Projects / Programmes
Systems approaches to human genome research for personalized medicine of chronic immune diseases
January 1, 2022
- December 31, 2027
| Code |
Science |
Field |
Subfield |
| 3.01.00 |
Medical sciences |
Microbiology and immunology |
|
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
systems biomedicine; personalized medicine; multi-omics; genomics; transcriptomics; proteomics; epigenomics; pharmacogenomics; bioinformatics; biomarkers; functional cell models; biobank; chronic immune diseases; inflammatory bowel disease; asthma; psoriasis; COVID-19; biological drugs;
Data for the last 5 years (citations for the last 10 years) on
April 18, 2024;
A3 for period
2018-2022
Data for ARIS tenders (
04.04.2019 – Programme tender,
archive
)
| Database |
Linked records |
Citations |
Pure citations |
Average pure citations |
| WoS |
856 |
29,710 |
28,746 |
33.58 |
| Scopus |
824 |
31,162 |
30,129 |
36.56 |
Researchers (29)
Organisations (2)
Abstract
Pharmacogenomic biomarkers for response to classical drugs (small synthetic molecules) are relatively well studied and are being translated into clinical practice. They mainly include variants in genes for drug (xenobiotic) metabolism and transport. New biologics aimed at various molecular targets are increasingly becoming available for chronic immune diseases, widening treatment options and enabling personalized treatment. However, patient response variability to newer biologics is not well understood. We will use new systems biology and (bio)medicine approaches to investigate the molecular processes, mechanisms of disease progression and response to treatment in a in deeply comprehensive way. We will use systems medicine approach to study molecular mechanisms of non-response to biological drugs in chronic immune diseases (inflammatory bowel disease, rheumatoid arthritis, psoriasis, asthma). We will also investigate some diseases that cause chronic inflammation and/or are treated by immune modulation, such as head and neck cancer and COVID-19. For the latter, we will identify biomarkers that will help determine the most effective and low-risk vaccine type for individual recipients. Comprehensive insight into different groups of biomolecules, their signaling and other cellular networks will be obtained from the large amount state-of-the-art multi-omics technology (genomics, transcriptomics, proteomics, epigenomics, metabolomics) data. We will use bioinformatics analyses for generation of molecular pathogenesis models and the discovery of biomarkers for patient classification based on molecular endotypes that will aid in personalized medicine and disease progression monitoring. Models of molecular processes will be upgraded by integrating data from different sources (organelle, cell, tissue, organ, organism). Predictive models for personalized medicine will be generated by integrating molecular data, clinical data and environmental risk factors. We will use our extensive biobank of clinical samples (DNA, RNA, proteins isolated from serum, saliva, faeces, urine, mucosal swabs, various tissues), which already includes over 6000 patients, and which is being regulary upgraded according to the highest international standards. Our biobank includes comprehensive clinical data for each patient, including treatment response. We will develop protocols for isolation of individual cell subtypes to discover more reliabile cell type specific biomarkers. For translation of the cell type specific biomarkers into clinical practise, automated, simple and cost-effective separation of different cell subtypes technology should be developed, such as one we are currently developing in collaboration with our industry partners. The newly discovered biomarkers will be functionally evaluated using in vitro cell models based on patients' primary cells. In addition to standard functional cell models, 3D organoid models will be developed and finally, organ-on-a-chip systems.
Significance for science
Biological drugs capable of blocking the cytokine TNFalpha (etanercept, infliximab and adalimumab) have proven to be efficient in up to 70% of patients with Inflammatory bowel diseases and other autoimmune diseases, including rheumatoid arthritis and psoriasis, who are resistant to standard corticosteroid therapy and develop the most severe disease. We and others have identified several genetic, expression and proteomic biomarkers associated with treatment response to anti-TNF biologicals. Currently, these biomarkers are not yet reliable enough for translation into clinical practice for identification of best responders, i.e. patients that could be enrolled into biological therapy even at an earlier stage. Moreover, several other biological drugs for autoimmune diseases were approved in recent years, including ustekinumab targeting the Il12/Il23 pathway, vedolizumab targeting integrin ?4ß7, tocilizumab targeting IL6R, bringing out an even higher need for reliable biomarkers that could guide personalized medicine. In addition, in asthma, several biologics aimed at various molecular targets (omalizumab/IgE, mepolizumab/IL5, benralizumab/IL5R, dupilomab/IL4Ra) are increasingly becoming available. Within the research program we will significantly improve the field of biomarker discovery and provide more reliable biomarkers for personalized medicine of chronic immune diseases treated with biologicals. The major developments and advances in biomarker discovery strategy provided by our program, which will result in specific, sensitive and reliable clinically applicable point-of-care biomarkers, include: 1. Development of systems (bio)medicine approaches that comprise multi-omics data (genome, epigenome, transcriptome (including regulatory noncoding RNAs), proteome), which will enable discovery of molecular endotypes, i.e. subtypes of disease defined by molecular signatures (underlying mechanisms and pathways), which will have best response to specific biologicals. 2. Developed protocols for isolation of individual cell subtypes from clinical samples such as blood cells, nasal epithelial cells etc., to discover more reliable cell-type specific biomarkers. For translation of the cell-type specific biomarkers into clinical practice, automated, simple and cost-effective technology for separation of different cell subtypes should be developed, like the one we are currently developing in collaboration with our industry partners. We will also provide a new approach that will help our understanding of how genetic variation influences tissue-specific mechanisms, by integrating serum proteome data with disease-specific SNPs to generate pQTLs gene expression patterns in multiple organ systems. 3. We will focus on non-invasive biomarkers that can be easily used in clinical practice for personalized treatment, by using multi-omics on nasal swabs in asthma or skin strip types in psoriasis. 