1.

May 25, 2020 - recruitment opens
June 7, 2020 - deadline for applications

Research projects for admissions 2020/2021-1:

Linking abnormal Ca2+ signaling and the unfolded protein response with Huntington’s disease pathology in both YAC128 mouse model and iPSC-derived neurons from HD patients.

Prof. Jacek Kuźnicki, PhD; Magdalena Czeredys, PhD, Laboratory of Neurodegeneration

Description: Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by the aggregation of mutant huntingtin and degeneration of medium spiny neurons (MSNs) in the striatum. Abnormal Ca2+ signaling is considered as an early event in HD pathology since disturbances in Ca2+ homeostasis were found in HD models and postmortem samples from HD patients. One of the pathways for Ca2+ signaling is store-operated calcium entry (SOCE). The activation of inositol-(1,4,5)triphosphate receptor 1 (IP3R1) results in Ca2+ release, which decreases ER Ca2+ content and activates Ca2+ influx through SOC channels. Elevated SOCE and increased IP3R1 activity was previously reported in MSNs from the transgenic model of HD, YAC128. The project is based on the hypothesis that neurodegeneration in HD is induced by disturbances in Ca2+ signaling in neurons. Previously we found that huntingtin-associated protein 1 (HAP1) that is overexpressed in striatal neurons and binds to mutant huntingtin causes dysregulation of Ca2+ signaling by increased activation of both SOCE and IP3R1 receptors. We intend to examine the link between dysregulated Ca2+ signals and neuronal cell death in HD. The experiments will be performed in YAC128 MSNs cultures and neurons delivered by the reprogramming of fibroblasts from HD patients with the application on CRISPR/Cas9-based editing strategies and Ca2+ signaling inhibitors.

Aim: The project aims to investigate whether and how the disturbed Ca2+ homeostasis affects HD pathology. A Ph.D. project related to this issue will be done using different HD models. One position is available in the project. We are looking for a person interested in neurobiology, with experience in working with animal models (mice, zebrafish), cell cultures, and biochemical techniques (immunoprecipitation, western blot). Knowledge/experience in iPSCs cultures is welcome.

Number of positions available: 1

Source of funding: NCN/OPUS grant

Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.

Cytoplasmic polyadenylation as a central regulator of physiological processes

Prof. Andrzej Dziembowski, PhD, Laboratory of RNA Biology

Description: Poly(A) tails generated by canonical poly(A) polymerases during mRNA 3’ formation are essential for mRNA stability and translation. It is now appreciated that poly(A) tail dynamics is more complex than previously suspected; deadenylated mRNAs in the cytoplasm can be degraded, uridylated or stored in a dormant state to be later re adenylated to activate protein synthesis. Cytoplasmic polyadenylation was mostly studied in the context of gametogenesis and in synapses, where the transcriptional activity is limited. Surprisingly, mouse lines devoid of the well known cytoplasmic poly(A) polymerase GLD2 display no apparent phenotypes. We recently described a novel family of cytoplasmic poly(A) polymerases, TENT5 (FAM46), comprising four members in vertebrates (Mroczek et al. & Bilska et al. Nat Comm 2017,2020). TENT5C acts as a tumor suppressor in multiple myeloma, while mutations in TENT5A lead to a rare disease osteogenesis imperfecta. We have generated KO mouse models for all TENT5 genes and detected a variety of different phenotypes affecting several organs and biological processes: gametogenesis, growth, skeletal development, hematopoiesis, immune response, and behavior. Moreover, analysis of the KO of worm TENT5 orthologue revealed dysfunction of innate immunity. Thus, TENT5 proteins contribute significantly to metazoan physiology and, more generally, that cytoplasmic polyadenylation plays a much broader role than previously anticipated, opening a new area of important research.

Aim: The project aims is to dissect functions and mechanisms of cytoplasmic polyadenylation by TENT5 in innate immunity, erythropoiesis, and neuronal physiology. Unique animal models constructed using CRISPR/Cas9, combined with advanced transcriptomic and proteomic approaches, will be used to achieve our goals. Several positions are available in the lab. The exact PhD project will depend on the particular skills and preferences of the student. We are looking for students with experience in work with animal modes (mouse, C. elegans), RNA biology, or bioinformatics.

Number of positions available: 4

Source of funding: NCN/Norway grants/FNP/Horizon2020 era chairs

Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.

