PhD Programme

Supervisor

Meritxell Alberich Jordà

Project description

Hematopoietic stem and progenitor cells (HSPCs) are a rare population of cells in the bone marrow responsible for the production of mature blood cells through life of an individual. Preserving the HSPCs and their function is critical for hematopoiesis, since alterations in this population are linked to the development of leukemia and bone marrow failure. We recently published that chronic inflammation affects HSPCs, mostly depriving them from their essential characteristics. In this project, we will explore the regulatory mechanisms that protect and maintain HSPCs, determine how they are altered under inflammatory conditions, and investigate how to reverse the negative effects. We will employ in vitro cell cultures, murine models, and -omic screenings to address these questions.

Candidate profile

The laboratory of hemato-oncology is searching for a highly motivated, enthusiastic and hard-working Ph.D. student. The candidate should hold a master degree in genetics, molecular biology, cell biology, or in a related field. Bioinformatic skills or basic knowledge of large dataset analysis will be positively evaluated. The candidate should be willing to work with murine models. Excellent English is required. The candidate should be a team-player and willing to work with other lab members and international collaborators.

We offer a friendly and supporting environment in a state-of-the-art institution.

Suggested reading

• Grusanovic S, Danek P, Kuzmina M, Adamcova MK, Burocziova M, Mikyskova R, Vanickova K, Kosanovic S, Pokorna J, Reinis M, Brdicka T, Alberich-Jorda M: Chronic inflammation decreases HSC fitness by activating the druggable Jak/Stat3 signaling pathway. EMBO Rep 2022, e54729. [pubmed] [doi]
• Burocziova M, Grusanovic S, Vanickova K, Kosanovic S, Alberich-Jorda M: Chronic Inflammation Promotes Cancer Progression as a Second hit. Exp Hematol 2023. [pubmed] [doi]
• Vanickova K, Milosevic M, Ribeiro Bas I, Burocziova M, Yokota A, Danek P, Grusanovic S, Chiliński M, Plewczynski D, Rohlena J, Hirai H, Rohlenova K, Alberich-Jorda M: Hematopoietic stem cells undergo a lymphoid to myeloid switch in early stages of emergency granulopoiesis. EMBO J 2023, e113527. [pubmed] [doi]
• Pavliuchenko N, Kuzmina M, Danek P, Spoutil F, Prochazka J, Skopcova T, Pokorna J, Sedlacek R, Jorda MA, Brdicka T: Genetic background affects neutrophil activity and determines the severity of autoinflammatory osteomyelitis in mice. J Leukoc Biol 2024. [pubmed] [doi]

Supervisor

Lukáš Čermák

Project description

This project aims to investigate the pivotal role of the proteasome in the regulation of apoptosis within cancer cells. The proteasome, a cellular complex responsible for protein degradation, is known to play a crucial role in maintaining cellular homeostasis. However, its specific involvement in modulating apoptosis in cancer cells remains understudied. Through a series of experiments utilizing cancer cell lines and proteasome inhibitors, we intend to unravel the intricate mechanisms by which the proteasome influences apoptotic pathways. By identifying key protein targets and understanding the interplay between the proteasome and apoptosis regulators, we hope to shed light on potential therapeutic strategies for manipulating apoptosis in cancer cells. This research not only contributes to our fundamental understanding of cell biology but also holds promise for the development of targeted therapies that exploit the proteasome’s control over apoptosis in the context of cancer treatment.

Candidate profile

We invite enthusiastic and goal-oriented students with a keen interest in molecular biology and basic understanding of biochemical methods to join this research project. A comprehensive understanding of fundamental molecular biology techniques will be highly beneficial in unraveling the intricacies of proteasome-mediated control of apoptosis in cancer cells.

