Vědy o živé přírodě

Telomerase, telomeric DNA, and their associated factors together represent a complex, finely tuned, and functionally conserved mechanism that ensures genome integrity by protecting and maintaining chromosome ends. Changes to any of these components can have serious consequences for the survival of the whole organism. Indeed, experimentally removing or altering these components typically leads to cell or organismal death. However, molecular innovation has occurred multiple times during eukaryote evolution, giving rise to e.g., species/taxa with unusual telomeric DNA sequences, telomerase components, or telomerase-independent telomere maintenance. Thanks to the massive expansion of new genome sequencing projects, available data, and our previous research, we have developed a combination of bioinformatic and experimental tools to identify eukaryotes in which telomeric novelty has arisen in response to challenges during telomere/telomerase evolution. The aim of the dissertation will be to explore the molecular nature of solving the end-protection and end-replication problems is such organisms.

MSc. in Biochemistry, Molecular biology, Bioinformatics or related disciplines

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://www.ceitec.eu/chromatin-molecular-complexes/rg51

Poznámky

Recommended literature:

Petr Fajkus, Vratislav Peška, Michal Závodník, Miloslava Fojtová, Jana Fulnečková, Šimon Dobias, Agata Kilar, Martina Dvořáčková, Dagmar Zachová, Ivona Nečasová, Jason Sims, Eva Sýkorová, Jiří Fajkus, Telomerase RNAs in land plants, Nucleic Acids Research, Volume 47, Issue 18, 10 October 2019, Pages 9842–9856, https://doi.org/10.1093/nar/gkz695

Petr Fajkus, Agata Kilar, Andrew D L Nelson, Marcela Holá, Vratislav Peška, Ivana Goffová, Miloslava Fojtová, Dagmar Zachová, Jana Fulnečková, Jiří Fajkus, Evolution of plant telomerase RNAs: farther to the past, deeper to the roots, Nucleic Acids Research, Volume 49, Issue 13, 21 July 2021, Pages 7680–7694, https://doi.org/10.1093/nar/gkab545

Petr Fajkus, Matej Adámik, Andrew D L Nelson, Agata M Kilar, Michal Franek, Michal Bubeník, Radmila Čapková Frydrychová, Alena Votavová, Eva Sýkorová, Jiří Fajkus, Vratislav Peška, Telomerase RNA in Hymenoptera (Insecta) switched to plant/ciliate-like biogenesis, Nucleic Acids Research, Volume 51, Issue 1, 11 January 2023, Pages 420–433, https://doi.org/10.1093/nar/gkac1202

Školitel

prof. RNDr. Jiří Fajkus, CSc.

The main neuropathological signs of Alzheimer’s disease are associated with the fibrillization of tau protein into neurofibrillary tangles. Studying how different factors influence the formation of protein fibrils is the key to understanding these neurodegenerative processes. The main aim of this PhD project will be computational simulations of conformational changes within the Tau protein and the fibrilization processes. The details of the conformation changes and the fibrilization induced by the phosphorylation, buffer conditions, truncation, or the interaction with the client proteins like 14-3-3s will be studied by molecular dynamics at the atomistic and the coarsegrained level. The obtained theoretical predictions will be validated with the experimental data provided by the biomolecular NMR and the biophysical methods. The described activities are part of international research projects allowing to spend the part of PhD study in the groups of our collaborators in Europe or North and South America and to learn specific research techniques, there.

preferable candidate’s background in biophysics, computational chemistry, or physical chemistry.

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://www.ceitec.eu/protein-structure-and-dynamics/rg110/tab?tabId=21

Poznámky

Recommended literature:

Trosanova Z., Lousa P., Kozelekova A., Brom T., Gasparik N., Tungli J., Weisova V., Zupa E., Zoldak G., Hritz J.*: Quantitation of human 14-3-3zéta dimerization and the effect of phosphorylation on dimer-monomer ekvilibria. J. Mol. Biol. 2022, 434, 167479

Zapletal, V.; Mládek, A.; Melková, K.; Louša, P.; Nomilner, E.; Jaseňáková, Z.; Kubáň, V.; Makovická, M.; Laníková, A.; Žídek L.; Hritz, J.* Choice of force field for proteins containing structured and intrinsically disordered regions. Biophys. J. 2020, 118, 1621 – 1633.

Pavlíková Přecechtělová J., Mládek A., Zapletal V., Hritz J. Quantum Chemical Calculations of NMR Chemical Shifts in Phosphorylated Intrinsically Disordered Proteins, JCTC 2019, 15, 5642-5658.

Jandova Z; Trosanova Z.; Weisova V.; Oostenbrink C., Hritz J.*: Free energy calculations on the stability of the 14-3-3zéta protein. BBA - Proteins and Proteomics, 2018, 1866, 442-450.

