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Projects / Programmes source: ARIS

CholesteROR in metabolic liver disease

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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
Cholesterol, sterol, liver disease, gender, lanosterol14a-demethylase, RORC signaliziranje, biomarkers, mathematical modelling
Evaluation (rules)
source: COBISS
Evaluation of bibliographic research performance indicators according to ARIS methodology
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Researchers (16)
no. Code Name and surname Research area Role Period No. of publications
1.  29488  PhD Alen Albreht  Chemistry  Researcher  2018 - 2021  132 
2.  38236  PhD Kaja Blagotinšek Cokan  Biochemistry and molecular biology  Junior researcher  2018 - 2021  45 
3.  21395  PhD Petra Hudler  Medical sciences  Researcher  2018 - 2021  158 
4.  21352  PhD Peter Juvan  Human reproduction  Researcher  2018 - 2021  164 
5.  37493  PhD Urša Kovač  Metabolic and hormonal disorders  Junior researcher  2018 - 2020  25 
6.  24445  PhD Mitja Križman  Chemistry  Researcher  2018 - 2021  154 
7.  14305  PhD Mirjana Liović  Metabolic and hormonal disorders  Researcher  2018 - 2021  151 
8.  29198  PhD Miha Moškon  Computer science and informatics  Researcher  2018 - 2021  271 
9.  13442  PhD Miha Mraz  Computer science and informatics  Researcher  2018 - 2021  378 
10.  39409  Nejc Nadižar    Technical associate  2019 - 2021  33 
11.  50630  PhD Rok Razpotnik  Biochemistry and molecular biology  Junior researcher  2018 - 2021  24 
12.  22459  PhD Tadeja Režen  Neurobiology  Researcher  2018 - 2021  258 
13.  06013  PhD Damjana Rozman  Biochemistry and molecular biology  Head  2018 - 2021  915 
14.  50455  PhD Cene Skubic  Biochemistry and molecular biology  Technical associate  2018 - 2021  80 
15.  11395  PhD Irena Vovk  Chemistry  Researcher  2018 - 2021  567 
16.  05957  PhD Nikolaj Zimic  Computer science and informatics  Researcher  2018 - 2021  329 
Organisations (3)
no. Code Research organisation City Registration number No. of publications
1.  0381  University of Ljubljana, Faculty of Medicine  Ljubljana  1627066  49,089 
2.  0104  National Institute of Chemistry  Ljubljana  5051592000  21,407 
3.  1539  University of Ljubljana, Faculty of Computer and Information Science  Ljubljana  1627023  16,798 
Abstract
This project aims to address some of the current unmet needs in identifying molecular players of Non-Alcoholic Fatty Liver Disease. NAFLD is the most prevalent form of chronic liver disease in the world. It affects 25% of the global adult population and as many as 1/3 of people in the developed world. The disease is manifested by a spectrum of liver pathologies ranging from simple steatosis to liver cell injury with fibrosis and can end in cirrhosis or liver cancer (HepatoCellular Carcinoma, HCC). The rising incidence of NAFLD led to dramatic rise of liver cancer, a disease with poor outcomes and limited therapeutic options. Without treatment, HCC is fatal, with a 5-year survival of only five percent. There are considerable gaps in our knowledge with regard to mechanisms by which NAFLD and its risk factors promote liver cancer. In this project we will focus on the new promising players: the “CholesteROR” pathway that links Retinoic Acid Orphan Receptor Gamma (RORg, RORC, NR1F–3) signalling to cholesterol. The discovery that sterols from cholesterol synthesis act as specific RORC modulators came in 2015 as a full surprise because these sterols are present in most mammalian cells due to the housekeeping nature of cholesterol synthesis. This opens new horizons since the potential of RORC signalling seems to be much broader as initially anticipated. At this point the literature is sparse and the endogenous function of the hepatic RORC signalling is in its early phase of understanding. It is important to determine unequivocally how RORC signalling affects the progression of NAFLD, how this is mediated by endogenous sterols and which targets of the CholesteROR network would be best suited for liver disease modulation. To solve such complex questions in multifactorial pathologies we must apply innovative systems solutions that in addition to experimentation include also modelling and validation in clinical samples. On these grounds, the CholesteROR  innovative project aims to tackle the deadly NAFLD with systems approaches. We will address the CholesteROR linked drivers of progressive NAFLD towards HCC in the light of biomarkers or treatment targets which is a novel aspect in liver disease aethiology.  We aim to determine the networks and regulatory nodes (transcription factors and its targets) in the hepatocytes with activated or diminished ROR signalling. We will also evaluate which CholesterROR regulatory nodes mirror different stages of NAFLD in the mouse model and propose characteristic patterns. We will establish a mechanistic model of the CholesteROR network and connect it with the state-of-the-art SteatoNet mathematical model. And finally, we aim to validate the NAFLD patterns in patients and propose targets for modulating progression of NAFLD based on experimental data and model simulations. If CholesteROR is funded, we are in a unique position to achieve the above goals. We have already developed some original biochemical and computational tools to study cholesterol metabolism in liver disease and will have by the start of the project the reference data available. Here we are in front of other research groups and we must have a chance to lead it a step forward.