Suggested reading

• Shanshan Duan 1, Lukas Cermak, Julia K Pagan, Mario Rossi, Cinzia Martinengo, Paola Francia di Celle, Bjoern Chapuy, Margaret Shipp, Roberto Chiarle, Michele Pagano: FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas. Nature 2012 481(7379): 90–93. [pubmed] [doi]
• Dibus N, Korinek V, Cermak L: FBXO38 Ubiquitin Ligase Controls Centromere Integrity via ZXDA/B Stability. Front Cell Dev Biol 2022 10: 929288. [pubmed] [doi]
• Dibus N, Zobalova E, Monleon MAM, Korinek V, Filipp D, Petrusova J, Sedlacek R, Kasparek P, Cermak L: FBXO38 Ubiquitin Ligase Controls Sertoli Cell Maturation. Front Cell Dev Biol 2022 10: 914053. [pubmed] [doi]

Supervisor

Martina Huranová

Project description

Primary cilia are thin structures present in most mammalian cells, involved in regulation of multiple developmental signaling pathways. Monitoring signaling pathways and their responses in vivo presents challenges due to the complexity of pathways and the need for highly sensitive and specific reporter tools.  

Within this project we will focus on establishing novel methodologies for studying cilia associated signalling in organogenesis, with potential applications in drug discovery and disease modelling. The applicant will developing methods to monitor the activity of ciliary signaling pathways, such as Sonic Hedgehog and Wnt. These tools will be employed to study the signalling dynamics in cell cultures and organoid models using advanced live-cell imaging techniques. We will employ transcriptomic and proteomic analyses in healthy and ciliopathy conditions to uncover the regulatory mechanisms governed by cilia-mediated signalling. Finally, we will investigate the potential of these tools in screening biological agents to identify compounds that modulate cilia-associated signaling in pathological conditions where ciliary function is impaired, such as ciliopathies or cancer.

Candidate profile

We are looking for an ethusiastic, curious and fearlessstudent with experience in cell biology, molecular biology, biochemistry or a related field who is motivated to work on a project with biological and medicinal relevance.

We offer a friendly and supporting environment, and excellent infrastructures at the Institute of Molecular Genetics. We are a young research group, where the students learn to lead a scientific project and accomplish the PhD studies within four to five years. We encourage the candidates to contact the supervisor directly (martina.huranova@img.cas.cz).

Suggested reading

• Niederlova V, Modrak M, Tsyklauri O, Huranova M, Stepanek O: Meta-analysis of genotype-phenotype associations in Bardet-Biedl syndrome uncovers differences among causative genes. Hum Mutat 2019 40(11): 2068-2087. [pubmed] [doi] [dataBBaSe]
• Prasai A, Schmidt Cernohorska M, Ruppova K, Niederlova V, Andelova M, Draber P, Stepanek O, Huranova M: The BBSome assembly is spatially controlled by BBS1 and BBS4 in human cells. J Biol Chem 2020 295(42): 14279-14290. [pubmed] [doi]
• Tsyklauri O, Niederlova V, Forsythe E, Prasai A, Drobek A, Kasparek P, Sparks K, Trachtulec Z, Prochazka J, Sedlacek R, Beales P, Huranova M, Stepanek O: Bardet-Biedl Syndrome ciliopathy is linked to altered hematopoiesis and dysregulated self-tolerance. EMBO Rep 2021, e50785. [pubmed] [doi]
• Prasai A, Ivashchenko O, Maskova K, Bykova S, Schmidt Cernohorska M, Stepanek O, Huranova M: BBSome-deficient cells activate intraciliary CDC42 to trigger actin-dependent ciliary ectocytosis. EMBO Rep 2024. [pubmed] [doi]

Supervisor

Lucie Janečková

Project description

The intestinal epithelium is a dynamic tissue that provides a protective barrier while supporting nutrient absorption and immune defense of the gut. Stem cells in the crypts renew the epithelium and maintain the intestinal homeostasis, while its dysregulation underlies diseases such as inflammatory bowel disease and colorectal cancer. Intestinal mesenchymal cells play a crucial role in orchestrating these processes by regulating epithelial cell behavior through paracrine signaling, extracellular matrix production, and mechanical interactions. Despite their importance, the mechanisms by which mesenchymal cells influence epithelial cells during intestinal regeneration and in pathological conditions remain poorly understood. Using genetic mouse models, co-culture of intestinal organoids with mesenchymal cells, and methods analyzing gene expression (single cell or bulk RNA sequencing, gene set enrichment analysis), we aim to characterize the role of mesenchymal cells in promoting epithelial renewal in the healthy intestine and their contribution to pathological processes such as tumorigenesis and chronic inflammation. This project offers a unique opportunity to unravel the complex cellular interrelationships in the gut and their implications for health and disease.

