Loading...
Projects / Programmes source: ARIS

Comprehensive characterization of GWAS hits – pipeline to novel drug targets for anabolic treatment of osteoporosis (GWASforAna)

Research activity

Code Science Field Subfield
3.07.00  Medical sciences  Metabolic and hormonal disorders   

Code Science Field
B000  Biomedical sciences   

Code Science Field
3.02  Medical and Health Sciences  Clinical medicine 
Keywords
aging, osteoporosis, functional studies, GWAS targets, mesenchymal stem cells, personalized medicine, biomarkers
Evaluation (rules)
source: COBISS
Researchers (20)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  26227  Manja Cedilnik    Technical associate  2019 - 2022 
2.  11308  PhD Andrej Cör  Oncology  Researcher  2019 - 2022  409 
3.  38672  PhD Klemen Čamernik  Pharmacy  Researcher  2019 - 2020  21 
4.  32036  PhD Martina Hrast Rambaher  Pharmacy  Researcher  2022  129 
5.  18372  PhD Andrej Janež  Metabolic and hormonal disorders  Researcher  2019 - 2022  667 
6.  32347  PhD Mojca Jensterle Sever  Metabolic and hormonal disorders  Researcher  2019 - 2022  566 
7.  15783  PhD Tomaž Kocjan  Metabolic and hormonal disorders  Researcher  2019 - 2022  518 
8.  32112  PhD Martina Lenarčič Živković  Biochemistry and molecular biology  Researcher  2019 - 2022  61 
9.  34385  PhD Jasna Lojk  Metabolic and hormonal disorders  Researcher  2019 - 2021  68 
10.  19649  PhD Marija Nika Lovšin  Microbiology and immunology  Researcher  2019 - 2022  124 
11.  12189  PhD Janja Marc  Metabolic and hormonal disorders  Head  2019 - 2022  712 
12.  33035  PhD Rene Mihalič  Neurobiology  Researcher  2019 - 2022  113 
13.  18154  PhD Barbara Ostanek  Metabolic and hormonal disorders  Researcher  2019 - 2022  188 
14.  10082  PhD Janez Plavec  Chemistry  Researcher  2019 - 2022  1,255 
15.  28022  PhD Peter Podbevšek  Chemistry  Researcher  2019 - 2022  118 
16.  22657  PhD Irena Prodan Žitnik  Metabolic and hormonal disorders  Researcher  2019 - 2022  48 
17.  35429  PhD Katja Šuster  Neurobiology  Researcher  2019 - 2022  38 
18.  23524  PhD Rihard Trebše  Neurobiology  Researcher  2019 - 2022  426 
19.  52377  Taja Zore  Pharmacy  Researcher  2020 - 2022  13 
20.  32306  PhD Janja Zupan  Metabolic and hormonal disorders  Researcher  2019  110 
Organisations (4)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0104  National Institute of Chemistry  Ljubljana  5051592000  20,916 
2.  0312  University Medical Centre Ljubljana  Ljubljana  5057272000  77,334 
3.  0355  Orthopaedic Hospital Valdoltra  Ankaran  5053765  2,360 
4.  0787  University of Ljubljana, Faculty of Pharmacy  Ljubljana  1626973  17,462 
Abstract
Osteoporosis is the most common skeletal disease with deterioration of bone structure and increased risk of bone fractures. Even though the biology of osteoporosis has been well studied, effective personalized approach to prevention, diagnosis and particular anabolic drugs to prevent bone fractures are still lacking and there is an urgent need to identify novel targets for anabolic treatment and prevention of bone fractures. One of the powerful approaches to identify novel drug targets is identification of genetic loci that are associated with osteoporosis phenotypes in genome-wide association studies (GWAS). GWAS result in hundreds of genetic loci bearing potential to be a drug target or biomarkers for prediction of fracture risks. Yet, to benefit from these big data, functional characterization of potential drug targets is necessary. Therefore, our objective is to set up a platform for functional characterization of genetic targets associated with bone diseases. In this project, we will thoroughly functionally characterize a set of GWAS hits using state-of the art methods including mesenchymal stem cells, genome editing by CRISPR/Cas9 techniques, in vivo animal model and analysis of clinical samples. Specifically, we will (A) first determine whether a selected gene target plays a role in bone formation by gain and loss of function experiments during osteogenic differentiation of human mesenchymal stem cells (MSC). The impact of target gene silencing on osteogenic differentiation will tell us whether or not a target gene plays a role in bone formation. Given the pleiotropic nature of targets, we will also examine the function of genetic targets during formation of adipocytes and miocytes. Similarly to osteogenic differentiation, MSCs will be genetically modified and the capacity of MSCs to differentiate into different cells assessed by gene expression. Results of this experiments will explain whether a gene plays a role in non-bone related biological processes. (B) Next, in addition to cell culture experiments, we will examine the physiological role of target genes by employing zebrafish animal model in the collaboration with Bar Ilan University. (C) Moreover, to elucidate the