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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.

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.

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.

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.