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Projects / Programmes source: ARRS

Aegerolysin-like proteins as new theranostic tools in periodontal disease and prosthetic rehabilitation

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Research activity

Code Science Field Subfield
3.02.00  Medical sciences  Stomatology   

Code Science Field
B000  Biomedical sciences   

Code Science Field
3.02  Medical and Health Sciences  Clinical medicine 
Keywords
egerolyzins, biomarkers, periodontal disease, prosthetic rehabilitation
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 (19)
no. Code Name and surname Research area Role Period No. of publications
1.  24290  PhD Matej Butala  Biochemistry and molecular biology  Researcher  2019 - 2022  224 
2.  54988  Anja Frantar  Stomatology  Junior researcher  2020 - 2022  7 
3.  19210  PhD Rok Gašperšič  Stomatology  Researcher  2019 - 2022  223 
4.  51653  Nina Grguraš Lestan  Stomatology  Researcher  2019 - 2022  12 
5.  32099  PhD Maja Grundner  Biochemistry and molecular biology  Researcher  2020 - 2022  27 
6.  55269  Uroš Homec    Technician  2021 - 2022  0 
7.  27920  Gregor Kapun  Chemistry  Researcher  2019 - 2022  96 
8.  52386  Eva Kočar  Biochemistry and molecular biology  Technician  2019 - 2020  20 
9.  53699  Amela Kujović  Biochemistry and molecular biology  Technician  2019  16 
10.  39099  PhD Katja Molan  Biochemistry and molecular biology  Junior researcher  2019  35 
11.  55449  Martina Mravinec  Biochemistry and molecular biology  Researcher  2021 - 2022  8 
12.  16301  PhD Čedomir Oblak  Stomatology  Principal Researcher  2019 - 2022  121 
13.  39090  PhD Anastasija Panevska  Biochemistry and molecular biology  Junior researcher  2019 - 2020  46 
14.  20653  PhD Uroš Petrovič  Biochemistry and molecular biology  Researcher  2019 - 2022  274 
15.  15328  PhD Kristina Sepčić  Biochemistry and molecular biology  Researcher  2019 - 2022  698 
16.  33137  PhD Matej Skočaj  Biochemistry and molecular biology  Researcher  2019 - 2022  95 
17.  35633  Jura Štok    Technician  2019 - 2022  0 
18.  37969  PhD Tanja Tomaževič  Stomatology  Researcher  2019 - 2020  58 
19.  52651  Sonja Žarković Gjurin  Stomatology  Researcher  2019 - 2022  8 
Organisations (3)
no. Code Research organisation City Registration number No. of publications
1.  0104  National Institute of Chemistry  Ljubljana  5051592000  20,820 
2.  0381  University of Ljubljana, Faculty of Medicine  Ljubljana  1627066  44,777 
3.  0481  University of Ljubljana, Biotechnical Faculty  Ljubljana  1626914  64,490 
Abstract
Abstract: Aegerolysin-like proteins as new theranostic tools in periodontal disease and prosthetic rehabilitation Periodontal diseases (PD) are initiated by periodontal pathogens which can be found in bacterial plaque, complex biofilms attached to the tooth surface. The most studied periodontal pathogens are Porphyromonas gingivalis, Tannerella forsythia, Prevotella intermedia, Aggregatibacter actinomycetemcomitans and some others. Their presence and/or quantity strongly relates to the initiation of PD, disease progression, and unsuccessful  periodontal therapies. In prosthetic treated teeth, the biofilm attachment depends on surface roughness of prosthetic restorative materials, free surface energy of the materials and their surface characteristics. There is a higher plaque retention on the surface of polymer materials in comparison to metal and ceramic materials, which may accelerate the course of periodontitis in high risk patients. Currently, diagnosis of PD is primarily based upon an assessment of the already apparent tissue breakdown (e.g. pocket probing depth, clinical attachment loss), which hampers early detection of the disease and after treatment follow-up. One of the potential molecules that can be considered as a biomarker for early detection of PD is a specific sphingolipid molecule, ceramide phosphoethanolamine (CPE), as well as its dihydrogenated form, dihydroceramide phosphoethanolamine (DCPE), since they are the major sphingolipids in cell membranes of Porphyromonas gingivalis, Tannerella forsythia and Prevotella intermedia. In the membranes of vertebrate cells and Gram-positive bacteria CPE and DCPE are present only in minute amounts. In the past years, an increasing number of lipid-binding proteins have been developed as probes for detecting and visualising the distribution of specific lipid species. In this respect,aegerolysins can be utilised as efficient molecular tools for detecting and visualizing CPE. Aegerolysin erylysin A (EryA) strongly associate with CPE/Chol-containing membranes, and show pore-forming activity, when combined with pleurotolysin B (PlyB), a 59-kDa protein partner with a membrane-attack-complex/perforin (MACPF). Therefore, we propose the use of CPE-sensing aegerolysin EryA for detection of PD and the combination of CPE-sensing EryA and MACPF domain containing PlyB for specific eradication of CPE-containing periodontal bacteria. In our preliminary results we have confirmed that the fluorescently labelled aegerolysin EryA (EryA-mCherry) strongly binds to the lipid mixtures composed of CPE/Chol and to the total lipids extracted from Porphyromonas gingivalis. Using calcein release assay, we have further demonstrated that the mixture of EryA and pleurotolysin B (PlyB), a MACPF domain containing protein, permeabilized CPE-containing membranes. We also have shownthe presence of CPE and DCPE in all samples of periodontitis patients, and in only 20% collected samples from young healthy individuals. Thus, the main objectives of the proposed project are: 1. analysis of interactions between aegerolysins and lipids/lipid mixtures using biophysical methods (TLC/dot blot, sedimentation assay, surface plasmon resonance, calcein release assay), 2. analysis of aegerolysin binding to CPE/DCPE containing bacteria associated with periodontal disease using scanning electron microscopy (HR-SEM), 3. the use of aegerolysins and their fluorescently labelled variants for the detection of CPE and DCPE in dental plaque and saliva samples of periodontitis and prosthetically rehabilitated patients and 4. verification of the antibacterial potential of selected aegerolysin EryA combined with their partnering proteins with the MACPF domain (e.g., PlyB, EryB) against periodontal pathogens.
