Ústav molekulární genetiky AV ČR, v. v. i.
In our research group, we investigate the regulation of haematopoietic stem cell (HSC) maintenance and fate by transcription factors and their target genes, determine whether these elements are altered in human leukaemias (in particular acute myeloid leukaemia, AML), and elucidate their contribution to leukaemogenesis…
Supervisor
Meritxell Alberich Jordà
Project description
Hematopoietic stem and progenitor cells (HSPCs) are responsible for lifelong maintenance of the blood system, yet their function progressively declines with age. Chronic inflammation, a hallmark of aging, represents a major and persistent stressor that reshapes HSPC transcriptional and metabolic programs. Rather than promoting adaptive immune responses, long-term inflammatory signaling drives cumulative damage, leading to loss of stem cell fitness, skewed differentiation, and reduced regenerative capacity.
Emerging evidence, including our recent work, indicates that chronic inflammatory exposure accelerates aging-associated deterioration of HSPCs and promotes the emergence of pre-leukemic states. This project aims to identify the molecular mechanisms that normally protect HSPCs from sustained inflammatory stress and to determine how these safeguarding programs fail during aging and chronic inflammation. A central objective is to define transcriptional and metabolic alterations that predispose HSPCs to clonal expansion and malignant transformation under chronic inflammation.
Using in vitro systems and murine models of aging and chronic inflammation, we will perform integrated transcriptomic and metabolic analyses to dissect these processes. In addition, we will explore strategies to restore HSPC function by targeting inflammation-induced vulnerabilities. This work will provide mechanistic insight into how aging-associated inflammation contributes to hematopoietic decline and pre-leukemic evolution, with potential relevance for early intervention strategies.
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.
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Supervisor
Meritxell Alberich Jordà
Project description
Hematopoietic stem and progenitor cells (HSPCs) constitute a rare yet indispensable population within the bone marrow that sustains lifelong blood cell production. Preservation of their integrity and functional capacity is essential for normal hematopoiesis, as perturbations in this compartment can result in bone marrow failure syndromes and leukemic transformation.
Recent work from our group has revealed that acute infections are sensed not only by mature immune cells but also directly by HSPCs, positioning these cells as active participants in early immune responses. Building on these findings, this project aims to elucidate how HSPCs contribute to infection control while simultaneously undergoing transcriptional and metabolic adaptations that safeguard their long-term functionality.
To address these questions, we will combine in vitro culture systems with in vivo murine models of infection, complemented by transcriptomic and metabolic profiling approaches. This integrative strategy will allow us to dissect the molecular mechanisms that enable HSPCs to balance immune responsiveness with self-preservation. Ultimately, this work will provide fundamental insights into HSPC biology under inflammatory stress and may reveal mechanisms relevant to infection-driven hematopoietic dysfunction and leukemogenesis.
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.
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We mainly focus on cytoskeletal linker proteins, in particular plectin, and we study the functional consequences of cytoskeletal organization in cell/tissue mechanics and mechanotransduction, i.e., conversion of physical cues into intracellular mechanosignalling pathways….
Supervisor
Martin Gregor
Project description
Plectin is a key cytoskeletal crosslinker required for mechanical stability and signaling in skeletal muscle and heart. Mutations in the plectin isoform P1f cause limb-girdle muscular dystrophy accompanied by progressive cardiomyopathy. Due to the large size of full-length plectin, classical gene-replacement strategies are not feasible, necessitating alternative therapeutic approaches.
This PhD project focuses on the development and functional characterization of mini-plectins engineered plectin variants retaining essential functional domains while being compatible with AAV-mediated gene delivery. The main objective is to evaluate their capacity to restore cytoskeletal organization and function in muscle and cardiac cells.
In the in vitro part, the student will analyze expression, localization, and functional integration of miniplectins in cultured cardiomyocytes. Using advanced fluorescence microscopy and biochemical approaches, the project will assess the ability of mini-plectins to reconstitute cytoskeletal networks, cell–cell junctions, and mechanosensitive signaling pathways impaired by P1f deficiency.