Nagy G., Oostenbrink C., Hritz J.*: Exploring the Binding Pathways of the 14-3-3zéta Protein: Structural and Free-Energy Profiles Revealed by Hamiltonian Replica Exchange Molecular Dynamics with Distance Field Distance Restraints. PLoS ONE 2017,12(7), e0180633.

Školitel

doc. RNDr. Mgr. Jozef Hritz, Ph.D.

Correlative Light Electron Microscopy (CLEM) uses a combination of an optical (fluorescence) microscope and a cryo-electron microscope. Two images of the sample are taken simultaneously – one with the optical light, the other with the electron beam. This technology allows to capture not only dynamic changes but also the molecular ultrastructure of living systems. New developments in accurate positional referencing of specimens on mounting grids, advances in the instrumentation, and the availability of software packages for cross-platform data correlation allow to image the ultrastructure of nucleolar sub-compartments and to track specific proteins found in phase-separated organelles.

In this project, we will implement the CLEM technology to investigate and visualize phase-separated organelles involved in transcription by RNA polymerase II and investigate their regulatory mechanism during transcription. This biophysically focused project will also involve other imaging approaches, including single-particle reconstruction cryo-electron microscopy and cryo-electron tomography, which will help to obtain an overall picture of condensate-based transcription at different resolutions. The project is linked to the CEITEC's teaming project CORMIC – bridging academia and industry in correlative microscopy.

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://stefl-lab.ceitec.cz/

Poznámky

Recommended literature:

Mediator and RNA polymerase II clusters associate in transcription-dependent condensates Won-Ki ChoJan-Hendrik SpilleMicca HechtChoongman LeeCharles LiValentin GrubeIbrahim I. Cisse Science, 361 (6400), DOI: 10.1126/science.aar4199.

Zhang et al Molecular Cell (2022), https://doi.org/10.1016/j.molcel.2022.06.032.

Nievergelt et al., COSB, 2019, https://doi.org/10.1016/j.sbi.2019.06.008.

Školitel

prof. Mgr. Richard Štefl, Ph.D.

Novel forms of nucleotides will be incorporated in silico in oligomers with sequences relevant for biosystems. The biocompatibility of artificial building blocks will be evaluated using advanced methods of quantum chemistry (that provide also analytical tools for investigation of crucial noncovalent interactions) and molecular dynamics. Available candidates of modified nucleobases and sugars will be investigated experimentally by using NMR spectroscopy in solution.

Computational and quantum chemistry, structural chemistry or biology.

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://www.ceitec.eu/structure-of-biosystems-and-molecular-materials/rg108/tab?tabId=22

Poznámky

Recommended literature:

CUYACOT, Ben J.R., Ivo DURNÍK, Cina FOROUTAN-NEJAD and Radek MAREK. Anatomy of Base Pairing in DNA by Interacting Quantum Atoms, Journal of Chemical Information and Modeling, 2021, 61, 211-222. doi:10.1021/acs.jcim.0c00642.

YURENKO, Yevgen, Jan NOVOTNÝ and Radek MAREK. Weak Supramolecular Interactions Governing Parallel and Antiparallel DNA Quadruplexes: Insights from LargeScale Quantum Mechanics Analysis of Experimentally Derived Models. Chemistry - A European Journal, 2017, 23, 5573-5584. doi:10.1002/chem.201700236.

DUREC, Matúš, Francesco ZACCARIA, Célia FONSECA GUERRA and Radek MAREK. Modified guanines as constituents of smart ligands for nucleic acid quadruplexes. Chemistry - A European Journal, 2016, 22, 10912-10922. doi:10.1002/chem.201601608.

BAZZI, Sophia, Jan NOVOTNÝ, Yevgen YURENKO and Radek MAREK. Designing a New Class of Bases for Nucleic Acid Quadruplexes and Quadruplex-Active Ligands. Chemistry - A European Journal, 2015, 21, 9414-9425. doi:10.1002/chem.201500743.

YURENKO, Yevgen, Jan NOVOTNÝ, Vladimír SKLENÁŘ and Radek MAREK. Substituting CF2 for O4' in Components of Nucleic Acids: Towards Systems with Reduced Propensity to Form Abasic Lesions. Chemistry - A European Journal, 2015, 21, 17933-17943. doi:10.1002/chem.201502977.

Školitel

prof. RNDr. Radek Marek, Ph.D.

Post-transcriptional RNA modification research, also known as epitranscriptomics, is a science field that recently became prominent during the covid pandemic for its role in immune response mediation. The role of epitranscriptomics in cancerogenesis is also very much studied.