See also:

2.

05/08 - recruitment opens
18/08 - deadline for applications
7/09 – 17/09 - interviews
21/09 – publication of results

Research projects for admissions 2020/2021-2:

Title: Elucidating the epigenetic contribution to cardiovascular lineage specification

Supervisor: Cecilia Winata

Institute: International Institute of Molecular and Cell Biology in Warsaw

Laboratory: Laboratory of Zebrafish Developmental Genomics

Background:

One key question in the field of organogenesis relates to how the many types of cells required to make an organ are generated from a pool of progenitor cells with initially similar characteristics. Heart (cardiac) progenitor cells are located close to those that will also generate blood and blood vessels (hemoangiogenic). At very early stages of embryonic development, they express nkx2.5 in common. Subsequently, each type of cells expresses different sets of genes and adopts epigenetic states which signifies their identity. Despite the knowledge that nkx2.5-expressing progenitors could contribute to diverse cell lineage types, several key questions remain unanswered. First, it is unclear at which developmental stage the segregation between cardiac and hemoangiogenic fates begin to occur. Second, the exact pathway and intermediate stages which these progenitors go through during the process of lineage specification are still largely unknown. In addition, despite the knowledge that cardiac transcription factors including Nkx2.5 itself are known to interact with chromatin modifying factors and promote chromatin changes, it is still unknown to what extent epigenetics play a role in driving cell fate decisions at the individual cell level. By tracing the evolution of cellular heterogeneity over time, and at the same time assessing the dynamics of epigenetic landscape at the single cell level, we will elucidate the mechanism of cardiovascular lineage specification.

Aim:

The goal of this project is to elucidate the epigenetic contribution towards the lineage decision of nkx2.5-expressing progenitors into either cardiac or hemoangiogenic lineage. We hypothesize that distinct epigenetic states occur among subpopulations of nkx2.5-expressing progenitors according to their lineage diversification potential. We will profile open chromatin regions at single cell level anddetermine whether Nkx2.5 plays a role in establishing the epigenetic state by scATAC-seq method(Jia et al., 2018,Nat Commun9, 4877).

Requirements:

Bachelor’s or Master’s degree in Biology, Biochemistry, or equivalent
Solid understanding of the principles of molecular biology and genetics
Previous laboratory experience in molecular biology and/or biochemistry techniques
Prior experience in flow cytometry, NGS, and/or working with animal models (mouse or zebrafish), as well as basic programming skills would be an advantage although not essential
Ability to communicate fluently in English and has a collaborative attitude

Title: Lysine deserts as a universal mechanism to escape premature proteins degradation

Supervisor: dr hab. Wojciech Pokrzywa

Institute: International Institute of Molecular and Cell Biology in Warsaw

Laboratory: Laboratory of Protein Metabolism in Development and Aging

Background:

Eukaryotic cells use degradation systems such as the ubiquitin-proteasome (UPS) system to remove unwanted proteins. UPS mediates proteolysis by attaching the small protein ubiquitin to the target protein, using a cascade of enzymes in a process called ubiquitination. Ubiquitin is attached primarily to a specific amino acid in the target protein - lysine. Recent studies have shown that the yeast protein Slx5 avoids UPS due to the extensive, lysine-free region in the so-called lysine desert. Such a lysine desert may be a part of the uncharacterized strategy used by proteins to avoid premature degradation. As a result of our initial analyzes, we found various lysine deserts among the proteins of both simple and complex organisms. Many of these proteins are associated with the UPS, suggesting a protective mechanism against self-determination for degradation. However, we have also found lysine deserts in proteins involved in fundamental cellular processes such as transcription.

Aim:

The overall objective of these studies is to understand the common occurrence of proteins with lysine deserts using evolutionary and structural bioinformatics analyzes supported by experimental methods. The theoretical part will consist of a quantitative analysis of the evolutionary preservation of lysine deserts in a number of taxonomic groups, followed by a qualitative analysis of their biological functions. Selected proteins will also be analyzed via molecular simulations to understand the dynamics of lysine desert exposure under selected conditions. The most promising candidates obtained from bioinformatics analyzes will be subjected to experimental tests using human cell lines and animal model Caenorhabditis elegans.

