Vědy o živé přírodě

In recent years, the advent of long-read sequencing technology, particularly nanopore sequencing, has unlocked new horizons in the exploration of genomic and transcriptomic landscapes. Unlike short-read sequencing, long-read sequencing can span entire transcripts or large genomic regions in a single read, providing a comprehensive view of structural variants and splice variants which are often elusive in short-read data. The ability to sequence whole transcripts is pivotal for understanding complex genomic rearrangements and transcript isoforms, which are crucial for deciphering the underlying mechanisms of various diseases and biological processes.

However, despite the potential of long-read nanopore sequencing, the lack of specialized bioinformatics tools to accurately analyze this kind of data has been a significant bottleneck. Existing tools primarily tailored for short-read sequencing often fall short when applied to long-read data due to the inherent differences in error profiles and read lengths. This gap underscores the urgent need for the development and optimization of dedicated bioinformatics tools and methods capable of effectively analyzing long-read sequencing data to detect structural variants, estimate splice variants, and explore other genomic and transcriptomic phenomena.

This Ph.D. project is at the helm of addressing this need by engaging in the development and refinement of bioinformatics tools meticulously crafted for long-read sequencing analysis, leveraging the nanopore sequencing technology. The candidate will collaborate closely with the genomics core facility and RNA biology research groups at CEITEC to spearhead novel methodologies for mining long-read and direct RNA sequencing data. The primary objective is to establish a robust analytical framework that can accurately detect structural variants and splice variants, thereby maximizing the wealth of information that can be extracted from long-read sequencing data.

The envisioned outcome of this endeavor is a suite of bioinformatics tools capable of delving into the rich data generated by nanopore sequencing, leading to a first-author publication. Through this initiative, the candidate is set to make substantial contributions to the field, enabling a deeper understanding of genomic and transcriptomic complexities which are integral for advancing research in health and disease paradigms. The project is a stepping stone towards harnessing the full potential of long-read sequencing technology in genomic and transcriptomic research, and lays the groundwork for future explorations in this domain.

Background in 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:

https://ls-phd.ceitec.cz/how-to-aplly/

https://www.ceitec.eu/bioinformatics-core-facility/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.

Ribosome-associated quality control (RQC) is crucial for degrading truncated nascent proteins produced on aberrant mRNAs. Mutations in RQC components cause neurodegeneration both in animal models and human patients. Moreover, RQC insufficiency and subsequent protein aggregation critically contribute to proteostasis impairment and systemic decline during ageing. The successful candidate will utilize a multidisciplinary approach to provide detailed mechanistic understanding of the critical human RQC system in combination with an in vivo study to reveal processes leading to RQC-driven pathological changes in neural tissue. He/she will utilize human cell cultures, protein expression and purification techniques and biochemistry methods to produce samples for cryogenic electron microscopy (cryo-EM). Comprehensive training in cryo-EM will be available to the successful candidate. The candidate will also have a unique opportunity to acquire expertise in the use of C. elegans as a model organism during a research stay at a collaborating laboratory in Bolzano (Italy).

The ideal candidate should have background in either molecular biology, biochemistry or structural biology. Experience with human cell culture work or protein biochemistry is a plus.

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/petr-tesina-research-group/rg396/tab?tabId=180

Poznámky

Recommended literature:

Tesina, P., et al., Molecular basis of eIF5A-dependent CAT tailing in eukaryotic ribosome-associated quality control. Mol Cell, 2023. 83(4): p. 607-621 e4.

Lu, B., Translational regulation by ribosome-associated quality control in neurodegenerative disease, cancer, and viral infection. Front Cell Dev Biol, 2022. 10: p. 970654.

Filbeck, S., et al., Ribosome-associated quality-control mechanisms from bacteria to humans. Mol Cell, 2022. 82(8): p. 1451-1466.

Udagawa, T., et al., Failure to Degrade CAT-Tailed Proteins Disrupts Neuronal Morphogenesis and Cell Survival. Cell Rep, 2021. 34(1): p. 108599.

Aviner, R., et al., Ribotoxic collisions on CAG expansions disrupt proteostasis and stress responses in Huntington’s Disease. bioRxiv, 2022: p. 2022.05.04.490528.

Školitel

RNDr. Petr Těšina, Ph.D.