Candidate profile

We are seeking a highly motivated and enthusiastic candidate with the following qualifications:

• Master’s degree in biological or biomedical sciences, solid background in cell biology and molecular biology.
• A strong interest in biomedical research, particularly in the areas of tissue regeneration, inflammation, and cancer biology.
• Experience with experimental techniques such as cell culture, microscopy, or molecular biology methods is desirable.

Suggested reading

• Brügger MD, Valenta T, Fazilaty H, Hausmann G, Basler K: Distinct populations of crypt-associated fibroblasts act as signaling hubs to control colon homeostasis. PLoS Biol. 2020 18(12):e3001032. [pubmed] [doi]
• Kim JE, Fei L, Yin WC, Coquenlorge S, Rao-Bhatia A, Zhang X, Shi SSW, Lee JH, Hahn NA, Rizvi W, Kim KH, Sung HK, Hui CC, Guo G, Kim TH: Single cell and genetic analyses reveal conserved populations and signaling mechanisms of gastrointestinal stromal niches. Nat Commun. 2020 11(1):334. [doi]

Supervisor

Libor Macůrek

Project description

Genome instability is one of the main features of cancer cells. DNA repair and the cell cycle arrest are protective mechanisms that prevent development of the genome instability. The tumor suppressor p53 plays a central role in regulating these events, and its loss leads to tumor development. Function of p53 is controlled by other proteins, including the phosphatase PPM1D. We have recently described oncogenic potential of the C-terminal truncating mutations of PPM1D (1-3). The observed gain-of-function phenotype depends on abnormally increased stability of the truncated PPM1D protein (4). This PhD project aims to identify the molecular mechanism of PPM1D degradation underlying its rapid turnover in normal conditions. We will also address how PPM1D associates with the chromatin which is another crucial determinant of its function (5-7). Besides the classical molecular/cell biology and biochemistry, we will investigate these processes using targeted genome editing by CRISPR/Cas9, analysis of protein complexes by mass spectrometry, evaluation of DNA damage in cell nuclei by high content quantitative microscopy, and identification of the sub-nuclear localization by super-resolution microscopy. Suitable candidates should have an interest in the basic molecular mechanisms occurring in human cells. This project will improve our understanding of the mechanisms leading to cellular transformation by inhibition of p53. In addition, reactivation of p53 function by forced degradation of PPM1D may be a potential strategy for treatment of various cancers.

Suggested reading

• Stoyanov M, Martinikova AS, Matejkova K, Horackova K, Zemankova P, Burdova K, Zemanova Z, Kleiblova P, Kleibl Z, Macurek L: PPM1D activity promotes cellular transformation by preventing senescence and cell death. Oncogene 2024. [pubmed] [doi]
• Martinikova AS, Stoyanov M, Oravetzova A, Kok YP, Yu S, Dobrovolna J, Janscak P, van Vugt M, Macurek L: PPM1D activity promotes the replication stress caused by cyclin E1 overexpression. Mol Oncol 2024 18(1): 6-20. [pubmed] [doi]
• Burocziova M, Danek P, Oravetzova A, Chalupova Z, Alberich-Jorda M, Macurek L: Ppm1d truncating mutations promote the development of genotoxic stress-induced AML. Leukemia 2023. [pubmed] [doi]
• Kleiblova P, Shaltiel IA, Benada J, Ševčík J, Pecháčková S, Pohlreich P, Voest EE, Dundr P, Bartek J, Kleibl Z, Medema RH, Macurek L: Gain-of-function mutations of PPM1D/Wip1 impair the p53-dependent G1 checkpoint. J Cell Biol 2013 201(4): 511-21. [pubmed] [doi]
• Macůrek L, Lindqvist A, Voets O, Kool J, Vos HR, Medema RH: Wip1 phosphatase is associated with chromatin and dephosphorylates gammaH2AX to promote checkpoint inhibition. Oncogene 2010 29(15): 2281-91. [pubmed] [doi]
• Storchova R, Palek M, Palkova N, Veverka P, Brom T, Hofr C, Macurek L: Phosphorylation of TRF2 promotes its interaction with TIN2 and regulates DNA damage response at telomeres. Nucleic Acids Res 2023. [pubmed] [doi]
• Jaiswal H, Benada J, Müllers E, Akopyan K, Burdova K, Koolmeister T, Helleday T, Medema RH, Macurek L, Lindqvist A: ATM/Wip1 activities at chromatin control Plk1 re-activation to determine G2 checkpoint duration. EMBO J 2017 36(14): 2161-2176. [pubmed] [doi]