Requirements:

Master's degree in biological sciences/bioinformatics
experience in programming (Python/R), omics data analysis and cluster computing
knowledge of biological databases, biochemistry, molecular biology, evolutionary and structural bioinformatics of proteins
fluency in English
strong motivation for scientific work (documented internships and apprenticeships in scientific institutes)
ability to organize working time independently
systematic work
experience in molecular modeling and/or laboratory work/C. elegans maintenance is an advantage

Title: The impact of cytoplasmic polyadenylation on local translation in neurons

Supervisor: prof. dr hab. Andrzej Dziembowski

Institute: International Institute of Molecular and Cell Biology in Warsaw

Laboratory: Laboratory of RNA Biology

Background:

Neurons communicate with each other through synapses, specialized contact sites that enable electrical impulses to be transmitted between cells. Synapses are small, but partly independent compartments of the neuron because they contain the molecular machinery indispensable for protein synthesis. This process of protein production on the basis of mRNAs transported to distant synapses from the cell body is called local translation. Local protein synthesis is essential for the proper functioning of the synapse, and its dysregulation is the cause of severe neurodevelopmental disorders. In recent years, thanks to the development of new technologies, we have learned more about these essential processes taking place in synapses. However, the precise molecular mechanisms by which synaptic translation is regulated is still far from being understood.

The ends of mRNA molecules are specifically modified in order to enhance their stability and ability to serve as a template for proteins synthesis at ribosomes: at the 5’ end so-called cap structure is positione, while at the end, there is a poly(A) tail. Nearly all mRNAs in the cell are polyadenylated in the nucleus right after being transcribed from DNA and before their transport to the cytoplasm. However, there is growing evidence that the process of polyadenylation can also take place in the cytoplasm and is therefore called cytoplasmic polyadenylation. In neurons, cytoplasmic polyadenylation of synaptic mRNAs plays a significant role in the regulation of protein synthesis. However, until now, it was studied only for a few mRNAs, and the global impact of this phenomenon and the specific enzymes carrying out the reactions are unknown.
This research project will be performed in cooperation with Prof. Clive Bramham from the University of Bergen and Prof. Magdalena Dziembowski from CENT UW.

Aim:

We aim to elucidate the function and mechanism of cytoplasmic polyadenylation of neurons. To achieve our goals, unique animal models constructed using the CRISR/Cas9 method, combined with advanced transcriptomic and proteomic approaches, will be used.

Two positions are available in the laboratory. The exact project will depend on the specific skills and preferences of the student. We are looking for students with experience in working with animal models, RNA biology or bioinformatics.

See also:

3.

December 8, 2020 - Recruitment announcement published
December 22, 2020 - Start of the recruitment
January 5, 2021 - Deadline for documents submission

Research projects for admissions 2020/2021-3:

1. Title: Rac1 contribution to brain connectivity impairments and neuropsychiatric disorders in Tuberous Sclerosis Complex (NCN/OPUS)

Supervisor: Prof. Jacek Jaworski

Auxiliary Supervisor: Justyna Zmorzyńska, PhD

Institute: International Institute of Molecular and Cell Biology in Warsaw

Laboratory: Laboratory of Molecular and Cellular Neurobiologylular Neurobiology

Project description:

During the brain development specific cellular events, including establishment of neural polarity, axon elongation, and synapse formation, happen in a temporally and spatially controlled manner to establish connectivity. These temporal and spatial boundaries are created by tight regulation of intrinsic and extrinsic factors. One of major components that may perform this regulation during connectivity development is Rac1 as it links plasma membrane receptors with actin dynamics. Also, mammalian target of rapamycin (mTOR) integrates intra- and extracellular factors. The diseases associated with over-expression of mTOR usually exhibit impairments of the brain development and neuropsychiatric phenotypes that do not necessarily correlate with mutation burden or cannot necessarily be explained by levels of mTOR activation. One of the examples is Tuberous Sclerosis Complex (TSC) in which neuropsychiatric disorders like autism spectrum disorder, intellectual disability, or anxiety do not fully correlate with mTOR expression levels, epilepsy, or tumor burden. Therefore, other molecular pathways must interact with mTOR pathway in order to produce these phenotypes. Our results and preliminary data suggest that Rac1 pathway and its diverse inputs may participate in the regulation of neuropsychiatric disorders in TSC through control of connectivity formation during development. The project will be conducted using zebrafish TSC model.