In the in vivo part, the therapeutic potential of mini-plectins will be tested in a newly established P1f knockout mouse model that recapitulates key features of human disease. AAV-mediated delivery will be evaluated for its ability to rescue pathological alterations in skeletal muscle and heart using histological, immunofluorescence, and functional readouts. The project will be conducted in close collaboration with international experts in gene therapy and muscle pathology.
This project combines mechanistic cell biology with translational gene-therapy approaches and aims to provide proof-of-concept data for mini-plectin–based therapies for plectin-related muscle and cardiac disease.
Candidate profile
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Supervisor
Martin Gregor
Project description
Hepatocellular carcinoma (HCC) is an aggressive liver malignancy with limited therapeutic options. Tumor progression critically depends on cytoskeletal organization and mechanotransduction, processes in which the cytolinker protein plectin plays a central role. Plectin integrates intermediate filaments, actin filaments, and microtubules and has emerged as a promising therapeutic target in HCC.
This PhD project aims to elucidate the molecular and cellular mechanisms of plectin inhibition using plecstatin, a first-in-class high-affinity plectin inhibitor. The project combines structural characterization with functional analyses in clinically relevant human tumor models.
In the first part, the student will define the plecstatin binding site on the plectin molecule. This will involve in vitro expression and purification of selected plectin domains and engineered variants, followed by biophysical and structural analyses. Hydrogen-deuterium exchange mass spectrometry will be used to identify plecstatin-induced conformational changes and interaction interfaces. Selected plectin–plecstatin complexes will be further analyzed by cryo-electron microscopy to resolve the structural basis of inhibitor binding and its impact on plectin function.
In the second part, the student will investigate plecstatin’s mode of action in patient-derived HCC explants maintained ex vivo to preserve native tumor architecture. Using advanced microscopy approaches, the project will assess plecstatin-induced changes in cytoskeletal organization, cell mechanics, and tumor cell behavior. These analyses will be complemented by quantitative proteomics to identify plecstatin-dependent remodeling of cytoskeletal and signaling networks in human tumor tissue.
By integrating structural biology with functional analyses in patient-derived HCC models, this project will provide mechanistic insight into cytoskeletal targeting strategies in cancer and support the development of plectin-directed therapies.
Candidate profile
Prior experience with protein expression and purification, mass spectrometry, advanced microscopy, or work with primary human tissues will be considered an advantage but is not required. The candidate is expected to actively contribute to data analysis, manuscript preparation, and international collaborations.
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Supervisor
Martin Gregor
Project description
Metastasis critically depends on the ability of single tumour cells to establish and maintain cytoskeletal polarity in three-dimensional environments and in suspension. Recent studies have identified intrinsic actin- and myosin-rich cortical poles and associated cortical flows in detached tumour cells, which correlate with metastatic potential. However, these processes lack a rigorous quantitative and three-dimensional description.
This PhD project aims to develop computational and image-analysis approaches for quantitative characterization of cytoskeletal organization, polarity, and flow dynamics in single metastasizing cells. The project is exclusively in silico and will focus on the analysis of advanced 3D and 4D microscopy datasets.
The student will establish methods for segmentation, reconstruction, and registration of whole-cell cytoskeletal architectures in three dimensions, enabling formal description of polarity axes and cortical asymmetries. Computational approaches such as optical-flow analysis and vector-field modeling will be applied to quantify actin and myosin flows on curved cellular surfaces, capturing directionality, stability, and fluctuations associated with pole formation.
Finally, image-derived features will be integrated with statistical and machine-learning methods to classify polarity states and identify quantitative signatures predictive of metastatic behavior. The project will deliver transferable analytical tools for studying cytoskeletal dynamics in cancer.
Candidate profile
Experience with optical flow, surface-based analysis, or machine learning is an advantage. The candidate should be motivated, independent, and comfortable working in an interdisciplinary environment.