Significance for science
Relevance to the development of science or a scientific field The Project Group is composed of experienced senior scientists in such a way that it enables multidisciplinary approaches to the successful completion of the project.  Despite major advances in the understanding of periodontal diseases, little progress has been made towards new diagnostic methods. Therefore, dentists still have to rely on classical signs of inflammation and tissue breakdown for the periodontal diagnosis. The success of this project and its demonstration through high-level publications and patent applications is based on recent findings showing the potential for aegerolysins to specifically interact with ceramide phosphoethanolamine (CPE) and dihydro ceramide phosphoethanolamine (DCPE). We will evaluate the diagnostic potential of aegerolysins by performing a correlation study for the two potential predictive biomarkers of periodontal disease; (i) endogenous human-derived biomarker, associated with the periodontal tissue break down – matrix metalloproteinase-8 (MMP-8) and (ii) periodontal-bacteria derived specific lipids CPE and DCPE. This project will also transfer new knowledge into the growing field of lipid research. To date, no efforts have been reported relating to the use non-self lipids as biomarkers of periodontal disease. Moreover, our study will provide novel basic knowledge on the biological role of aegerolysins, (oral) microbiota, and inflammatory and auto-immune diseases. Our long-term goal will be to determine whether these lipid species are connected also with other inflammatory diseases or autoimmune diseases. It has been known for quite some time that periodontitis is a risk factor for atherosclerosis. Indeed, recent research introduced CPE as a biomarker of atherosclerosis, which thus indicates that the aegerolysin have a tremendous potential to be used also as sensors of other inflammatory diseases. Furthermore, new predictive biomarkers CPE and DCPE will be used for evaluation of materials used for fixed dental prosthesis. Finally, besides developing a new diagnostic approach for detecting paradontal disease, we will try to establish a therapy for preventing and treating the disease by exploiting cytotoxic potential of complexes of aegerolysins and their MACPF-protein partners. This new approach for treating the periodontal disease, by specific inactivation of periodontal  bacteria would allow the development of new class of antibiotic group, targeting lipids instead of specific proteins or components of bacterial cell wall.
Significance for the country
Relevance to the development of science or a scientific field The Project Group is composed of experienced senior scientists in such a way that it enables multidisciplinary approaches to the successful completion of the project.  Despite major advances in the understanding of periodontal diseases, little progress has been made towards new diagnostic methods. Therefore, dentists still have to rely on classical signs of inflammation and tissue breakdown for the periodontal diagnosis. The success of this project and its demonstration through high-level publications and patent applications is based on recent findings showing the potential for aegerolysins to specifically interact with ceramide phosphoethanolamine (CPE) and dihydro ceramide phosphoethanolamine (DCPE). We will evaluate the diagnostic potential of aegerolysins by performing a correlation study for the two potential predictive biomarkers of periodontal disease; (i) endogenous human-derived biomarker, associated with the periodontal tissue break down – matrix metalloproteinase-8 (MMP-8) and (ii) periodontal-bacteria derived specific lipids CPE and DCPE. This project will also transfer new knowledge into the growing field of lipid research. To date, no efforts have been reported relating to the use non-self lipids as biomarkers of periodontal disease. Moreover, our study will provide novel basic knowledge on the biological role of aegerolysins, (oral) microbiota, and inflammatory and auto-immune diseases. Our long-term goal will be to determine whether these lipid species are connected also with other inflammatory diseases or autoimmune diseases. It has been known for quite some time that periodontitis is a risk factor for atherosclerosis. Indeed, recent research introduced CPE as a biomarker of atherosclerosis, which thus indicates that the aegerolysin have a tremendous potential to be used also as sensors of other inflammatory diseases. Furthermore, new predictive biomarkers CPE and DCPE will be used for evaluation of materials used for fixed dental prosthesis. Finally, besides developing a new diagnostic approach for detecting paradontal disease, we will try to establish a therapy for preventing and treating the disease by exploiting cytotoxic potential of complexes of aegerolysins and their MACPF-protein partners. This new approach for treating the periodontal disease, by specific inactivation of periodontal  bacteria would allow the development of new class of antibiotic group, targeting lipids instead of specific proteins or components of bacterial cell wall.
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