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Structure and Function of Cells in Their Normal State and in Pathology - Integrative Biology and Pathology Studying evolutionarily conserved mechanisms involved in human health and disease. © Zdenek Kostrouch GPS 49.891982, 14.674869, Countryside 19 km South of Biocev Group of Molecular Pathology • • • • • • • • • • • • • Zdeněk Kostrouch, MD, PhD, Markéta Kostrouchová, MD Petr Yilma, MSc. (Ing.) Johana Kollárová, MSc. (Ing.) David Kostrouch, MD Ahmed Chughtai, MD Philipp Jan Novotný, MD Tereza Horniková, MD Lucie Zadinová Veronika Kostrouchová Filip Kaššák Azzat AlRedouan Bruno Pelissier Senior Investigator Junior Investigator PhD student PhD student PhD student PhD student PhD student PhD student Technician IT MD student MD student MD student The Group of Molecular Pathology focuses primarily on the possible involvement of nuclear receptors in cancers and other metabolic diseases. The research strategy is centered around nuclear receptors in Diploblasts that are likely to be closely related to Deuterostome ancestors. The group also studies the regulation of metabolism and development in flatworms and in Caenorhabditis elegans and searches for parallel pathways in mammalian cell lines and in human cancers. In our working hypothesis Deuterostomes are a sister group to Diploblasts. Modern species evolved in parallel from an evolutionary time point in the Precambrian era. Protostomes evolved more distantly laterally. We view cancers as tissues acquiring archetypal cellular behavior. We search for the regulatory roles of nuclear receptors in this archetypal behavior of cells with the aim to contribute to the understanding of the role of nuclear receptors in cancers. Group of Molecular Biology and Genetics (C. elegans lab) • • • • • Marta Kostrouchová, MD, PhD, Kateřina Šebková, MD Nathaniel Kouns, MD Vladimir Zima, MSc. Hana Prouzová Principal Investigator PhD student PhD student PhD student Technician The Group of Molecular Biology and Genetics specializes in the biology of Caenorhabditis elegans and other Rhabditidae. The group focuses on nuclear receptors and their cofactors. The nematodes evolved a complex regulatory network of nuclear receptors that include almost 300 nuclear receptor genes, six times more than mammals and 14 times more than insects. The genomes of nematode species include nuclear receptors that are conserved between animal phyla and a large number of these nuclear receptors are diversified in their sequence and are found only in nematodes. The group studies conserved nuclear receptors with the aim to uncover regulatory levels that may be shared between nematodes and mammals, but also looks at the diversified nematode nuclear receptors with the aim to uncover the regulatory potential of specifically modified nuclear receptors. The group also studies several other protein families and genes potentially involved in human diseases. Outline of two principal directions of our research: I. Regulation by nuclear hormone receptors in Nematodes II. Regulation by nuclear receptors at the base of the evolution of Metazoa. I. Regulation by nuclear hormone receptors in Nematodes The Nematodes evolved hundreds of nuclear receptors. Caenorhabditis elegans has 284 nuclear receptors. Only 15 of them are conserved between Vertebrates and insects. We work on NHR-23, which is a close homologue and possibly orthologue of RORs in Vertebrates and HR3 in insects (DHR3 in Drosophila). The known regulatory levels in the NHR-23 cascade include proteins that have orthologues in Vertebrates and Insects, but may be positioned at other levels than in the other phyla. We aim to analyze this cascade in detail. The regulatory pathways of NHR-23/ROR/DHR3 Worms Vertebrates Insects miRs TRH Neuronal regulation TSH Peripheral endocr. gland miRs TR ECR E75A and ECR E75B DHR4 Target tissue Metabolic genes NHR-23 GEI-8 NHR-91 GEI-8 NHR-60 ROR DHR3 ? FTZ-F1 GEI-8 piRNAs Collagens Hh related Collagens Shh Late genes Hedgehog ? Cell cycle genes Green dots mark regulatory levels & metabolic identified in our published work genes The analysis of the regulatory pathways of NHR-23/ROR Worms Neuronal regulation Peripheral endocr. gland Target tissue Metabolic genes miRs NHR-23 GEI-8 NHR-91 GEI-8 NHR-60 GEI-8 piRNAs Collagens Hh related Cell cycle genes & metabolic genes We aim to uncover additional levels in the NHR-23 regulatory axis and search for parallels in vertebrates. We search for regulatory mechanisms upstream of NHR-23, factors acting on NHR-23 and additional genes downstream of NHR-23 II. Regulation by nuclear receptors at the base of evolution of Metazoa. Genomic sequences coding for nuclear hormone receptors are found in all Metazoan species which genomes were sequenced. Seventeen to twenty nuclear receptors are already present in genomes of Diploblastic species. The similarity of some of them with mammalian orthologues (e.g. RXR in the jellyfish Tripedalia cysotphora) indicates a conservation of some fundamental mechanisms in endocrine regulation in Metazoa. We are searching for these mechanisms in studies focused on several Diploblastic species. These species include our laboratory cultures as well as species that we have to collect in their natural habitats. A very well studied ecosystem in the Caribbean. The mangroves and coral reefs in La Parguera are the source of species that we work on through a cooperation with scientists from the University of Puerto Rico. © Zdenek Kostrouch Our outdoor lab. GPS 17.972467,-67.049389 © Zdenek Kostrouch Our outdoor lab. Protostomes Our working hypothesis: Deuterostomes are a sister group to Diploblasts Modified (with permission) from Schierwater B, Eitel M, Jakob W, Osigus H-J, Hadrys H, et al. (2009) Concatenated analysis sheds light on early metazoan evolution and fuels a modern ‘‘Urmetazoon’’ hypothesis. PLoS Biol 7(1): e1000020. Diploblasts Protosomes evolved laterally Deuterostomes & The evolutionary distances from the common ancestor to Arthropods Chordates Diploblasts Additional evolutionary time of Arthropods We aim to understand the functions of nuclear receptors in the evolutionary time point that constituted the basis of evolution of Deuterostomes and which may be conserved in diploblastic species. It is likely that cells in cancers acquire archetypal cellular behavior. We need to understand this cellular behavior. Protostomes Diploblasts We aim to identify and characterize mechanisms involving NRs in Diploblasts and search for analogous mechanisms in mammalian cells. Deuterostomes Our strategy:
