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Projects / Programmes source: ARIS

The effect of citrullination of extracellular matrix proteins to degradation by cysteine in metalloproteases in arthritic joints

Research activity

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

Code Science Field
B000  Biomedical sciences   
Keywords
arthritis, proteases, cathepsins, metalloproteases, citrullination, proteomics, activity-based probes, chemogenomics
Evaluation (rules)
source: COBISS
Researchers (8)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  23573  PhD Dejan Caglič  Biochemistry and molecular biology  Researcher  2008 - 2009  53 
2.  18801  PhD Marko Fonović  Biochemistry and molecular biology  Researcher  2007 - 2009  187 
3.  25642  PhD Urška Požgan  Pharmacy  Junior researcher  2007 - 2009  24 
4.  19366  PhD Aleš Premzl  Pharmacy  Researcher  2007  81 
5.  21560  PhD Urška Repnik  Microbiology and immunology  Researcher  2008 - 2009  149 
6.  16411  PhD Jerica Rozman Pungerčar  Biochemistry and molecular biology  Researcher  2007  61 
7.  23524  PhD Rihard Trebše  Neurobiology  Researcher  2007 - 2009  427 
8.  07561  PhD Boris Turk  Biochemistry and molecular biology  Head  2007 - 2009  1,037 
Organisations (2)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0106  Jožef Stefan Institute  Ljubljana  5051606000  90,724 
2.  0355  Orthopaedic Hospital Valdoltra  Ankaran  5053765  2,363 
Abstract
Citrullination of proteins represents a crucial event in the initiation and progression of the autoimmune rheumatoid arthritis. It is believed that after citrullination proteins obtain the ability to break immune tolerance and become more susceptible to proteolytic degradation. The major goals of our study are to evaluate the importance of citrullination of extracellular proteins for tissue degradation and to identify the proteases responsible. As reported fibroblast-like synoviocytes in RA joints might undergo a sort of transformation which renders them aggressive and invasive independently of macrophage stimulation. This is why inhibition of the inflammatory elements alone is not sufficient to prevent further joint destruction. In the proposed project we will identify the citrullinated proteins in the clinical samples from arthritic patients, evaluate in vitro degradation of citrullinated proteins by different proteases and study the role of cysteine proteases (cathepsins B, K, L, S) and metallo proteases (MMP-1,-3,-13) in the invasiveness of synovial fibroblasts through matrix of citrullinated proteins.
Significance for science
The major goal of our study was to understand protease signalling by cysteine and metalloproteases in the joint diseases. The project presents new aspects in understanding the physiological role of cysteine proteases in tissue degradation, which was in past largely attributed solely to the neutral metalloproteases. Results obtained contribute to biomedical and medical sciences in understanding the arthritic diseases. The long-term goal of the project to use the knowledge obtained and methodology developed in other systems with the final goal to evaluate cysteine and metalloproteases as potential targets for the therapeutical treatment of inflammatory diseases such as osteoarthritis and rheumatoid arthritis, is, however, a valid strategy also for future. In addition the proposed project strengthened the research at the Department of Biochemistry and Molecular and Structural Biology at Jožef Stefan Institute in the field of cell biology and molecular medicine, and opened a new area of research at OH Valdoltra, which emerged from the project and resulted in first successes.
Significance for the country
Although the project research was basic research, it also had its applied component and can be classified as strategic basic research. Members of the group have extensively collaborated with Slovene industry (Lek, Krka), which resulted in a substantial amount of contract-based research, and offers numerous possibilities for future as transfer of knowledge into industry was always one of the long-term goals of the project. Proteases are namely directly involved in the development and progression of joint diseases and therefore represent one of the main target classes for the development of new drugs. In addition, joint diseases represent one of the most prosperous fields of research focused on understanding of the molecular mechanism of disease development with intense participation of pharmaceutical industry. Elucidation of the role of proteases in the invasiveness of synovial fibroblasts thus represents an important contribution to biomedical sciences and has a significant impact also for pharmaceutical industry in identification of novel targets. Techniques developed and optimized within the frame of this research project may thus represent an important tool for evaluation of therapeutics in preclinical development. Results obtained are also of major importance for the specialists rheumatologists and orthopaedists to improve their understanding of the development of joint diseases and help them in making decisions for appropriate therapise. This research project was also the first in line of projects, which importantly expanded the research portfolio of the orthopaedic institution involved from the initial studies of the effects and successes of surgical reconstitution solutions as a consequence of the enzymatic action in joint tissues in OA and RA towards basic research, where first important achievements emerged. As such, the project also served as an excellent basis for further collaborations in basic research both in Slovenia and abroad, especially with Finland (Y. Konttinen). Understanding of the molecular aspects of the most common orthopaedic diseases and participation in basic research projects also raised the reputation of the OH Valdoltra, its international recognition and its influence in the local environment. The work also offered great opportunity for students to be trained in the most advanced methods and areas, such as proteomics, which is currently being established at the IJS within the group, and chemogenomics together with European and other international partners. Both fields have namely high international priority as they are of extreme importance in target identification and validation during drug development. In addition, members of the project, in particular the principal investigator, have received wide-spread international recognition (involvement in boards of international organizations and editorial boards of journals, invitations for lectures at meetings and universities, high citation, invited papers, work in evaluation panels, international awards, …) which is very important for the world-wide promotion of Slovenia and as such also for preservation of national identity of Slovenia.
Most important scientific results Annual report 2008, final report, complete report on dLib.si
Most important socioeconomically and culturally relevant results Annual report 2008, final report, complete report on dLib.si
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