In CEITEC MU, several research groups are trying to understand the biological role of RNA modifications.

An emerging method to study RNA modification is nanopore sequencing because the long-read sequencing can better capture the whole transcripts, but mainly because it allows direct RNA sequencing. However, novel algorithms and methods must be developed to utilize the potential of the method to its full potential. The Ph.D. candidate will collaborate with RNA biology research groups, a genomics core facility to establish methods for long-read sequences and eventually direct RNA sequencing data analysis. The Ph.D. candidate will, through bioinformatics support, facilitate the research of RNA modification concerning the immune response and cancer.

bioinformatics, informatics, data science

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://www.ceitec.cz/centralni-laborator-bioinformatika/cf284

Poznámky

Recommended literature:

Quin, Jaclyn, et al. "ADAR RNA modifications, the epitranscriptome and innate immunity." Trends in biochemical sciences 46.9 (2021): 758-771.

Furlan, Mattia, et al. "Computational methods for RNA modification detection from nanopore direct RNA sequencing data." RNA biology 18.sup1 (2021): 31-40.

Školitel

Mgr. Vojtěch Bystrý, Ph.D.

Dishevelled (DVL) is the central hub of Wnt signal transduction that integrates and transduces upstream signals through distinct cytoplasmic cascades. Looking at the many DVL faces reported in the literature, three salient features underlying its function in signalling can be highlighted: (1) it interacts with more than seventy binding partners, (2) it is heavily phosphorylated at multiple sites by at least eight different kinases, in particular by Ck1ε/δ after Wnt stimulation, and (3) it consistently forms puncta in the cytosol, that are phase-separated self-assemblies also called liquid droplets.

Our working hypothesis is that DVL conformational plasticity mediated by the order-disorder interactions allows the combinatorial integration of phosphorylation input, partners binding, self-assembly in droplets, and allosteric coupling, to exquisitely control signal routing. We integrate structural biology (NMR, SAXS, X-ray) and biophysical techniques (FRET, ITC, BLI) with cellular readouts (TopFlash, BRET) to understand DVL structure, function, and regulation. Candidates can choose among three open questions, that if resolved, will have a significant impact on Wnt research. 1) Does disorder provide new contexts to structured domain(s) and, hence, enhance the DVL functional space associated with them? 2) Is there a direction, order or hierarchy in the phosphorylation of individual S/T sites and clusters in DVL? 3) What are the physical behaviours associated with the intrinsic disorder and their connection to DVL liquid-liquid phase separation?

Requirements on candidates:

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor and phd@ceitec.muni.cz

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://www.ceitec.eu/protein-dna-interactions/rg111

Poznámky

Recommended literature:

Hanáková K. et al. Comparative phosphorylation map of Dishevelled 3 links phospho-signatures to biological outputs. Cell Commun. Signal., 2019. 17: p. 170

Harnoš J. et al. Dishevelled-3 conformation dynamics analyzed by FRET-based biosensors reveals a key role of casein kinase 1. Nat. Commun., 2019. 10: p. 1804.

Školitel

Konstantinos Tripsianes, Ph.D.

P-bodies are cytoplasmic condensates that are thought to play a role in regulation of translation and RNA decay. We discovered that P-bodies play an important role in meiotic progression in Arabidopsis. They dynamically alter their composition in the course of meiosis, which may contribute to differential regulation of gene expression. This project is focused on functional characterization of protein and RNA components of meiotic P-bodies obtained by genetic screening and affinity purification. Another approach will focus on morphological characterization of P-bodies using super-resolution and corelative light-electron microscopy.

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://riha.ceitec.cz/

Poznámky

Recommended literature:

https://doi.org/10.1126/science.abo0904

https://doi.org/10.1371/journal.pgen.1009779

https://doi.org/10.1016/j.semcdb.2022.11.008

https://doi.org/10.1104/pp.17.01468

Školitel

Mgr. Karel Říha, Ph.D.

CDK11 is ubiquitously expressed in all tissues and the CDK11 null mouse is lethal at an early stage of development indicating an important role for Cdk11 in the adult as well as during development. CDK11 is believed to play a role in RNAPII-directed transcription and co-transcriptional mRNA-processing, particularly alternative splicing and 3end processing. However, its genome-wide function in regulating the human transcriptome is unknown. Notably, several recent studies identified CDK11 as a candidate essential gene for growth of several cancers therefore, understanding the molecular mechanism(s) of CDK11-dependent gene expression would be also of significant clinical interest. In this research we will use various techniques of molecular biology and biochemistry to characterize genome-wide role of CDK11 in regulation of gene expression and tumorigenesis.

Background in molecular biology, biochemistry or life sciences. Interest in bioinformatics and data analyses is desirable.

