1. Nuclear receptors in xenobiotic and endobiotic metabolism regulation
Nuclear receptors (NRs) such as Pregnane X receptor (PXR), constitutive androstane receptor (CAR), Farnesoid X receptor (FXR) and Aryl Hydrocarbon Receptor (AHR) are the most important endogenous ligand/xenobiotic-activated transcription factors responsible for both basal and inducible expression of genes involved in drug metabolism, glucose, lipid, cholesterol and bile acid homeostasis. However, only little is known about the dynamics of cytochrome P450 enzymes regulation and about posttranscriptional regulation of these NRs by miRNAs. The aim of the research line is to examine dynamics in NRs and their target genes expression and regulation, and molecular mechanisms behind. The project could describe novel mechanistic aspects of metabolizing enzymes regulation in human hepatocytes, temporal effects of nuclear receptors based on mathematical modelling and have important clinical implication for personalized pharmacotherapy. The project is conducted in collaboration with Professor Stanislav Mičuda, PhD (Medical Faculty in Hradec Kralove, Charles University) and Prof. Elfriede Friedmann (Institut für Mathematik, University of Kassel) and Dr. Martin Lanzendörfer (Faculty of Sciences, Charles University). In development of novel cellular hepatocyte models including 3D spheroids of primary human hepatocytes, we closely collaborate with Dr. Sabine Gerbail-Chaloin (INSERM U1183, Montpellier, Prof. Daujat group) and Magnus Ingeman-Sundber (Karolinska Institutet).
In addition, we study if some environmental contaminants and industrial chemicals may affect hormonal and metabolism homeostasis due to the interaction with nuclear receptors. This research topic is studied in collaboration with the EDCMET H2020 consortium.
2. Novel ligands of nuclear receptors
In collaboration with Dr. Radim Nencka and Dr. Eva Kudova (Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague) and Associate Professor Jaroslav Roh and Professor Lucie Cahlikova (Faculty of Pharmacy, Charles University), we are developing and testing novel ligands for several nuclear receptors. In collaboration with colleagues from our faculty, we are also involved in the development of novel antituberculotic drugs (Dr. J. Roh, Prof. Hrabalek group). Candidate compounds are tested in collaboration with Dr. Karel Chalupský (Czech Centre for Phenogenomics) and Prof. Micuda (Medical Faculty CU). 3D modeling and in silico prediction are performed by Dr. Drastik, Dr. Holas or in collaboration with Dr. Thales Kronenberger (University Hospital of Tübingen and University of Eastern Finland).
3. Novel formulation for the delivery of nuclear receptor ligands
We are developing novel nanoformulation for the delivery of nuclear receptors ligands into cells of immune system. APIs of interest are small molecules as well as nucleic acids. We focus on PLGA nanoparticles and lipid nanoformulations (liposomes, solid-lipid nanoparticles, SNEDDS) based on cationic lipids. We collaborate with Professor Anette Mullertz (University of Copenhagen) and with Professor Daniel Scherman (Centre National de la Recherche Scientifique (CNRS).
4. Radiopharmacy (prof. František Trejtnar)
The work is concentrated on potential radiopharmaceuticals from two groups: radiolabeled receptor-specific peptides and radiolabeled monoclonal antibodies. The research includes some pharmacodynamic aspects of drug-organism interactions such as evaluation of radiolabeled ligand binding to selected targeted receptors. Concomitantly, we investigate selected aspects of pharmacokinetics of the tested compounds. The studies are aimed at absorption, biodistribution, renal and liver elimination but we also carry out experimental studies on total pharmacokinetics in vivo.
Last update: 18/10/2022