Significance for science
Discovery of Novel Scientific Findings. By applying original animal models and systems approaches with combination of experimental, clinical and computational methods, novel molecular mechanisms of the advanced Non-Alcoholic (Fatty) Liver Disease NA(F)LD will be assessed. This will importantly contribute to global understanding of this threatening disease of the developed world and to discovery of novel biomarkers. It is important to underline that there are no true NAFLD biomarkers available at present and there also are no specific drugs to treat the disease. This project is also in a unique position to discover the sterol ligands of the liver RORC receptor in vivo and provide novel evidence of the biological roles of these late cholesterol synthesis intermediates. Our basic research findings in this field already attained an international recognition, which is evident from the list of publications and the citation index. Improving and Enlarging Methodology Tools. This project aims to address some of the current unmet needs in understanding the Non-Alcoholic (Fatty) Liver Disease NA(F)LD progression towards hepatocellular carcinoma (HCC). It will provide innovative systems biology/medicine solutions and promote informed and rational design of novel diagnostics and treatment options, taking into account sexual dimorphism of the liver metabolism. The classical research approaches did not lead to sufficient progress in liver disease area. It is thus timely to introduce the multi-disciplinary systems medicine approaches to tackle NAFLD as a group of multifactorial conditions and to combine it with the state-of-the-art liver models.  Development of Own Basic Research. Scientific findings stated above belong to the category of fundamental scientific findings in the field of biochemistry and molecular biology and functional genomics, systems biology / medicine of metabolic and hormonal disturbances, altogether representing a venue of translational medicine where discoveries in (animal) models are used to improve human health. Publications of recent years result from own basic research in co­ operation with international partners. Development of Other Fundamental Sciences and New Technologies. The proposed project is explicitly of interdisciplinary character and will contribute importantly to foster further development of post­genome technologies and systems approaches in Slovenia. The newest tools of functional genomics and systems medicine will be applied, in line with international guidelines where participants of this project also actively contribute to these. Besides offering fundamental knowledge in the basic field of biochemistry, molecular biology and endocrinology it also reaches into the domain of bioinformatics and modeling. It is expected that investigations planned in the present project will exert an influence on all fields stated.
Significance for the country
Discovery of Novel Scientific Findings. By applying original animal models and systems approaches with combination of experimental, clinical and computational methods, novel molecular mechanisms of the advanced Non-Alcoholic (Fatty) Liver Disease NA(F)LD will be assessed. This will importantly contribute to global understanding of this threatening disease of the developed world and to discovery of novel biomarkers. It is important to underline that there are no true NAFLD biomarkers available at present and there also are no specific drugs to treat the disease. This project is also in a unique position to discover the sterol ligands of the liver RORC receptor in vivo and provide novel evidence of the biological roles of these late cholesterol synthesis intermediates. Our basic research findings in this field already attained an international recognition, which is evident from the list of publications and the citation index. Improving and Enlarging Methodology Tools. This project aims to address some of the current unmet needs in understanding the Non-Alcoholic (Fatty) Liver Disease NA(F)LD progression towards hepatocellular carcinoma (HCC). It will provide innovative systems biology/medicine solutions and promote informed and rational design of novel diagnostics and treatment options, taking into account sexual dimorphism of the liver metabolism. The classical research approaches did not lead to sufficient progress in liver disease area. It is thus timely to introduce the multi-disciplinary systems medicine approaches to tackle NAFLD as a group of multifactorial conditions and to combine it with the state-of-the-art liver models.  Development of Own Basic Research. Scientific findings stated above belong to the category of fundamental scientific findings in the field of biochemistry and molecular biology and functional genomics, systems biology / medicine of metabolic and hormonal disturbances, altogether representing a venue of translational medicine where discoveries in (animal) models are used to improve human health. Publications of recent years result from own basic research in co­ operation with international partners. Development of Other Fundamental Sciences and New Technologies. The proposed project is explicitly of interdisciplinary character and will contribute importantly to foster further development of post­genome technologies and systems approaches in Slovenia. The newest tools of functional genomics and systems medicine will be applied, in line with international guidelines where participants of this project also actively contribute to these. Besides offering fundamental knowledge in the basic field of biochemistry, molecular biology and endocrinology it also reaches into the domain of bioinformatics and modeling. It is expected that investigations planned in the present project will exert an influence on all fields stated.
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