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://www.ceitec.eu/inherited-diseases-transcriptional-regulation/rg38

Poznámky

Recommended literature:

Gajduskova, P., Ruiz de Los Mozos I, Rajecky M., Hluchy M., Ule J., Blazek D*: CDK11 is required for transcription of replication dependent histone genes. Nature Structural & Molecular Biology 27 (5):500-510 (2020).

Školitel

Mgr. Dalibor Blažek, Ph.D.

Cdk12 is transcriptional cyclin-dependent kinase (Cdk) found mutated in various cancers. In previous studies we found that Cdk12 maintains genome stability via optimal transcription of key homologous recombination repair pathway genes including BRCA1. Apart from the C-terminal domain of RNA Polymerase II other cellular substrates for both kinases are not known. In this research we propose using a screen in cells carrying an analog sensitive mutant of CDK12 to discover its novel cellular substrates. The substrates and their roles in normal and cancerous cells will be characterized by various techniques of molecular biology and biochemistry.

Background in molecular biology, biochemistry or life sciences. Interest in bioinformatics and data analyses is desirable.

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://www.ceitec.eu/microenvironment-of-immune-cells/rg115

Poznámky

Recommended literature:

Pilarova K, Herudek J, Blazek D.*: CDK12: Cellular functions and therapeutic potential of versatile player in cancer: Nucleic Acids Research Cancer (Oxford University Press) k2 (1): zcaa003 (2020).

Chirackal Manavalan A.P., Pilarova K., Kluge M., Bartholomeeusen K., Oppelt J., Khirsariya P., Paruch K., Krejci L., Friedel C.C., Blazek D* : CDK12 controls G1/S progression via regulating RNAPII processivity at core DNA replication genes. EMBO reports 20(9):47592 (2019).

Ekumi KM, Paculova H, Lenasi T, Pospichalova V, Bösken CA, Rybarikova J, Bryja V, Geyer M, Blazek D*, Barboric M*. Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex. Nucleic Acids Research 43(5):2575-89 (2015).

Bösken CA, Farnung L, Hintermair C, Merzel Schachter M, Vogel-Bachmayr K, Blazek D, Anand K, Fisher RP, Eick D, Geyer M. The structure and substrate specificity of human Cdk12/Cyclin K. Nature Communications 5 (2014).

Blazek D*., Kohoutek J., Bartholomeeusen K., Johansen E., Hulinkova P., Luo Z., Cimermancic P.,Ule J., Peterlin B.M.: The CycK/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes and Development 25 (20): 2158-2172 (2011).

Školitel

Mgr. Dalibor Blažek, Ph.D.

Transcript variants generated by alternative splicing (AS) of a precursor mRNA transcript expand the cellular protein catalog for the plant response to various stresses without the requirement of de novo transcription. AS is a molecular strategy taken by plants under temperature stress to limit the adverse effects of high temperatures and to adjust their growth and physiology during the stress period. Spliced variants may be targeted for degradation by non-sense mediated decay (NMD) or encode alternative proteins to feedback on the stress response. Heat Shock Proteins (HSP) and Heat Shock Factors (HSF) are among the targets of temperature-induced AS. Our lab investigates how high temperatures affect embryo morphogenesis and seed development. We identified that AS regulators are upregulated in seeds of plants grown at high temperatures. The project will investigate the implications of AS in the morphogenic alterations of Arabidopsis embryos when developing at high temperatures. The proposed experimental approaches include profiling of AS events in high-temperature seeds. Specific candidates whose transcripts are targeted by AS at high temperatures, and known for their involvement in embryo morphogenesis, will be functionally characterized: expression analysis (microscopy), phenotyping (genetics), ectopic expression (cloning, generation of transgenics), etc.

The candidate will have notions of bioinformatics. The candidate has experience in molecular biology (cloning, RT-qPCR), expression analysis (microscopy), and notions of plant genetics and epigenetics.

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://boisivonlab.ceitec.cz/

Poznámky

Recommended literature:

John, S., Olas, J. J. & Roeber, B. M. Regulation of alternative splicing in response to temperature variation in plants. J Exp Bot erab232 (2021) doi:10.1093/jxb/erab232.

Kulichová, K. et al. PRP8A and PRP8B spliceosome subunits act coordinately to control pollen tube attraction in Arabidopsis thaliana. Development (Cambridge, England) 147, dev186742 (2020).

Mácová, K. et al. Effects of long-term high-temperature stress on reproductive growth and seed development in development in Brassica napus. Biorxiv 2021.03.11.434971 (2021) doi:10.1101/2021.03.11.434971.

