Projects / Programmes
Molecular mechanisms of regulation of cellular processes related to some human diseaes
January 1, 2004
- December 31, 2008
| Code |
Science |
Field |
Subfield |
| 1.05.00 |
Natural sciences and mathematics |
Biochemistry and molecular biology |
|
| 3.03.00 |
Medical sciences |
Neurobiology |
|
| Code |
Science |
Field |
| P004 |
Natural sciences and mathematics |
Biochemistry, Metabolism |
Signal transduction, enzymes, gene expression, gene polymorphysm, drug delivery vectors, cell cultures, eukaryotic microorganisms, stressors, steroids, recombinant proteins
Researchers (30)
Organisations (1)
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
With the research results of our group we participate in the development all three fields of our engagement: in basic enzymology we develop kinetic methods for the analysis of complex reaction mechanisms, in signal transduction we are elucidating biological communication and events for adaptation; the hardest and long lasting is the way of implementation of our findings in medicine: a wide response, even in the FDA approved updated Warfarin Prescribing Information by a pharmaceutical company and high citations are solid evidence.
Significance for the country
Mainly basic biochemical studies appear to have a little impact on the economy and society. Nevertheless, we succedded to protect by letters patent a part of our findings. We have thus proven the applicability of our research efforts. Besides, it is very clear, that the high level of our research is reflected in our major occupation, i.e. teaching. This is especially expected from the University teaching stuff . Awards, like a Golden prize of J.Stefan, to the candidate that was even not a young resercher, is the confirmation of our right direction. Additionaly, our young researchers are wellcome as post doctoral fellows all over the world. We have successfully introduced new technologies into clinical praxis. Our research on microorganisms, populating salterns at Sečuvlje, is important for maintaining and developing national natural heritage.
Most important scientific results
Final report,
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Most important socioeconomically and culturally relevant results
Final report,
complete report on dLib.si