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Replication of retroviruses in host cells is a result of the interplay between the virus and multiple cellular factors, either the virus dependence factors necessary for subsequent steps of the replication cycle or restriction factors that block virus replication and contribute to the innate antiviral immunity. The major focus of our group are receptors for retroviruses that specifically attach the virus and assist in virus entry…
Supervisor
Filip Šenigl
Project description
Somatic hypermutation (SHM) is a key process in diversification of antibodies. This process is initiated by cytosine deamination by the activation-induced cytidine deaminase (AID) and completed by error-prone processing of the resulting uracils. Though SHM aims primarily to Ig loci frequent targeting of non-Ig loci was reported accentuating the role of SHM in lymphomagenesis. We developed a series of novel methods providing data on SHM susceptibility in B cell genome and identifying a series of factors involved in SHM. Based on our preliminary results, we propose a model of somatic hypermutation targeting combining the roles of AID access to various genomic regions and site-specific variability of error-proneness of DNA repair. Our novel approach will decipher transcriptional kinetic features involved in targeting of AID activity and identify factors responsible for specific distribution of cytidine deamination and high error rate of DNA repair in SHM-targeted regions. Our study will provide a novel insight into the mechanism of SHM targeting and its involvement in lymphomagenesis.
The project will be demanding on establishment of various high-throughput methods (integration site libraries, ChIP-seq, RNA-seq, etc.). The project will also require extensive bioinformatic analysis which doesn’t need to be necessarily performed by the candidate, however, experience with high-throughput datasets or bioinformatic analysis is advantageous.
The project is run in very close collaboration with the laboratory of David Schatz, Immunobiology, Yale School of Medicine, CT, USA
Candidate profile
The candidate should have experience with tissue culture experiments and basic molecular biology techniques (PCR, plasmid construction) as well as basic microscopic skills. The candidate should be able to work with scientific literature and communicate in English language.
We offer
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Tissues in the adult organism contain a population of tissue-specific stem cells that provide the cellular basis for homeostatic maintenance of adult tissues. Our goal is to elucidate the molecular mechanisms influencing the fate of normal and transformed adult stem cells in the intestine and haematopoietic system…
Supervisor
Lucie Láníková
Project description
Hematopoiesis is a highly organized and dynamic process of blood cell production, progressing hierarchically from hematopoietic stem cells (HSCs) through multipotent progenitors to fully differentiated cells of the myeloid and lymphoid lineages. This system is controlled by a complex network of cytokines and growth factors, with signal transduction predominantly mediated by the JAK-STAT pathway, which regulates proliferation, differentiation, survival, and the stability and trafficking of cytokine receptors.
Long-term HSC function critically depends on the maintenance of genomic integrity, safeguarded by DNA damage response (DDR) mechanisms. DDR orchestrates the detection and repair of DNA lesions, activation of cell-cycle checkpoints, and the repair of both double-strand (DSBs) and single-strand DNA breaks. Additionally, DDR protects stem cells from apoptosis, senescence, and premature functional decline. Impairment or failure of DDR—driven by congenital or acquired genetic variation or chronic cellular stress—leads to the accumulation of DNA damage, HSC exhaustion, disrupted differentiation programs, and activation of stress-induced and inflammatory signaling pathways. These alterations promote the clonal expansion of selectively advantaged hematopoietic cells, support clonal evolution, and may contribute to malignant transformation.
The dissertation focuses on understanding the molecular and genetic mechanisms that disrupt normal blood cell formation. Special attention is given to how inherited predisposition, acquired somatic mutations, and defects in DNA damage response influence stem cell behavior and clonal development. To study these processes, advanced experimental models will be used, including genetically modified animals, iPSC-derived hematopoietic cells, 3D organoids, and in vitro HSC culture systems. The aim of the project is to build a general model that explains how increased signaling activity together with impaired DNA repair control can change blood cell differentiation, clonal dynamics, and support the onset of the malignant myeloid transformation.