function of genetic targets in pathological conditions, correlation of target gene expression in patient tissue samples will be examined in collaboration with University Medical Centre and Orthopaedic Hospital Valdoltra. For that purpose bone, muscle and adipose tissues will be collected and gene expression analysed. Results of clinical part of the project will unveil the relevance of genetic targets in pathological processes in humans and provide crucial information on medical relevance of examined targets and determine the predictive potential of the genetic loci. (D) Finally, in the collaboration with National Institute of Chemistry, we will analyze whether genetic loci form a specific three-dimensional DNA structure that may explain alteration of their function. The proposed project is one of the first comprehensive studies that will functionally evaluate several osteoporosis associated genetic loci in vitro, in vivo and in clinical studies. Moreover, the role of genetic targets will be simultaneously examined in three different cell types (bone, fat, muscle) and in animal model. Therefore, we expect to obtain important results that will unveil the relevance of potential biomarkers/drug targets from different perspectives and thus significantly contribute also to the field of bone biology research. In summary, we will develop a pipeline for identification of novel drug targets for anabolic treatment of osteoporosis and provide fundamental advances in the field of bone biology. Importantly, our study may lead to discovery of novel biomarkers of fracture risks assessments with the direct implications in clinical practice.
Significance for science
In the proposed project, GWAS hits will be functionally characterised from different perspectives, leading to comprehensive and relevant results required for decision making process for choosing appropriate drug targets for novel treatments of osteoporosis. The major result of the project will be a set of very well characterised gene targets suitable for drug development and personalized based medicine for prevention of osteoporosis. Importantly, we will set up the methods that will serve as a system for functional characterization of any other candidate gene that will be identified as potential target interfering with bone remodelling, fat or muscle metabolism. Given the comprehensive approach, we expect to provide fundamental advances in the field of bone biology. Besides strengthening international collaborations with outstanding researches from abroad, and connecting basic and clinical research in Slovenia, this project will also be part of education process at the Faculty of Pharmacy. Two PhD students (already enrolled in the PhD Program) and several master students will be recruited to work on the project. Notably, this project is part of an ongoing collaboration within international GEFOS consortium (financed by EU COST project GEMSTONE), which has already led to outstanding scientific findings. Given that current project involves international collaboration with excellent foreign scientist and the topic is extremely hot this promises highly relevant results of the proposed study.
Significance for the country
In the proposed project, GWAS hits will be functionally characterised from different perspectives, leading to comprehensive and relevant results required for decision making process for choosing appropriate drug targets for novel treatments of osteoporosis. The major result of the project will be a set of very well characterised gene targets suitable for drug development and personalized based medicine for prevention of osteoporosis. Importantly, we will set up the methods that will serve as a system for functional characterization of any other candidate gene that will be identified as potential target interfering with bone remodelling, fat or muscle metabolism. Given the comprehensive approach, we expect to provide fundamental advances in the field of bone biology. Besides strengthening international collaborations with outstanding researches from abroad, and connecting basic and clinical research in Slovenia, this project will also be part of education process at the Faculty of Pharmacy. Two PhD students (already enrolled in the PhD Program) and several master students will be recruited to work on the project. Notably, this project is part of an ongoing collaboration within international GEFOS consortium (financed by EU COST project GEMSTONE), which has already led to outstanding scientific findings. Given that current project involves international collaboration with excellent foreign scientist and the topic is extremely hot this promises highly relevant results of the proposed study.
Most important scientific results Interim report
Most important socioeconomically and culturally relevant results Interim report
Views history
Favourite