Supervisor

Zuzana Sumbalová Koledová

Project description

Lactation is a critical physiological process requiring precise coordination of cellular functions, including DNA replication, transcription, and the DNA damage response, to support milk production. This PhD project aims to unravel the molecular mechanisms underlying these processes in lactating mammary epithelial cells. Using a cutting-edge lactation organoid model developed in our laboratory, combined with in vivo mouse models, the student will explore how DNA replication and transcription and DNA damage response regulate differentiation of luminal cells to milk-secreting alveolar cells. Advanced imaging techniques, transcriptomics, and molecular biology tools will be employed to investigate these pathways in detail. The findings will provide new insights into the fundamental biology of lactation and may identify novel targets for addressing lactation-related disorders, contributing to improved maternal and neonatal health.

Candidate profile

• Strong interest in developmental, cell or cancer biology,
• Master’s degree in biological sciences,
• Highly motivated and independent with excellent communication skills,
• Excellent organizational skills and the ability to maintain meticulous records, with ability to plan and prioritize own work in order to meet deadlines,
• Ability to work collaboratively in a multidisciplinary research environment,
• Strong written and verbal communication skills for data presentation and manuscript preparation,
• Committed to personal development and updating of knowledge and skills,
• Hands-on experience in work with genetic mouse models, organoids, live cell imaging, 3D immunofluorescence will be viewed positively.
• Prior experience with DNA damage or mammary gland research will be considered an advantage.

Suggested reading

• Sumbal J, Chiche A, Charifou E, Koledova Z, Li H: Primary mammary organoid model of lactation and involution. Front Cell Dev Biol. 2020; 8: 68. [doi]
• Molinuevo R, Menendez J, Cadle K et al. Physiological DNA damage promotes functional endoreplication of mammary gland alveolar cells during lactation. Nat Commun. 2024; 15: 3288. [doi]
• Rios A, Fu N, Jamieson P et al. Essential role for a novel population of binucleated mammary epithelial cells in lactation. Nat Commun. 2016; 7: 11400. [doi]

Supervisor

Zuzana Sumbalová Koledová

Project description

This project focuses on the development of innovative human mammary organoids as an advanced in vitro model to investigate breast morphogenesis, a fundamental process in mammary gland development and a critical factor in breast cancer progression. The aims are to optimize protocols for generating human mammary organoids that faithfully recapitulate key aspects of mammary gland morphogenesis, including branching morphogenesis, epithelial differentiation, and hormonal responsiveness. Using advanced imaging methodologies such as confocal microscopy and live-cell imaging, the structural organization and dynamic behavior of these organoids will be characterized in unprecedented detail. Molecular profiling techniques, including transcriptomics and proteomics, will provide insights into the regulatory networks and signaling pathways governing mammary organoid development.