Candidate profile
The candidate holds a Master’s degree (or similar) in molecular biology, cell biology or a related life-science field and has a strong interest in hematopoiesis, genome integrity, and molecular mechanisms of disease. Practical experience with standard molecular biology and cell biology techniques is expected. Experience with Western blot analysis is considered an advantage. Bioinformatics skills, including basic data processing, statistical analysis, or work with high-throughput or sequencing data, are highly welcome and will be beneficial for the project. The candidate should be willing to work with murine models. The candidate should be able to work independently as well as part of a research team, demonstrate critical thinking, and show willingness to learn new experimental and computational approaches. Good communication skills in English, reliability, and a proactive attitude toward research are essential.
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In our laboratory, we employ cell and molecular biology approaches, CRISPR-mediated gene editing and transgenic mouse models to investigate how cells respond to DNA damage. We also seek for genetic defects in cancer cells that could be exploited for personalized cancer treatment…
Supervisor
Libor Macůrek
Project description
Genome instability is one of the drivers of cellular transformation and cancer development. Tumor suppressor p53 prevents proliferation of cells with damaged DNA and eliminates them either by programmed cell death or by induction of a permanent cell cycle arrest. We have recently shown that increased activity of protein phosphatase PPM1D promotes development of breast cancer and/or hematological malignancies by inhibiting p53 pathway. Interestingly, suppression of the cell cycle checkpoint may not be the only pathogenic mechanism supporting the transformation of cells lacking p53 or overexpressing PPM1D. In this project, we will investigate defects in signaling pathways in cells that transformed due to the presence of the pathogenic variant of PPM1D. In particular, we will focus on mechanisms that are not directly linked with the cell cycle control and instead are involved in cellular metabolism. PPM1D activity can also contribute to resistance of cancer cells to chemotherapy. We will therefore exploit CRISPR/Cas9 screens to identify potential synthetic lethal interactions with the pathogenic variants of PPM1D. Selected hits will be validated using xenograft mouse models. This project will identify new vulnerabilities of cancer cells expressing active PPM1D and can potentially define novel chemotherapeutic combinations.
Candidate profile
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The shape of an animal arises in a species-specific, step-wise fashion during embryonic development. During this sequence of events, collectively referred to as ‘embryo morphogenesis’, the embryo constantly remodels its shape. Our lab is interested in the force-generating mechanisms that drive these shape changes…
Supervisor
Teije Corneel Middelkoop
Project description
Cell polarization is essential for many biological processes such as asymmetric cell division, cell migration and body axis establishment, and can be observed throughout the tree of life. Cell polarization can be achieved 1) biochemically, via networks of interacting polarity proteins, 2) mechanically, via active transport of components from one side of the cell to another, or 3) mechanochemically, by the integration of biochemical and mechanical control mechanisms. In the past decades, much has been learned about the mechanochemistry underlying cell polarization in various biological contexts. However, it is still entirely unclear how the mechanochemical mechanisms underlying cell polarization evolve, thereby giving rise to different ways by which cells polarize.
The main goal of this PhD project is to understand how mechanochemically-driven cell polarization evolves.
You will focus on polarization of the C. elegans one-cell embryo, which is essential for establishment of one of the main body axes. This polarization event involves the integration of interacting polarity proteins with movements of the actomyosin cytoskeleton (refs 1-3). To understand how this mechanochemical cell polarization mechanism evolves, you will employ experimental evolution and study morphogenesis in C. elegans populations evolving in the lab. Importantly, our preliminary results show that this approach is feasible as we observed evolutionary adaptation already within 20-30 generations (2-3 months). Every 20-30 generations you will 1) measure the population fitness, 2) conduct a biophysical characterization of cell polarization using quantitative fluorescence live imaging, and 3) conduct a genetic characterization of evolving populations by performing whole genome sequencing.
Altogether, this interdisciplinary approach links genomic analysis and biophysical phenotypic analysis with fitness analysis and will therefore provide an in-depth characterization of the evolution of cell polarity. This will pave the way towards understanding how the vast diversity of cell polarization mechanisms evolved.
Candidate profile
Candidate should have a master’s degree in biology, chemistry, engineering or physics. Experience with any of the following methodologies is considered positively, but is not a requirement: live cell microscopy, image analysis, whole genome sequencing, physical/mathematical modeling, coding in Python and/or Matlab.