This PhD theme focuses on unraveling the intricate process of Argonaute protein loading by small RNAs, a critical step in gene regulation within RNA-silencing pathways, which are pivotal in both healthy and diseased states of animals and plants. Despite over two decades of research into the microRNA pathway and RNA interference, the precise mechanisms of miRNA strand selection and transfer to Argonaute proteins remain elusive. We propose the existence of two distinct mammalian Argonaute loading pathways, orchestrated by Dicer and heat shock protein chaperones, which both involve charged intrinsically disordered regions that have been overlooked in previous structural studies. The PhD project aims to dissect these mechanisms using electron cryomicroscopy (cryoEM). The objective is to elucidate the structures of critical complexes involving heat shock protein chaperone/co-chaperone-Argonaute-RNA and Dicer-Argonaute-RNA assemblies. By integrating cryoEM with functional analyses, the project aspires to establish the mechanistic principles of Argonaute loading. The findings of this PhD project will be instrumental in advancing RNA-based therapeutic applications and understanding one of the most crucial regulatory cellular processes.

A scientific background with an emphasis on molecular biology, genomics or proteomics is required. Additionally, a basic understanding of bioinformatics and advanced expertise in this field is advantageous, although not a mandatory requirement.

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:

https://ls-phd.ceitec.cz/how-to-aplly/

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

Poznámky

Recommended literature:

Dicer structure and function: conserved and evolving features. Zapletal D, Kubicek, K, Svoboda P, Stefl R EMBO Reports (2023) 24:e57215 doi:10.15252/embr.202357215

MicroRNAs in action: biogenesis, function and regulation. Shang R, Lee S, Senavirathne G, Lai EC. Nat Rev Genet. 2023 doi:10.1038/s41576-023-00611-y

Školitel

prof. Mgr. Richard Štefl, Ph.D.

In our lab we are interested in the study of plant hormonal signaling pathways, particularly cytokinins (CKs) in the development of model plant Arabidopsis thaliana, for more details see here. Multistep phosphorelay (MSP) represents one of the backbone signaling pathways in plants. MSP was originally described as a pathway mediating signaling of plant hormones cytokinins. However, ours as well as well as others’ results suggest integration of multiple signaling types, particularly light and ethylene into MSP pathway (1-4). Integration of multiple signals into single signaling pathway can be one of the strategy enabling plants respond and adapt to a highly changing environment conditions. Recently, ethylene was shown to control MSP signaling via histidine kinase (HK) activity of the ethylene receptor ETR1 (1). Although ETR1 is an active HK, its C-terminal receiver domain is unable to participate in MSP signaling. Instead, ETR1 interacts with another HK to transfer the phosphate to the downstream members of the MSP signaling pathway (Szmitkowska et al., manuscript in preparation). The main goal of the project is to investigate the structural and functional aspects of intermolecular interaction involved in the control of MSP signaling via ethylene and/or other signaling types and elucidate the importance of this integration in the regulation of plant development and adaptive responses. In the work, we will combine leading-edge approaches of structural, molecular and synthetic biology, genetics, genomics, biochemistry, plant phenotyping and molecular plant physiology.

We offer - Experimental work on own project with the possibility of publication in top-ranked international journals, Friendly lab staff, world-class equipment, attractive environment of novel university campus, help with both intellectual and practical problems, Competitive salary corresponding to the work efficiency We expect - Excellent Master degree in Chemistry, Biochemistry, Molecular Biology, or related fields; own publication record is advantageous, High motivation to perform creative basic research, Candidates should be team players, have good communication skills and good knowledge of the English language

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/funkcni-genomika-a-proteomika-rostlin/rg46

Poznámky

Recommended literature:

Zdarska, M., et al. (2019). Mol Plant 12, 1338-1352.

Dobisova, T., et al. (2017). Plant Physiol 174, 387-404.

Zdarska, M., et al. (2015). Journal of Experimental Botany 66, 4913-4931.

Skalak, J., et al. (2021). Front Plant Sci 12, 644823.

Školitel

doc. RNDr. Jan Hejátko, 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.

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.cz/dedicne-poruchy-transkripcni-regulace/rg38

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.

Gametes are key determinants of reproductive success, and their responses to adverse climatic events are particularly relevant for developing heat-resilient plants. Many studies describe the impact of heat stress on pollen development, leading to the production of pollen grain, carrier of the male gametes. Very little is known of the effects of heat on ovules, the female gametophyte. Seed production relies on a successful double fertilization of the egg cell and the central cell by the two sperm cells. In the ovule, a third type of cells, the synergids, attracts the pollen tube to the egg cell for an effective fertilization. The PhD candidate will investigate the effect of heat stress on pollen tube attraction and fertilization of the ovule at molecular and physiological levels, using genetics, microscopy, transcriptomics, and molecular biology approaches.

