated. However, understanding the precise role of an individual protease in a disease remains a major challenge for successful therapeutic applications. The major goal of our program is therefore to further understand the signaling pathways by which selected proteases regulate physiological processes in health and disease and to understand interactions governing this signaling at the molecular level, including regulation of their activities with major focus on inflammation-associated diseases. Part of the activities will focus on the development of tools and approaches, which could be exploited for disease diagnosis and therapy, including monitoring protease activities, regulating protease activities in disease states or identifying protease signaling pathways. A major potential in this aspect have the novel activity-based probes for diagnostic imaging and especially novel targeted drug delivery systems with theranostic potential. Moreover, the identified protease substrates in the disease context have a significant biomarker potential, which will be explored in human and animal clinical samples. We therefore believe that this research will enhance our understanding of protease signaling pathways and their regulation in health and disease progression at the molecular level, our ability to diagnose disease and monitor its progression, and improve the existing therapeutic opportunities, which would take personalized medicine to the next level.
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. The proposed research program offers new possibilities for further understanding of protease regulation, including its role in inflammation-associated diseases (cancer, arthritis, inflammatory bowel diseases, etc.), as well as possibilities for rational drug design, biomarker discovery and other novel diagostic and therapeutic opportunities, including development of novel theranostic systems on a way towards personalized medicine. 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 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 proposed 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 last programme (2009-2014) and consequently the high citation of the works of the programme leader (over 6600 citations total, H-index 42), 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. 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 from the programme went to pharmaceutical industry (over 10 in last 7-8 years). 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. With our achievements we contribute also to the cultural rise of Slovenia as both science and arts are indispensable for that.
Most important scientific results Annual report 2015, interim report
Most important socioeconomically and culturally relevant results Annual report 2015, interim report
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