Robert, H. S. et al. Local auxin sources orient the apical-basal axis in Arabidopsis embryos. Current Biology 23, 2506–2512 (2013).

Školitel

Helene Robert Boisivon, Ph.D.

We are looking for a motivated PhD student that would like to work on the following project funded by the ERC (European Research Council) Starting grant. It has been shown that short non-coding RNAs significantly contribute the onset, progression, and therapy resistance in multiple B cell leukemias and lymphomas. We have recently described the role of miRNAs in microenvironmental interactions and aggressiveness of chronic lymphocytic leukemia and follicular lymphoma (Sharma et al…Mraz, Blood, 2021; Musilova et al…Mraz, Blood, 2018; Cerna et al…Mraz, Leukemia, 2019). However, the role of long non-coding RNAs in the pathogenesis of these diseases remains completely unknown.

In this project, the student will decipher how lncRNAs regulated BCR signaling and microenvironmental interactions in B cell malignancies. We are mainly interested in chronic lymphocytic leukaemia (CLL) and follicular lymphoma (FL). CLL is the most common leukemia in adults and FL is the most common indolent non-Hodgkin lymphoma. The clinical course of CLL/FL patients can be surprisingly variable (survival from months to decades), and both diseases still remain incurable. The course of the diseases is characterized by repeated relapses leading to the evolution of resistant disease or to the high-grade transformation to a more aggressive diffuse large B-cell lymphoma/Richter. This is associated with a poor prognosis and a high risk of early death. Number of studies showed that multiple genetic lesions are associated with CLL/FL aggressiveness or transformation; however, precise molecular mechanisms underlying these processes are largely unclear. The project aims to reveal the molecular mechanisms involving lncRNAs and/or miRNAs responsible for CLL/FL aggressiveness, especially activation of BCR signaling and B-T cell interactions. The primary samples will be analyzed on the level of protein-coding as well as non-coding genes (NGS with Illumina, preliminary data available). This will be followed by searching for the function of lncRNAs using CRISPR interference, mouse models, and molecular biology technics. This will help to better understand the disease biology and possibly to identify novel molecular targets that could be used therapeutically.

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://www.ceitec.eu/microenvironment-of-immune-cells/rg115

Poznámky

Recommended literature:

Sharma et al. …Mraz. miR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia by Targeting TRAF4: an Axis Affected by BCR inhibitors. Blood 2021. https://pubmed.ncbi.nlm.nih.gov/33171493/.

Musilova et al. …Mraz. miR-150 downregulation contributes to the high-grade transformation of follicular lymphoma by upregulating FOXP1 levels . BLOOD. 2018 NOV 29;132(22):2389-2400. https://pubmed.ncbi.nlm.nih.gov/33786575/.

Musilova K, Mraz M. MicroRNAs in B-cell lymphomas: how a complex biology gets more complex. Leukemia. 2015 May;29(5):1004-17.

Zeni and Mraz LncRNAs in adaptive immunity: role in physiological and pathological conditions. RNA Biol. 2021 May;18(5):619-632. https://pubmed.ncbi.nlm.nih.gov/33094664/

Školitel

doc. MUDr. Mgr. Marek Mráz, Ph.D.

Chronic lymphocytic leukemia (CLL) cells and indolent lymphomas are known to be dependent on diverse microenvironmental stimuli providing them signals for survival, development, proliferation, and therapy resistance. It is known that CLL cells undergo apoptosis after cultivation in vitro, and therefore it is necessary to use models of CLL microenvironment to culture CLL cells long-term and/or to study their proliferation. Several in vitro and in vivo models meet some of the characteristics of the natural microenvironment based on the coculture of malignant cells with T-lymphocytes or stromal cell lines as supportive cell, but they also have specific limitations.

The aim of this research is to develop and use models mimicking lymphoid microenvironment to study mechanisms leading to aggressiveness in B cell malignancies and/or novel therapeutic options, e.g. drugs targeting CLL proliferation, development of resistance in long-term culture or combinatory approaches, which cannot be analyzed in experiments based on the conventional culture of CLL/lymphoma primary cells. This project will utilize models developed in the laboratory and will further optimize and modify them. The biology of CLL and responses to targeted treatment will be interrogated using the developed models. The student will utilize various functional assays, Cripr editing, RNA sequencing, genome editing, drug screening etc., with the use of primary patient’s samples and cell lines. The research might bring new insights into the microenvironmental dependencies and development of resistance to targeted therapy

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://www.ceitec.eu/microenvironment-of-immune-cells/rg115

Poznámky

Recommended literature:

Hoferkova E, Kadakova S, Mraz M. In Vitro and In Vivo Models of CLL-T Cell Interactions: Implications for Drug tetsing.Cancers (Basel). 2022 Jun 23;14(13):3087.