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

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:

https://ls-phd.ceitec.cz/how-to-aplly/

https://boisivonlab.ceitec.cz/main-introduction/

Poznámky

Recommended literature:

Mácová, K. et al. Long–Term High–Temperature Stress Impacts on Embryo and Seed Development in Brassica napus. Front Plant Sci 13, 844292 (2022)

Hafidh, S. & Honys, D. Reproduction Multitasking: The Male Gametophyte. Annu Rev Plant Biol 72, 1–34 (2021)

Völz, R., Harris, W., Hirt, H. & Lee, Y.–H. ROS homeostasis mediated by MPK4 and SUMM2 determines synergid cell death. Nat Commun 13, 1746 (2022)

Školitel

Helene Robert Boisivon, Ph.D.

Plant sexual reproduction is a complex and coordinated developmental process crucial especially for agricultural production. The PhD project will investigate the role of short cis-regulatory elements (CREs) within promoter regions, and their associated proteins, in the regulation of plant gametophyte development. Specifically, we will investigate the distribution and epigenetic changes of the motif telo-box, whose sequence is identical to the (TTTAGGG)n repeat previously identified in plant telomeres (physical ends of linear chromosomes). Telo-box belongs among CREs with a non-random distribution within genome or even promoters. This research will shed light on the role of telo-boxes and other associated CREs in gene regulation during male gametophyte development and their involvement in epigenetic control in plants. Our research will provide insights into the evolution of these CREs not only in model plants, as in most primitive land plants (Bryophytes) and seed plants like Arabidopsis, but also in crop plants. We are looking for highly motivated graduates to join the Laboratory of Functional Genomics and Proteomics (FGP). The laboratory is well equipped by instrumentation for molecular biology and biochemistry. The research group will benefit from close collaboration with internal or the international partnerships (EMBL Heidelberg, GE; ITQB, Lisabon, PT). Expected Start Date: 1st September 2024.

A scientific background with an emphasis on molecular biology, genomics or proteomics is required. Additionally, a basic understanding of bioinformatics and advanced expertise in this field is advantageous, although not a mandatory requirement.

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:

https://ls-phd.ceitec.cz/how-to-aplly/

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

Poznámky

Recommended literature:

Lukáš Nevosád, Božena Klodová, David Honys, Radka Svobodová, Tomáš Raček, Petra Procházková Schrumpfová (2023) GOLEM: distribution of Gene regulatOry eLEMents within the plant promoters, arXiv Cornell university, doi: 2310.15206

Alžbeta Kusová, Lenka Steinbachová, Tereza Přerovská, Lenka Záveská Drábková, Jan Paleček, Ahamed Khan, Gabriela Rigóová, Zuzana Gadiou, Claire Jourdain, Tino Stricker, Daniel Schubert, David Honys, and Petra Procházková Schrumpfová (2023). Completing the TRB family: newly characterized members show ancient evolutionary origins and distinct localization, yet similar interactions. Plant Mol. Biol. 112, 61–83. doi: 10.1007/s11103-023-01348-2

Eva Dvořák Tomaštíková, Fen Yang, Kristína Mlynárová, Said Hafidh, Šárka Schořová, Alžbeta Kusová, Markéta Pernisová, Tereza Přerovská, Božena Klodová, David Honys, Jiří Fajkus, Ales Pecinka, Petra Procházková Schrumpfová (2023) RUVBL proteins are involved in plant gametophyte development. The Plant Journal. 144, 2. doi.org/10.1111/tpj.16136

Božena Klodová, David Potěšil, Lenka Steinbachová, Christos Michailidis, Ann-Cathrin Lindner, Dieter Hackenberg, Jörg D. Becker, Zbyněk Zdráhal, David Twell, and David Honys. (2023) Regulatory dynamics of gene expression in the developing male gametophyte of Arabidopsis. Plant reproduction. 36(3): 213–241. doi: 10.1007/s00497-022-00452-5

Školitel

Mgr. Petra Procházková Schrumpfová, Ph.D.