By integrating these approaches, the study seeks to address critical gaps in our understanding of the molecular mechanisms underlying breast development and disease. The resulting human mammary organoids will serve as a robust platform for studying breast cancer initiation and progression, offering a more physiologically relevant alternative to traditional models. Ultimately, this work has the potential to drive the development of more effective therapeutic strategies for breast cancer, a disease that remains a leading cause of morbidity and mortality worldwide.

Candidate profile

• Strong interest in developmental biology, mammary gland biology, or cancer research,
• Master’s degree in biological sciences, biotechnology, or a related field,
• Highly motivated, independent thinker with a strong commitment to scientific Discovery,
• Excellent organizational skills and meticulous attention to detail, with the ability to maintain thorough experimental records,
• Strong proficiency in cell culture techniques, preferably with experience in 3D culture systems or organoids,
• Experience with advanced imaging methodologies, such as confocal microscopy or live-cell imaging, is highly desirable,
• Familiarity with molecular profiling techniques, including transcriptomics or proteomics, will be viewed positively,
• Ability to work collaboratively in a multidisciplinary research environment,
• Strong written and verbal communication skills for data presentation and manuscript preparation,
• Commitment to personal and professional development, with a proactive approach to learning new techniques,
• Prior experience with mammary gland research will be considered an advantage.

Suggested reading

• Sumbal J, Sumbalova Koledova Z. Fibroblast-epithelium co-culture methods using epithelial organoids and cell line-derived spheroids. In: Sumbalova Koledova Z (eds) 3D Cell Culture. Methods in Molecular Biology 2024, vol. 2764, Humana, New York, pp.107 – 129. [doi]
• Sumbal J, Fre S, Sumbalova Koledova Z: Fibroblast-induced mammary epithelial branching depends on fibroblast contractility. PLoS Bio. 2024; 22(1):e3002093. [doi]
• Sumbal J, Gudjonsson T, Traustadottir GA, Koledova Z: An organotypic assay to study epithelial-fibroblast interactions in human breast. In: Vivanco, M.d. (eds) Mammary Stem Cells. Methods in Molecular Biology 2022, vol. 2471, Humana, New York, pp. 283 – 299. [doi]
• Sumbal J, Chiche A, Charifou E, Koledova Z, Li H: Primary mammary organoid model of lactation and involution. Front Cell Dev Biol. 2020; 8: 68. [doi]

Supervisor

Petr Svoboda

Project description

Small RNAs serve as sequence-specific guides in numerous RNA silencing pathways. Evolution of these pathways took different trajectories during animal evolution. For example, mammals extensively utilize the microRNA pathway in almost all cells to regulate genes and the piRNA pathway in the germline for repression of mobile elements and occasional gene control. This PhD project will capitalize on previous research of the group and investigate specific instances in animals, where the molecular machinery of RNA silencing acquired unique adaptations to support specific functions of RNA silencing. Of particular focus will be adaptations associated with miRNA pathway function and their defects in cancer and other pathologies. This position is funded by Project OP JAK – RNA for therapy, registration number: CZ.02.01.01/00/22_008/0004575

Candidate profile

• M.Sc. or equivalent in molecular biology or related field obtained before July 2025
• Curiosity and Endurance
• Solid knowledge of molecular and cell biology
• At least some elementary experience with molecular biology (level PCR and miniprep)
• Advantage if having experience with recombinant proteins and mammalian cell culture

Suggested reading

• Martin Jinek and Jennifer A. Doudna: A three-dimensional view of the molecular machinery of RNA interference. Nature 2009 457: 405-412. [doi]
• Ketting RF. The many faces of RNAi. Dev Cell. 2011 Feb 15;20(2):148-61. [pubmed] [doi]
• Zapletal D, Kubicek K, Svoboda P, Stefl R: Dicer structure and function: conserved and evolving features. EMBO Rep 2023 24(7): e57215. [pubmed] [doi]

Supervisor

Petr Svoboda

Project description

The aim of this project is to characterize the piRNA pathway and its biological role in a molluscan laboratory model, the snail of the genus Deroceras. Both, cross-fertilization and self-fertilization occur in the snail species Deroceras laeve. The type of fertilization is determined by the penis presence. Thus, within a species, aphalic forms evolve as clonal populations approaching a near inbred state, which likely limits the expansion of mobile elements. In contrast, euphalic forms exchange genetic information and allow the expansion of mobile elements in the genome. The main mechanism controlling mobile elements in the genome is the piRNA pathway. This project will identify the active mobile elements in the slug genome, determine how the mode of reproduction affects the expansion of these mobile elements in the genomes of the aphalic and euphalic forms, and how it that impacts the piRNA mechanism recognizing and silencing these mobile elements.