Sharma et al. …Mraz. miR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia by Targeting TRAF4: an Axis Affected by BCR inhibitors. Blood 2021. https://pubmed.ncbi.nlm.nih.gov/33171493/

Seda V. et al….Mraz. FoxO1-GAB1 Axis Regulates Homing Capacity and Tonic AKT Activity in Chronic Lymphocytic Leukemia. Blood, 2021, https://doi.org/10.1182/blood.2020008101.

Kipps et al. Chronic lymphocytic leukaemia. Nat Rev 2017 https://pubmed.ncbi.nlm.nih.gov/28102226/.

Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol. 2015 Mar;94(3):193-205. doi: 10.1111/ejh.12427. Epub 2014 Sep 13. PMID: 25080849 Review.

Školitel

doc. MUDr. Mgr. Marek Mráz, Ph.D.

In 2017, the World Health Organization declared Staphylococcus aureus to be an antibiotic-resistant pathogen for which new therapeutics are urgently needed. Upon infection, S. aureus forms biofilms that can only be treated by the long-term application of several antibiotics in high doses or the surgical removal of the infected tissues. An alternative approach, phage therapy, has not been approved for clinical use, because the effects of phage infection on a biofilm are not sufficiently characterized. The student will study the dynamics of the propagation of a phage in a S. aureus biofilm and molecular details of its replication in a cell. He/she will determine how sub-populations of metabolically dormant or phage-resistant cells in a biofilm provide herd immunity against phage infection. In addition, he/she will use focused ion beam milling together with cryo-electron microscopy and tomography to determine high-resolution structures of previously uncharacterized phage replication and assembly intermediates in S. aureus cells.

Ideal candidate should have background in one of the following: molecular biology, biochemistry, physical chemistry, structural biology or informatics.

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://plevkalab.ceitec.cz/

Poznámky

Recommended literature:

Rigort et al., Focused ion beam micromachining of eukaryotic cells for cryoelectron tomography. Proc Natl Acad Sci U S A 109, 4449-4454 (2012).

N. Cerca, R. Oliveira, J. Azeredo, Susceptibility of Staphylococcus epidermidis planktonic cells and biofilms to the lytic action of staphylococcus bacteriophage K. Lett Appl Microbiol 45, 313-317 (2007)

M. Jemielita, M. J. Taormina, A. Delaurier, C. B. Kimmel, R. Parthasarathy, Comparing phototoxicity during the development of a zebrafish craniofacial bone using confocal and light sheet fluorescence microscopy techniques. J Biophotonics 6, 920-928 (2013).

J. Girstmair et al., Light-sheet microscopy for everyone? Experience of building an OpenSPIM to study flatworm development. BMC Dev Biol 16, 22 (2016).

E. J. Novacek et al., Structure and genome release of Twort-like Myoviridae phage with a double-layered baseplate. Proc Natl Acad Sci U S A 113, 9351-9356 (2016).

Školitel

doc. Mgr. Pavel Plevka, Ph.D.

Dicer is an RNA-cutting enzyme, which is essential for regulation of gene activities in cells. The way Dicer cuts and trims RNA and how this affects gene silencing and antiviral immunity in lower organisms is well known. It combines two enzymatic activities, the helicase activity that is responsible for feeding RNA and the nuclease activity that is responsible for cutting it. The first function, feeding RNA into the enzyme, has altered during evolution despite conservation of the helicase catalytic center, with far-reaching consequences, such as the loss of Dicer’s antiviral properties. Our preliminary structural and functional work suggested that during evolution of vertebrates, the helicase domain of Dicer became locked in a specific position in which Dicer favours processing microRNAs and is unable to cleave viral RNA. In this project, we will find a strategy how to unlock the helicase domain to re-activate the ancestral antiviral activity of Dicer. This project will provide previously unexploited opportunities for design of a new defence mechanism against RNA viruses in humans.

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://stefl-lab.ceitec.cz/

Poznámky

Recommended literature:

Yamaguchi, S., Naganuma, M., Nishizawa, T. et al. Structure of the Dicer-2–R2D2 heterodimer bound to a small RNA duplex. Nature 607, 393–398 (2022). https://doi.org/10.1038/s41586-022-04790-2.

Su, S., Wang, J., Deng, T. et al. Structural insights into dsRNA processing by DrosophilaDicer-2–Loqs-PD. Nature 607, 399–406 (2022). https://doi.org/10.1038/s41586-022-04911-x.

Školitel

prof. Mgr. Richard Štefl, Ph.D.

