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Projects / Programmes source: ARIS

Role of cysteine cathepsins in inflammation-associated diseases

Research activity

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

Code Science Field
B000  Biomedical sciences   

Code Science Field
1.06  Natural Sciences  Biological sciences 
Keywords
cathepsins, inflammation-associated dieseases, noninvasive molecular imaging, designed ankyrin repeat proteins (DARPins)
Evaluation (rules)
source: COBISS
Researchers (12)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  18801  PhD Marko Fonović  Biochemistry and molecular biology  Researcher  2014 - 2017  187 
2.  21392  PhD Štefan Fujs  Biotechnology  Researcher  2014 - 2017  87 
3.  22312  PhD Gregor Kosec  Biotechnology  Researcher  2014 - 2017  127 
4.  35467  PhD Lovro Kramer  Biochemistry and molecular biology  Junior researcher  2014 - 2017  42 
5.  29470  PhD Katarina Pegan  Biochemistry and molecular biology  Researcher  2014 - 2016  44 
6.  34212  PhD Jelena Rajković  Biochemistry and molecular biology  Researcher  2014 - 2016  21 
7.  14829  PhD Veronika Stoka  Biochemistry and molecular biology  Researcher  2014 - 2017  237 
8.  07561  PhD Boris Turk  Biochemistry and molecular biology  Head  2014 - 2017  1,037 
9.  04988  PhD Dušan Turk  Biochemistry and molecular biology  Researcher  2014 - 2017  622 
10.  21619  PhD Olga Vasiljeva  Oncology  Researcher  2014 - 2017  183 
11.  32171  PhD Matej Vizovišek  Biochemistry and molecular biology  Researcher  2014 - 2017  142 
12.  03368  PhD Eva Žerovnik  Biochemistry and molecular biology  Researcher  2016 - 2017  389 
Organisations (3)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0106  Jožef Stefan Institute  Ljubljana  5051606000  91,017 
2.  2592  ACIES BIO, biotehnološke raziskave in razvoj, d.o.o. (Slovene)  Ljubljana  2226391  401 
3.  2990  Center of excellence for integrated approaches in chemistry and biology of proteins, Ljubljana  Ljubljana  3663388  725 
Abstract
Inflammation is a complex biological response of the host organism to invading pathogens, neoplasm, or physical tissue injury that involves various cells of the immune system as well as other local cells and components of extracellular milieu. While the onset of inflammation is normally beneficial because it represents an alarm signal to injury or disease emergence, the lack of resolution of inflammation can lead to several diseases, such as cancer and atherosclerosis. In addition, the inflammatory response can be induced because of degenerated crosstalk of the host’s immune cells and surrounding tissue, which can lead to autoimmune conditions, such as in rheumatoid arthritis, psoriasis and type 1 diabetes. Monitoring onset of inflammation, its response to therapy and relapse in these diseases, collectively known as inflammation-associated diseases, is therefore crucial for successful treatment and efficient selection of therapeutics. Among the factors that are usually highly overexpressed in these diseases and therefore offer a major potential as both diagnostic and/or therapeutic targets are proteases. However, understanding the precise role of an individual protease in a disease remains a major challenge for successful therapeutic applications. Cysteine cathepsins, in particular cathepsins B and S, have often been linked with such inflammation-associated diseases, especially cancer, rheumatoid arthritis and atherosclerosis. Their genetic ablation and in some instances chemical inhibition were found to significantly delay or even prevent disease progression. However, it remains to be established whether this is a consequence of reduced inflammation or due to their broader role in disease onset and progression. In order to address these issues, we propose to develop selective macromoleular imaging tools for cathepsins B and S, based on the designed ankyrin repeat protein technology, which is well-established for non-protease targets, and on the scaffold of stefin A, an endogenous thight-binding cathepsin inhibitor that has never been evaluated as such a tool, and characterize them. We will use in vivo imaging to evaluate these novel macromolecular imaging probes as tools for monitoring disease progression and drug efficacy, including that of novel antiinflammatory drugs, as well as to evaluate the causal role of the two cathepsins in animal disease models associated with inflammation, which have been established in our laboratory. This will enhance our understanding of disease progression at the molecular level and our ability to rapidly evaluate novel therapies, which would take Personalized Medicine to the next level. Selected macromolecular probes will be optimized to assess their potential as clinical diagnostics, whereas the inhibitory probes will be also evaluated for their theranostic potential.
Significance for science
Very important achievements were reached. Cathepsin B was validated as a target for cancer diagnosis and therapy. The selective DARPin 8h6 developed showed potential for further use in preclinical sttings and has a potential for further development into a theranostic agent. The work was commented in Theranostics (IF 2016= 8.76), one of the leading journals in the field, as a very important advance in the field.
Significance for the country
Highly important for Slovenia. In addition to promotion, 1 PhD student has finished the studies and is now postdoc in Netherlands, whereas one more PhD work is in progress. The work also lead to important technological advancement as the DARPin technology is now regularly used in the lab. A further technological benefit is in the field of in vivo imaging. In addition, ACIES BIO developed several novel immunosuppresive compounds, analogues of rapamycin, which are now considered for patent filing.
Most important scientific results Final report
Most important socioeconomically and culturally relevant results Annual report 2014, 2015, final report
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