Membranes are the site of many processes in living organisms. Various aspects, including nanotoxicology, cell cytotoxicity, liposomes, extracellular vesicles (EVs) and nanomaterials will be studied, mainly using various microscopic and spectroscopic techniques, such as optical, fluorescence, AFM and Raman. The research should include characterisation of the synthetic bilayer, such as phase transitions and lipid domain formation, and further comparison with membrane studies in living cells. Changes in membrane properties under different physiological conditions will be studied. Fast processes can be observed using video rate AFM. This method should be carried out by the student in the laboratory with the newly installed instrument. In addition, the effects of nanomaterial exposure on cell membranes will be studied using the above methods; changes in membrane morphology, roughness and mechanical properties in the presence of nanomaterials may clarify the correlation of nanotoxicity with structural changes. The work should also include the characterisation of nanoparticles whose shell is a phospholipid bilayer, i.e. a synthetic membrane. Such particles are liposomes and extracellular particles. As part of his/her activities, the student should also participate in the activities of the core facility, but the focus of his/her activities will be his/her own scientific activity leading to a first author publication within the first 3 years of study.

In particular, the candidate should have an overview of the subject, a background in biochemistry or biology or related subjects, and above all a willingness to learn new things.

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 MUNI CEITEC PhD School (link below).

MORE INFORMATION:

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

https://www.ceitec.cz/centralni-laborator-nanobiotechnologie/cf104/tab?tabId=159

Poznámky

Recommended literature:

1. Shaw, James E., Raquel F. Epand, Richard M. Epand, Zaiguo Li, Robert Bittman, and Christopher M. Yip. “Correlated Fluorescence-Atomic Force Microscopy of Membrane Domains: Structure of Fluorescence Probes Determines Lipid Localization.” Biophysical Journal 90, no. 6 (March 15, 2006): 2170–78. https://doi.org/10.1529/biophysj.105.073510.

2. Sadžak, Anja, Zlatko Brkljača, Mihael Eraković, Manfred Kriechbaum, Nadica Maltar-Strmečki, Jan Přibyl, and Suzana Šegota. “Puncturing Lipid Membranes: Onset of Pore Formation and the Role of Hydrogen Bonding in the Presence of Flavonoids.” Journal of Lipid Research 64, no. 10 (October 1, 2023). https://doi.org/10.1016/j.jlr.2023.100430.

3. Gyeong Lee, Hyo, Seokbeom Roh, Hyun Jung Kim, Seokho Kim, Yoochan Hong, Gyudo Lee, and Ok Hee Jeon. “Nanoscale Biophysical Properties of Small Extracellular Vesicles from Senescent Cells Using Atomic Force Microscopy, Surface Potential Microscopy, and Raman Spectroscopy.” Nanoscale Horizons 7, no. 12 (2022): 1488–1500. https://doi.org/10.1039/D2NH00220E.

4. Rikkert, L. G., P. Beekman, J. Caro, F. A. W. Coumans, A. Enciso-Martinez, G. Jenster, S. Le Gac, et al. “Cancer-ID: Toward Identification of Cancer by Tumor-Derived Extracellular Vesicles in Blood.” Frontiers in Oncology 10 (2020).

5. LeClaire, Michael, James Gimzewski, and Shivani Sharma. “A Review of the Biomechanical Properties of Single Extracellular Vesicles.” Nano Select 2, no. 1 (2021): 1–15. https://doi.org/10.1002/nano.202000129.

Školitel

Mgr. Jan Přibyl, 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

prof. MUDr. Mgr. Marek Mráz, Ph.D.

Antimicrobial peptides (AMPs) possess the ability to disrupt the membrane barrier function, effectively eliminating bacteria, viruses, and even cancer cells. Consequently, AMPs have emerged as promising candidates for the development of a new class of therapeutics. However, the majority of known AMPs exhibit toxic properties due to their origin from human-unfriendly sources, such as venoms. Our understanding of peptide targeting mechanisms towards specific pathogens and their membranes remains limited, hindering further peptide development. This ERC funded project aims to identify peptide sequence motifs that are responsible for selective targeting pathogens with respect to human cells. Apart from the differences in lipid composition of membranes, we will investigate the impact of membrane local curvature. The main tool for the study will be Molecular dynamics simulations with free energy calculations using Gromacs program package. These simulations will be complemented by in-house experiments providing crucial verification and feedback on peptide-membrane affinity. The acquired knowledge will guide the design of de novo peptides with enhanced pathogen-targeting specificity.