Diseases caused by enteroviruses include upper and lower respiratory tract infections, gastroenteritis, hand-foot-and-mouth-disease, and life-threatening meningoencephalitis. Rhinoviruses are responsible for 40% of common cold cases, which result in a yearly cost of tens of billions of US$ in treatments and lost working hours worldwide. The student will study the replication cycle of enteroviruses in situ by a combination of focused ion beam milling (FIBM) and cryo-electron tomography (cryoET). He/she will investigate the changes in intra-cellular organization induced by enterovirus infection, and the assembly of progeny virions. To facilitate the structural studies he/she will utilize patterned grids for electron microscopy to enable the automation of the FIBM of lamellas from tissue culture cells and the preparation of columnal sample geometry to increase the completeness of recordable cryo-ET data beyond the limit imposed by commonly used slab-shaped samples.

Ideal candidate should have background in one of the following: molecular biology, biochemistry, physical chemistry, structural biology or informatics.

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://plevkalab.ceitec.cz/

Poznámky

Recommended literature:

Palmenberg AC, et al. (2009) Sequencing and analyses of all known human rhinovirus genomes reveal structure and evolution. Science 324(5923):55-59.

Fendrick AM, Monto AS, Nightengale B, & Sarnes M (2003) The economic burden of non-influenza- related viral respiratory tract infection in the United States. Archives of internal medicine 163(4):487-494.

C. Tuthill TJ, Groppelli E, Hogle JM, & Rowlands DJ (2010) Picornaviruses. Curr Top Microbiol Immunol 343:43-89.

Schaffer M, et al. (2017) Optimized cryo-focused ion beam sample preparation aimed at in situ.

Structural studies of membrane proteins. J Struct Biol 197(2):73-82.

Ren J, et al. (2013) Picornavirus uncoating intermediate captured in atomic detail. Nature communications 4:1929.

Školitel

doc. Mgr. Pavel Plevka, Ph.D.

The project is focused on detailed structural characterization of short purine oligonucleotides clipped by proper sequential motifs that induce parallel orientation of DNA strands. For this purpose, NMR experiments combined with MD simulations will be employed. The effect of modifications of selected nucleotides on the structural properties of designed models will be investigated to gain deeper understanding of key interactions that contribute to the folding of such systems.

Structural chemistry or biology, advanced NMR spectroscopy, computational chemistry.

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://www.ceitec.eu/structure-of-biosystems-and-molecular-materials/rg108/tab?tabId=22

Poznámky

Recommended literature:

Aleš NOVOTNÝ, Jan NOVOTNÝ, Iva KEJNOVSKÁ, Michaela VORLÍČKOVÁ, Radovan FIALA and Radek MAREK. Revealing structural peculiarities of homopurine GA repetition stuck by i-motif clip. Nucleic Acids Research, 2021, 49, 11425. doi:10.1093/nar/gkab915.

Školitel

prof. RNDr. Radek Marek, Ph.D.

The main neuropathological signs of Alzheimer’s disease are associated with the fibrillization of tau protein into neurofibrillary tangles. Studying how different factors influence the formation of protein fibrils is the key to understanding these neurodegenerative processes. The main aim of this PhD project will be the characterization of conformational changes in the formation of tau fibrils due to their truncations, phosphorylation, and interaction with 14-3-3 proteins. An interdisciplinary approach combining biomolecular NMR, biophysical interaction techniques, and computational methods will be applied. The described activities are part of international research projects allowing us to spend part of PhD study in the groups of our collaborators in Europe or North and South America and to learn specific research techniques, there.

preferable candidate’s background in biophysics, biochemistry, structural or molecular biology.

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://www.ceitec.eu/protein-structure-and-dynamics/rg110/tab?tabId=21

Poznámky

Recommended literature:

Trosanova Z., Lousa P., Kozelekova A., Brom T., Gasparik N., Tungli J., Weisova V., Zupa E., Zoldak G., Hritz J.*: Quantitation of human 14-3-3zéta dimerization and the effect of phosphorylation on dimer-monomer ekvilibria. J. Mol. Biol. 2022, 434, 167479

Kitoka K., Skrabana R., Gašparik N., Hritz J., Jaudzems K. NMR Studies of Tau Protein in Tauopathies. Front. Mol. Biosci. 2021, 8:761227.

Zapletal, V.; Mládek, A.; Melková, K.; Louša, P.; Nomilner, E.; Jaseňáková, Z.; Kubáň, V.; Makovická, M.; Laníková, A.; Žídek L.; Hritz, J.* Choice of force field for proteins containing structured and intrinsically disordered regions. Biophys. J. 2020, 118, 1621 – 1633.