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In our research group, we investigate the interplay between immune cells and the surrounding environment, focusing on immune cell development (haematopoiesis), immune cell localization (ecotaxis) and lymphocyte priming….
Supervisor
António Pires da Silva Baptista
Project description
Immune tolerance involves self-reactive T cell deletion in the thymus, and peripheral constraint of self-reactive escapees by regulatory T cells (Tregs). The latter occurs mostly in secondary lymphoid organs such as lymph nodes, where Tregs actively limit self-reactive T cell activation by stealing of IL2. We have shown that lymph node fibroblastic reticular cells (FRCs) mediate intranodal Treg maintenance via MHC-II-dependent antigen presentation. In this project, we aim to 1) unravel the molecular mechanisms that determine MHC-II expression by FRCs; 2) determine which self-antigens are presented by FRCs (examining possible region-specific patterns of self-antigen presentation); and 3) determine the influence of immune activation in FRC MHC-II and self-antigen expression.
Candidate profile
This research involves mouse studies (surgery and adoptive cell transfer), wet-lab techniques (cell culture, flow cytometry and imaging), and analysis of sequencing and spatial data. The candidate is expected to have basic knowledge of bioinformatics (coding in R).
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Supervisor
António Pires da Silva Baptista
Project description
Lymphoid-myeloid crosstalk and cooperation are essential for host protection against infection. Involving multiple signaling pathways, this communication is thought to involve sensing of infection by myeloid cells which in turn activate lymphocytes, followed by feedback regulation of the myeloid response by the activated lymphocytes. Notably, in the absence of infection, this communication is thought to be limited, with both lymphoid and myeloid compartments mostly behaving independently from each other. Here, using mice with multiple deficiencies in lymphoid cells, reconstitution approaches involving cellular transplantation, single-cell RNA sequencing and genetic screens we aim to 1) determine the influence of lymphoid cells in quantitative and qualitative myeloid cell homeostasis; 2) determine the signaling pathways involved in setting the appropriate homeostatic lymphocyte-myeloid balances; and 3) determine how myeloid cells „raised“ in the absence of lymphocyte conditioning recognize and respond to infectious stimuli.
Candidate profile
This research involves mouse protocols (adoptive cell transfers, infections), wet-lab techniques (cell culture, genetic editing, flow cytometry and imaging), and analysis of sequencing data. The candidate is expected to have basic knowledge of mouse handling and genetics.
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In our laboratory we study processes and mechanisms, which govern epithelial morphogenesis and homeostasis, and how their deregulation can lead to developmental defects and cancer…
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
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In the Laboratory of Cell Motility, we study the eukaryotic flagellum and cilium (the terms are interchangeable), a fascinating organelle with motile, signalling and sensory roles…
Supervisor
Vladimír Varga
Project description
Cilia are elongated organelles on the surface of many human cell types. They have important motility, signaling and sensory roles, and their malfunctioning causes diseases called ciliopathies. There are two major types of cilia, motile and primary cilia. Their cytoskeleton, the so-called axoneme, is based on microtubules. Recent studies revealed that the axoneme of the primary cilia significantly deviates from the classic pattern of 9 outer doublet microtubules arranged circularly around the central pair, which is found in the motile cilia. The project aims to investigate how is the microtubule arrangement of the primary cilium axoneme established and what are the implications of this arrangement for ciliary functions and transport of material along the cilium. To answer these questions advanced live cell imaging approaches, such as TIRF and FRAP, as well as high-resolution approaches, such as correlative light and electron microscopy and expansion microscopy, will be employed. This will lead to better understanding of primary cilium biology and causes of certain ciliopathies.
Candidate profile
We are looking for a highly motivated student with a degree in cell biology, biochemistry, molecular biology or related disciplines, and with an interest in the eukaryotic cytoskeleton. The candidate should be eager to learn new techniques and eventually be able to drive the project. We offer a friendly environment of a young group with a deep interest in cilia biology and an access to state of the art equipment in the laboratory and institute facilities.
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