Candidate profile

• M.Sc. or equivalent in molecular biology or related field obtained before July 2025
• Curiosity and Endurance
• Solid knowledge of molecular and cell biology
• At least some elementary experience with molecular biology (level PCR and miniprep)
• Advantage if having experience with field work

Suggested reading

• Fejes Tóth K, Pezic D, Stuwe E, Webster A: The piRNA Pathway Guards the Germline Genome Against Transposable Elements. Adv Exp Med Biol. 2016 886:51–77. [doi]

Supervisor

Ondřej Štěpánek

Project description

The project will investigate the role of SRC-family kinases LCK and FYN in the T-cell antigen receptor signaling, which is crucial for proper T-cell development and immune response. It is known for decades that LCK, and to lesser extent FYN, catalyze the first biochemical step in TCR signaling, i.e., tyrosine phosphorylation of activation motifs in the TCR/CD3 complex. However, the role of these kinases in particular biological context is still incompletely understood. This project is a follow-up to our previous studies (Stepanek et al. 2014, Cell Horkova et al. 2020 Cell Reports, Horkova et al. 2023 Nature Immunology) and focuses mostly on the role LCK and FYN in the peripheral responses and in particular cells types. We have generated a genetically modified mouse model that enables cell specific and/or time-induced deletion of LCK. We will use this novel model together with other established models (whole-body LCK, FYN knock-outs, LCK knock-in mouse unable to bind to CD4 and CD8 co-receptors, TCR transgenic mice) to address:

1. The role of LCK and FYN in the differentiation of helper CD4 T cells into particular subtypes during infection.
2. The role of LCK and FYN in the function of regulatory T cells in autoimmunity and cancer.

Join a thriving, internationally recognized research group focusing on cutting-edge immunological studies.

Candidate profile

• A Master’s degree (or expected graduation by October 2025) in biology, immunology, medicine, or a related field.
• Exceptional problem-solving and critical thinking skills.
• Strong motivation, dedication to scientific research, and eagerness to learn and master new techniques.
• Proficiency in English (both written and verbal communication).
• Integrity, responsibility, and a team-oriented mindset.

Suggested reading

• Ondrej Stepanek, Arvind S Prabhakar, Celine Osswald, Carolyn G King, Anna Bulek, Dieter Naeher, Marina Beaufils-Hugot, Michael L Abanto, Virginie Galati, Barbara Hausmann, Rosemarie Lang, David K Cole, Eric S Huseby, Andrew K Sewell, Arup K Chakraborty, Ed Palmer: Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance. Cell 2014 159(2): 333-45. [pubmed] [doi]
• Horkova V, Drobek A, Paprckova D, Niederlova V, Prasai A, Uleri V, Glatzova D, Kraller M, Cesnekova M, Janusova S, Salyova E, Tsyklauri O, Kadlecek TA, Krizova K, Platzer R, Schober K, Busch DH, Weiss A, Huppa JB, Stepanek O: Unique roles of co-receptor-bound LCK in helper and cytotoxic T cells. Nat Immunol 2023 24(1): 174-185. [pubmed] [doi]
• Horkova V, Drobek A, Mueller D, Gubser C, Niederlova V, Wyss L, King CG, Zehn D, Stepanek O: Dynamics of the Coreceptor-LCK Interactions during T Cell Development Shape the Self-Reactivity of Peripheral CD4 and CD8 T Cells. Cell Rep 2020 30(5): 1504-1514.e7. [pubmed] [doi]