Aim:

The main objective of this project is to unravel how the interplay between various pathways that converge on Rac1 may participate in the brain connectivity and underlie TSC-associated neuropsychiatric disorders. The project will include behavioral testing, extensive microscopy imaging and image analysis, and transcriptome analysis.

Requirements:

Master’s degree in Biology, Biochemistry, Bioinformatics, or related area
Solid understanding of the principles of molecular and cellular biology; knowledge on brain development, neuroscience, or computer vision will be a plus
Willingness to work with zebrafish animal model
Previous laboratory experience in basic molecular biology, biochemistry techniques, and/or imaging experience
Prior experience in NGS, and/or working with animal models (mouse or zebrafish), as well as basic programming skills would be an advantage although not essential
Ability to communicate fluently in English and a collaborative attitude

Number of positions available: 1

Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.

2. Title: Identification of novel vulnerabilities of VPS4B-deficient cancer cells (NCN/OPUS)

Supervisor: Prof. Marta Miączyńska

Auxilliary Supervisor: Ewelina Szymańska, PhD

Institute: International Institute of Molecular and Cell Biology in Warsaw

Laboratory: Laboratory of Cell Biology

Project description:

One of the key challenges in oncology is to effectively kill cancer cells while leaving healthy cells intact. To meet this goal, precision oncology aims to tailor anti-tumor therapies to individual genetic changes in cancer cells of a given patient. To provide new targets for precision oncology we need to understand the relationship between the genetic alterations of cancer cells and the dependencies (vulnerabilities) they cause.

VPS4A and VPS4B enzymes together with the Endosomal Sorting Complex Required for Transport (ESCRT) machinery are involved in membrane remodeling during e.g. endocytosis, cell division, and plasma membrane repair. In our previous project, we identified VPS4B deficiency as a selective weakness of colorectal cancer cells with chromosome 18q deletion. We also demonstrated that survival of VPS4B-depleted cancer cells depends on the presence of VPS4A and characterized the molecular consequences of simultaneous depletion of VPS4 proteins that lead to cell death (more details in Szymańska et al, EMBO Mol Med, 2020). Very probably, VPS4B deficiency makes cancer cells more vulnerable not only to VPS4A loss but also to other perturbations affecting gene(s) cooperating with VPS4B in cellular processes essential for life.

Aim:

We aim to identify and characterize novel vulnerabilities of VPS4B-deficient cancer cells among candidates selected from datasets of the Cancer Dependency Map Project (Broad Institute). To this end, we will examine the impact of simultaneous depletion of VPS4B and a selected candidate on in vitro and in vivo growth of cancer cells. Further, we will elucidate the consequences of depletion of VPS4B and a candidate for cancer-relevant cellular processes, e.g. endocytosis, cytokinesis and migration.

Requirements:

Master's degree in biology, biochemistry or related field.
Solid understanding of the principles of cell and molecular biology.
Previous experience in laboratory work and familiarity with basic molecular biology techniques.
Written and spoken fluency in English.
Good interpersonal skills and a collaborative attitude.

Number of positions available: 1

Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.

3. RNA-Protein Interactions in Human Health and Disease (NCN/DIOSUCRI)

Supervisor: Gracjan Michlewski, PhD, DSc

Institute: International Institute of Molecular and Cell Biology in Warsaw

Laboratory: Laboratory of RNA-Protein Interactions

Project description:

RNA-binding proteins (RBPs) are key molecules that control gene expression through RNA-protein interactions. Consequently, they contribute to cellular homeostasis, normal development and majority of human diseases. Importantly, new RBPs are being discovered by high-throughput proteomics, but we still have a limited understanding of their function.

RNA viruses have caused several epidemics in the 21st century. Taking influenza A virus (IAV) infection as an exemplar, it kills 250,000 to 500,000 people annually and generates a significant global socioeconomic burden. Importantly the emergence of COVID-19 pandemic caused by an RNA virus SARS-CoV-2 continue to have catastrophic consequences on public health and world economy. Thus, a detailed molecular understanding of host-virus interactions is imperative in order to know how best to inactivate these viruses and prevent major disruptions in the future.

We have recently discovered and started characterising novel RNA binding protein – E3 ubiquitin ligase TRIM25 (Choudhury et al. 2014; Choudhury et al. 2017). TRIM25 belongs to a large family of tripartite motif-containing proteins (more than 80), most of which have E3 ubiquitin ligase activity. Many of TIRIMs are positive or negative regulators of innate immune response pathways. Importantly, TRIM25 is emerging as a key factor in the innate immune response to RNA viruses (including IAV, CoV, dengue virus and many others). Despite the essential involvement of TRIM25 in viral RNA-induced innate immunity, its RNA-binding functions are still poorly understood.