Outstanding candidates with experience in computer simulations and with an MSc/PhD degree in the fields of biophysics, soft matter physics, physical chemistry, computational chemistry, statistical mechanics, or related fields. Experience with molecular dynamics simulations (with GROMACS, CHARMM, NAMD, AMBER, LAMMPS, etc.) or other simulation techniques (Monte Carlo, DPD, etc.) at the atomistic or coarse-grained level would be an advantage.

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://vacha.ceitec.cz/

Poznámky

Recommended literature:

J Cell Biol. 2018; 217(9): 3109–3126, doi: 10.1083/jcb.201802027

Colloids Surf B Biointerfaces 2017; 153:152-159, doi: 10.1016/j.colsurfb.2017.02.003

Školitel

prof. RNDr. Robert Vácha, PhD.

Cells employ protein liquid droplets to form dynamic clusters, which function as nanoreactors or storages with the increased local concentration of specific protein components. These membrane-less organelles self-assemble based on weak protein-protein interactions of intrinsically disordered domains. However, the role of specific sequences remains elusive and the mixing between different protein droplets unexplored. This project is focused on the droplets involved in genome transcription, where posttranslational modifications control the droplet composition and regulate the transcription. Expected findings are not only important for the general knowledge but could also be useful in the design of new treatments because translocation malfunction is involved in numerous diseases including cancer. The research is strongly coupled to collaborations with excellent experimental teams and will be more closely discussed during the interview. The employed tools will contain multi-scale simulations using a wide range of advanced sampling techniques and development of protein parametrization.

Outstanding candidates with experience in computer simulations and with an MSc/PhD degree in the fields of biophysics, soft matter physics, physical chemistry, computational chemistry, statistical mechanics, or related fields. Experience with molecular dynamics simulations (with GROMACS, CHARMM, NAMD, AMBER, LAMMPS, etc.) or other simulation techniques (Monte Carlo, DPD, etc.) at the atomistic or coarse-grained level would be an advantage.

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:

https://ls-phd.ceitec.cz/how-to-aplly/

https://vacha.ceitec.cz/

Poznámky

Recommended literature:

Biochemistry 2022, 61, 2456–2460, doi: 10.1021/acs.biochem.2c00220

Nucleus 2023, 14:1, 2213551, doi: 10.1080/19491034.2023.2213551

PLoS Comput Biol 2023, 19(7): e1011321. doi: 10.1371/journal.pcbi.1011321

Science 2018, 361, 6, 6400, doi: 10.1126/science.aar2555

Školitel

prof. RNDr. Robert Vácha, PhD.

The topic of this proposal is to investigate the role of cytoplasmic RNA condensates (P-bodies and stress granules) in plant adaptation to abiotic stress, including heat stress and salt stress. P-bodies and stress granules (SG) are known to play a crucial role in RNA storage, translation, and decay, and their structure and behavior dynamically respond to both developmental and environmental stimuli. However, we still have a limited understanding of how these biomolecular condensates contribute to the regulation of plant growth and stress responses. In this project, the candidate will utilize genetics, genomics, and cell biology approaches to explore the regulation of SG and P-bodies by stress response kinases in model plants like Arabidopsis thaliana, as well as in rice and barley.

Solid theoretical background in genetics, molecular biology and cell biology. Practical experience in plant biology, bioinformatics or microscopy is a bonus, but not essential. Motivation and drive are must.

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:

https://ls-phd.ceitec.cz/how-to-aplly/

https://riha.ceitec.cz/

Poznámky

Recommended literature:

DOI: 10.1104/pp.17.01468

DOI: https://doi.org/10.1038/nrm.2017.7

Školitel

Mgr. Karel Říha, Ph.D.

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.

