Projects / Programmes
Molecular mechanisms of regulation of cellular processes related to some human diseaes
January 1, 2009
- December 31, 2013
| Code |
Science |
Field |
Subfield |
| 1.05.00 |
Natural sciences and mathematics |
Biochemistry and molecular biology |
|
| 3.03.00 |
Medical sciences |
Neurobiology |
|
| Code |
Science |
Field |
| P4 |
Natural sciences and mathematics |
P4 |
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
Signal transduction, enzymes, gene expression, gene polymorphysm, drug delivery vectors, cell cultures, eukaryotic microorganisms, stressors, steroids, recombinant proteins
Researchers (44)
Organisations (2)
Abstract
In scope of our research program we study the mechanisms involved in regulation of cellular processes at the level of isolated, recombinant wild type and mutant enzymes, at the level of signal transduction, triggered by specific hormones or changes in salinity of the environment, and at the level of identification and expression of genes. Studies at the level of enzyme action include the following enzymes: cholinesterases that are involved in propagation of nerve signals across the synapses, enzymes belonging to the superfamily of SDR (short chain dehydrogenases/reductases) and cytochrome P450 hydroxylases involved in steroid metabolism as well as enzymes, involved in carbohydrate metabolism and metabolism of xenobiotics in mesophilic and halophilic model microorganisms. Signal transduction is studied on model systems and is aimed in hormone - receptor interactions, signal transduction via G-proteins and transfer of the signal via the MAP kinase cascade. In scope of hormone - receptor interaction, we study the effect of non-steroid compounds on fungal cytosolic progesterone receptor, as well as the coupling of fungal membrane-bound progesterone receptor, human angiotensin receptor and human glucagon like peptide-1 receptor to G-proteins. HOG signal transduction pathway, which is involved in osmosensing and play an important role in the adaptation to changes in environmental salinity, is studied as an example of MAP protein kinase signalling cascade. Extremely salt tolerant H.werneckii, isolated from the environments with high NaCl concentration, is used as the model organism. At the genomic level, genes expressed under general and specific stressors are studied. The dynamics of the fungus R. nigricans molecular response to general stressors - fungitoxic steroids (progesterone, testosterone and deoxycorticosterone) is analyzed at the level of gene expression of cytosolic subgroup of Hsp70 family, enzymes of hydroxylation system and carbohydrate metabolizing enzyme. Moreover, we attempt to identify additional genes, which are up- or downregulated during exposure of this fungus to different stressors. Expression profile of Hog1 kinase target genes gpd and ena will be analysed in halophilic model organisms. By using global approach, we will try to identify novel, yet unidentified genes which are potentially involved in the mechanism of adaptation to high salt concentration, both at the level of transcriptome and at the level of proteome. In the field of genetic polymorphisms of xenobiotic metabolising enzymes we are mostly interested in polymorphisms that could affect the metabolism of drugs with a narrow therapeutic window. Using genotyping approach we study the influence of genetic polymorphisms on the interindividual variability in drug metabolism, drug efficiency and adverse drug effects, with the aims for rational and individualised drug treatment. Genetic susceptibility to environmental carcinogenesis due to interindividual variability in xenobiotic metabolism will be studied by comparing the frequency distribution of polymorphic alleles between cancer patients and healthy controls. In design and development of peptide drug-delivery vectors, we are focused in sequence modulation of the cell-penetrating peptide transportan with the aim to minimize damaging effect of this peptide on the membrane in order to improve its internalisation properties. We will also try to design peptides with combined cell-penetrating ability and ability to activate G-proteins in order to modulate physiological processes in the selected organs "ex vivo" and in model organisms; we are particularly interested in vascular system and blood pressure regulation.
Significance for science
The results of our research group made a major impact in the fields of our interest: in the field of basic enzymology we developed new kinetic methods for the analysis of complex reaction mechanisms; our studies of signal pathways in cell systems and model organisms helped to improved the current understanding of signal transduction and adaptation to stress; while studies of molecular mechanisms in health and diseases lead to identification of new diagnostic and prognostic biomarkers and new targets for treatment. The important contribution of our research for science is evident from over 150 original scientific papers published in the evaluation period. More than two-thirds of these papers were rated as important achievements, one third as very important achievements. The impact of our publications on the respective research fileds is reflected in over 8000 citations and the originality and novelty of our research topics is reflected in 24 completed doctoral theses. Members of the program group presented over 50 lectures and 280 contributions at international meetings. They also help to shape their respective scientific fields by serving as editors and members of editorial boards of scientific journals. High potential for dissemination and translation of our novel findings into technological processes and clinical studies is reflected in several basic, applied and postdoctoral research projects of the group members. However, most of the clinical collaborations occurs outside formal research projects due to a limited set of research hours and is reflected only in joint publications and co-mentorship of doctoral theses.
Significance for the country
The fact that 7 researchers in the programme group are full professors, speaks for our outstanding achievements in terms of research excellence, and teaching and professional quality. We lectured several core and elective courses in the field of biochemistry and molecular biology at the undergraduate and post-graduate studies and mentored 19 PhD theses and comentored 6 PhD theses in the last 5 years. We also mentored 21 and comentored 18 graduation theses. Considering the fact that students at the Faculty of Medicine do not have graduation theses, these numbers show that we also actively participate in teaching at other faculties. Thus we significantly contribute to the quality of the undergraduate and graduate education at the University of Ljubljana, as well as to the development of the field of biochemistry and molecular biology in Slovenia. When taking into account our full-time teaching load, our programme group achieved outstanding results per FTE unit. In addition to the development of higher education, the research program had significant impact on the international recognition of Slovenia. As the studied halophilic organisms were first isolated in Sečovlje salterns, Slovenian researchers in this field achieved unprecedented international recognition, which is very important for the promotion of Slovenia. The first results of studies on the genome of these organisms were already published, but the emerging results may lead to new patent applications and may also have a great importance for the economy, because organisms with enhanced tolerance to salt are interesting for bioremediation, biotechnology and agronomy. Our research programme also had a big impact on health care. Translation of basic research to clinical applications constituted an important part of our programme. In the course of our clinical studies in the field of hormone-related disorders, cancer and rheumatoid arthritis, we have identified new potential diagnostic and prognostic markers, new targets for treatment as well as pharmacogenetic markers of response to treatment. When supported by replication and multicenter studies, our research may support the transition from the current treatments, based on the characteristics of the total patient population, to the predictive, preventive and personalized medicine. In addition to more effective treatment, which means big savings for health care system, also patients' quality of life of will significantly improve.
Most important scientific results
Annual report
2009,
2010,
2011,
2012,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2009,
2010,
2011,
2012,
final report,
complete report on dLib.si