Louša, P.; Nedozrálová, H.; Župa, E.; Nováček, J.; Hritz, J.*: Phosphorylation of the regulatory domain of human tyrosine hydroxylase 1 monitored using nonuniformly sampled NMR. Biophys. Chem. 2017, 223, 25-29.

Jansen S., Melková K., Trošanová Z., Hanáková K., Zachrdla M., Nováček J., Župa E., Zdráhal Z., Hritz J.*, Žídek L.*: Quantitative Mapping of MAP2c Phosphorylation and 14-3-3zéta Binding Sites Reveals Key Differences Between MAP2c and Tau. J. Biol. Chem. 2017, 292, 6715-6727.

Školitel

doc. RNDr. Mgr. Jozef Hritz, Ph.D.

Our recent results identified telomerase RNAs in land plants, and then also from other taxa from Diaphoretickes phylogenetic megagroup. Surprisingly, we found the same type of telomerase RNA also in Hymenoptera and Lepidoptera insects, although a different type of telomerase RNA has been presumed across the whole Animalia kingdom. Although the identification of the RNA component of telomerase was an important breakthrough towards the understanding of telomerase function and regulation in the extended repertoire of organisms, it requires a complementary knowledge of the other components of the telomerase ribonucleoprotein particle. Recent results indicate that telomerase RNA interactors in plants are far from being identical with those of human, where the situation is best known. Therefore, the main aim of the dissertation will be to identify protein components of the plant telomerase RNP, their interacting sites and their impact on telomerase activity or non-telomeric functions.

MSc. in Biochemistry, Molecular biology, Bioinformatics or related disciplines

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://www.ceitec.eu/chromatin-molecular-complexes/rg51

Poznámky

Recommended literature:

Petr Fajkus, Vratislav Peška, Michal Závodník, Miloslava Fojtová, Jana Fulnečková, Šimon Dobias, Agata Kilar, Martina Dvořáčková, Dagmar Zachová, Ivona Nečasová, Jason Sims, Eva Sýkorová, Jiří Fajkus, Telomerase RNAs in land plants, Nucleic Acids Research, Volume 47, Issue 18, 10 October 2019, Pages 9842–9856, https://doi.org/10.1093/nar/gkz695

Petr Fajkus, Agata Kilar, Andrew D L Nelson, Marcela Holá, Vratislav Peška, Ivana Goffová, Miloslava Fojtová, Dagmar Zachová, Jana Fulnečková, Jiří Fajkus, Evolution of plant telomerase RNAs: farther to the past, deeper to the roots, Nucleic Acids Research, Volume 49, Issue 13, 21 July 2021, Pages 7680–7694, https://doi.org/10.1093/nar/gkab545

Petr Fajkus, Matej Adámik, Andrew D L Nelson, Agata M Kilar, Michal Franek, Michal Bubeník, Radmila Čapková Frydrychová, Alena Votavová, Eva Sýkorová, Jiří Fajkus, Vratislav Peška, Telomerase RNA in Hymenoptera (Insecta) switched to plant/ciliate-like biogenesis, Nucleic Acids Research, Volume 51, Issue 1, 11 January 2023, Pages 420–433, https://doi.org/10.1093/nar/gkac1202

Školitel

prof. RNDr. Jiří Fajkus, CSc.

Posttranscriptional RNA modifications possess key roles in diverse pathways in humans, including development, disease and infections. This PhD project will focus on the machines and role of terminal modifications of coding and noncoding RNAs. They can affect mRNA metabolism and protein synthesis by direct mRNA modifications or via tailing of regulatory noncoding RNAs (ncRNAs). The topic is a follow up of our studies of RNA processing and surveillance mechanisms in human cells mediated by terminal uridylyltransferases (TUTases) and terminal nucleotide transferases (TENTS). You will address the question of regulators of this pathway and its impact in viral infections.

The student will master diverse methodologies, such as human cell culture manipulations (cultivation, RNAi, CRISPR/Cas9, etc.), recombinant DNA preparation, protein expression and purification, high-throughput analyses and enzymatic assays.

She/he will have the opportunity to present the results at prestigious international conferences. Moreover, this project will involve collaboration with other leading researches in European institutes.

Requirements on candidates:

The specification of the candidate's expected background in a case of importance Prospective student should ideally have done master degree in molecular biology/biochemistry and have a laboratory experience in nucleic acids and/or protein purification and analyses. Experience with coding in R and statistics is a big plus. The most highly valued feature however is excitement and curiosity for science and strong drive in tackling important biological questions.

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact the supervisor and phd@ceitec.muni.cz

MORE INFORMATION:

http://ls-phd.ceitec.cz/

https://www.ceitec.eu/rna-quality-control/rg55/tab?tabId=5

Školitel

prof. Mgr. Štěpánka Vaňáčová, Ph.D.