4. Developments in functional models that help guide biomarker discovery and enable functional validation of identified biomarkers. Using patient primary cells, we will develop 3D organelles to establish new immunological disease cell models. The models will enable us to study the action of biologics and the mechanisms of non-responsiveness in chronic immune diseases (primarily the gut/blood-IBD-adalimumab model and the lung/blood-asthma-omalizumab and mepolizumab models). The discovered concepts will stimulate research into other biologics in IBD, while the optimization of mentioned models will allow future upgrades to the so-called organ-on-a-chip, which enables manipulation of fluids and cells with extremely high spatial and temporal resolutions in an automated fashion. Compared to conventional two-dimensional cultures, it allows real-time, high-resolution observations and quantification of cellular activities and represents the in vivo situation more reliably. 5. Developments in bioinformatics that will enable automatized integration of multi-omics data, such as the development of a new contemporary and novel analysis pipeline Mendelian Genomics Pipeline Service (MGPS). The analysis pipeline will be implemented in linux shell with merging of gold standard tools implemented in different program and script languages. In order to preserve the compatibility of the pipeline on different systems, the pipeline will be additionally implemented into Nextflow environment, thus transfer of the analysis pipeline onto different computer systems will be enabled via docker container, which will in turn ensure the repeatability of analyses. Using the developed pipeline, extensive bioinformatical analysis will be accessible to scientists without prior extensive computer knowledge. Additionally, developed pipeline can be applied to various complex diseases and biological problems, where the raw data was obtained using state-of-the-art next-generation laboratory equipment. Additionally, prediction models will be developed using algorithms for machine learning and artificial intelligence to guide personalized medicine. Confirmed functional relevancy of the selected biomarkers will enable development of new strategies to avoid patient non-response to biologicals. The acquired in-depth understanding of the molecular mechanisms of disease and therapy response will also enable identification of possible novel therapeutic targets. Additionally, as many putative biomarkers discovered up to date have poor / no known functional affiliations, our approach will also improve the general knowledge on functionality of the studied genes, transcripts, peptides, proteins.
Significance for the country
The program group is the national coordinator of the "Biomarkers" platform of the national consortium EATRIS-TRI.si for the implementation of the project "Development of research infrastructure for international competitiveness of the Slovenian RRI area in the field of biomedicine and drug development", and a member of the international consortium EATRIS-ERIC (The European Advanced Translational Research Infrastructure in Medicine- European Research Infrastructure Consortium). The aim of the "Biomarkers" platform is to promote the integration and integration of research legal entities that promote translational research in the field of biomedicine, in particular biomarker research, organization of workshops and scientific meetings to exchange knowledge and experience, promote cooperation in technology, standards, research infrastructure and transfer knowledge from and into the industry and education. The program group develops the infrastructure that enables advancement of research on biomarkers and the transfer of discoveries into clinical practice for personalized medicine in Slovenia, which includes: 1. A laboratory center bringing together at one place state-of-the-art multi-omics technologies (genomics, transcriptomics, proteomics, epigenomics, proteomics, metabolomics), featuring NGS sequencers, laser biochip reader for high throughput genotyping, high-resolution mass spectroscopy associated with nHPLC. The technology platform iscombined with expertise in functional validation of biomarkers using functional cell models and expertise of bioinformatics and systems medicine. 2. Biobank of clinical samples in that meets the highest international standards. As members of the board of directors of the consortium of Slovenian biobank research infrastructure BBMRI.si with the plan to join the international network BBMRI-ERIC (Biobanking and Biomolecular Resources Research Infrastructure - European Research Infrastructure Consortium) we develop expertise in developing standard operational protocols in cooperation in international consortia. This enables us to transfer knowledge, experience and good practices to Slovenian partners with whom we cooperate within national projects, which accelerates basic and translational biomedical research in Slovenia and improves the possibilities of Slovenian research institutions and companies to join international consortia for biomedical research and obtain EU funding. We are creating a state-of-the-art environment for biomedical research in which we attract Slovenian researchers back to their homeland after many years of training abroad to contribute to scientific excellence and the socio-economic development of Slovenia. Postdoctoral experts who joined our group after returning from abroad participate and raise quality in the pedagogical process, national and international scientific projects and development projects for industry. We participate in undergraduate and postgraduate courses, participate in mentoring doctoral theses and train students for research thinking and work through interdisciplinary student projects in which medical students connect with students in complementary fields (chemistry, computer science) in joint project groups (projects "ŠIPK2 - Project work with the non-economic and non-profit sector - Student innovative projects for social benefit" and "PKP - On the creative path to knowledge"). Knowledge and basic discoveries in the field of biomarkers for personalized medicine are transferred to clinical practice for improved treatment of patients, mainly through internal development projects in UKC MB. The introduction of newly discovered biomarkers and prognostic models will enable a personalized treatment of patients with chronic immune diseases, which will help physicians to more accurately treat patients and make a more appropriate diagnosis, and facilitate the choice of more effective therapy and consequent targeted, cost-effective use of biological drugs. This would achieve a faster response of patients with chronic immune diseases to biologic therapy and prevent side effects. We collaborate with businesses in joint development projects and help establish high-tech "start-up" companies, e.g. we contributed to the founding of BioReCell, a company that develops stem cell isolation equipment for regenerative medicine. We are involved in the development of several small companies that develop non-invasive diagnostic methods for detecting biomarkers based on the principle of biosensors and artificial intelligence applications.