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 or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

https://ls-phd.ceitec.cz/how-to-aplly/

https://www.ceitec.eu/rna-quality-control/rg55

Poznámky

Recommended literature:

Zigáčková, D., Vaňáčová, Š. 2018 The role of 3 end uridylation in RNA metabolism and cellular physiology. Phil. Trans. R. Soc. B 373 20180171; DOI: 10.1098/rstb.2018.0171

Ustianenko, D; Pasulka J; Feketova, Z; Bednarik, L; Zigackova, D.; Fortova, A; Zavolan, M; Vanacova, S. 2016 TUT-DIS3L2 is a mammalian surveillance pathway for aberrant structured noncoding RNAs. EMBO Journal, 35:2179-2191. doi: 10.15252/embj.201694857

Hrossova, D., Sikorsky T., Potesil D., Bartosovic M., Pasulka J., Zdrahal Z., Stefl R., Vanacova S. 2015 RBM7 subunit of the NEXT complex binds U-rich sequences and targets 3-end extended forms of snRNAs. Nucleic Acids Res. 43:4236-48

Ustianenko D., Hrossova D., Potesil D., Chalupnikova K., Hrazdilova K., Pachernik J., Cetkovska K., Uldrijan S., Zdrahal Z., Vanacova S. 2013 Mammalian DIS3L2 exoribonuclease targets the uridylated precursors of let-7 miRNAs. RNA 9:1632-8.

Školitel

prof. Mgr. Štěpánka Vaňáčová, Ph.D.

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 internal RNA modifications of coding and noncoding RNAs in human cancer, particularly in colon cancer. 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.

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 or/and fill in the registration form on the web page of the CEITEC PhD School (link below).

MORE INFORMATION:

https://ls-phd.ceitec.cz/how-to-aplly/

https://www.ceitec.eu/rna-quality-control/rg55

Poznámky

Recommended literature:

Covelo-Molares, H., Bartosovic, M., Vanacova S. 2018 RNA methylation in nuclear pre-mRNA processing, WIRES RNA, DOI: 10.1002/wrna.1489

Rengaraj P., Obrdlík A., Vukić D., Varadarajan N.M., Keegan L.P., Vaňáčová S., O’Connell M.O. Interplays of different types of epitranscriptomic mRNA modifications. RNA Biology. https://doi.org/10.1080/15476286.2021.1969113

Rajecka, V., Skalicky, T., Vanacova, S. 2019. The role of RNA adenosine demethylases in the control of gene expression. Biochim Biophys Acta Gene Regul Mech. 1862:343-355. DOI: 10.1016/j.bbagrm.2018.12.001.

Covelo-Molares H., Obrdlik A., Postulkova I., Rengaraj P., Dohnalkova M., Gregorova P., Ganji R., Potesil D., Gawriyski L., Varjosalo M., Vanacova S. 2021 The comprehensive interactomes of human adenosine RNA methyltransferases and demethylases reveal distinct functional and regulatory features, Nucleic Acids Res.:gkab900. doi: 10.1093/nar/gkab900

Bartosovic, M; Covelo Molares, H; Gregorova, P; Hrossova, D; Kudla, G; Vanacova S. 2017 N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3-end processing. Nucleic Acids Res, 45: 11356–11370. doi: 10.1093/nar/gkx778

Školitel

prof. Mgr. Štěpánka Vaňáčová, Ph.D.

Proteins are produced by ribosome-catalyzed translation of mRNAs in all domains of life. Translation is also critical in the context of human host-pathogen interaction where the ribosome, as the central molecular machine for genetic information expression, is the subject to numerous regulatory and quality control events and pathological interventions. The strategies adopted by viruses to reprogram translation and co-translational quality control machinery to promote infection are poorly understood. Thus, there is an urgent need for further research in this area to develop effective strategies for combating viral infections. The successful candidate will study how viruses affect human translation and co-translational quality control with the aim of providing high-resolution structures of large macromolecular assemblies. He/she will utilize human cell cultures, protein expression and purification techniques and biochemistry methods to produce samples for cryogenic electron microscopy (cryo-EM). Comprehensive training in cryo-EM will be available to the successful candidate.

The ideal candidate should have background in either molecular biology, biochemistry or structural biology. Experience with human cell culture work or protein biochemistry is a plus.

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/petr-tesina-research-group/rg396/tab?tabId=180

Poznámky

Recommended literature:

Xu, Z., et al., SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation. Proc Natl Acad Sci U S A, 2022. 119(32): p. e2204539119.

Hsu, J.C., et al., Viperin triggers ribosome collision-dependent translation inhibition to restrict viral replication. Mol Cell, 2022. 82(9): p. 1631-1642 e6.

Thoms, M., et al., Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science, 2020. 369(6508): p. 1249-1255.

Lu, B., Translational regulation by ribosome-associated quality control in neurodegenerative disease, cancer, and viral infection. Front Cell Dev Biol, 2022. 10: p. 970654.

Školitel

RNDr. Petr Těšina, Ph.D.