Aim:

With this project, we aim to take advantage of an assembled multi-disciplinary team to uncover the roles of the novel RNA-protein interactions in the antiviral response to selected RNA virus infections. We hypothesise that TRIM25 binds directly to viral RNAs to restrict virus propagation. We also hypothesise that other members from TRIM family bind RNA. Finally, we hypothesise that specific host RBPs bind to virus derived RNAs and inhibit or augment innate immune response. In summary, this project has the potential to make crucial contributions to understanding the innate immune response to RNA viruses and provide a platform for the development of novel, RNA-based antiviral therapeutics.

Requirements:

MSc degree in biology, biochemistry or related field
Solid knowledge of the principles of cell and molecular biology, virology or biochemistry
Hands-on experience in laboratory work and is familiar with basic cell and molecular biology techniques
Prior experience in virus handling and analysis, cell culture, mass spectrometry or bioinformatics will be an advantage
Proficiency in written and spoken English
Excellent interpersonal skills, initiative and ability to work independently and in a high-performance team

Number of positions available: 2

Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.

4. Title: Cellular adaptation to cold (NCN/GRIEG)

Supervisor: Wojciech Pokrzywa, PhD, DSc

Institute: International Institute of Molecular and Cell Biology

Laboratory: Laboratory of Protein Metabolism

Project description:

Environmental stressors can seriously jeopardize animals’ ability to survive and reproduce. One, potentially dangerous, environmental stressor is acute cold. To counteract cold, affected organisms mount various types of responses, ranging from cold avoidance to adaptation.

The latter strategy is used by hibernating animals, which, in extreme cases, can survive subzero temperatures for many days. Here, we propose to utilize a simple animal model, the nematode Caenorhabditis elegans, as a rapid tool to understand cellular adaptations to cold. We will focus on mechanisms altering the abundance and types of cellular messenger RNAs and proteins, as these kinds of molecules are critical for the live-or-die decision of the cell. In some disease states, like stroke, cooling can facilitate patient’s recovery. Moreover, hibernation is of interest to ageing research, as animals tend to live longer at lower temperatures. Thus, understanding how cells adapt to cold has the potential to influence treatments of human disorders.

Aim:

As a Ph.D. student, you will use the powerful genetic model of Caenorhabditis elegans, which can display a hibernation-like behavior, to determine the mechanism and role of the UCS domain-containing proteins and co-working chaperones in the regulation of cross-talk between translation and proteostasis in the cold. To develop the preliminary results, you will use, e.g., polysome profiling, tissue-specific ribosome imaging, RNA sequencing, in vitro assays on purified proteins, and more.

Requirements:

Holds a master’s degree in biology, biochemistry or related field
Solid knowledge of the principles of cell and molecular biology, genetics, and/or biochemistry
Hands-on experience in laboratory work and familiarity with basic molecular biology techniques
Keen interest in translation and proteostasis regulation
Prior experience or knowledge of C. elegans or similar model organisms will be an advantage
Proficiency in written and spoken English
Willingness to learn and take new challenges, ability to work independently, analytical thinking

Number of positions available: 1

Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.

5. Title: Elucidating the epigenetic contribution to cardiovascular lineage specification (NCN/OPUS)

Supervisor: Cecilia Winata, PhD

Institute: International Institute of Molecular and Cell Biology in Warsaw

Laboratory: Laboratory of Zebrafish Developmental Genomics / Zebrafish Developmental Genomics Laboratory

Project description:

Aim:

The goal of this project is to elucidate the epigenetic contribution towards the lineage decision of nkx2.5-expressing progenitors into either cardiac or hemoangiogenic lineage. We hypothesize that distinct epigenetic states occur among subpopulations of nkx2.5-expressing progenitors according to their lineage diversification potential. We will profile open chromatin regions at single cell level and determine whether Nkx2.5 plays a role in establishing the epigenetic state by scATAC-seq method (Jia et al., 2018, Nat Commun 9, 4877).

Requirements:

Master’s degree in Biology, Biochemistry, or related area
Solid understanding of the principles of molecular biology and genetics
Previous laboratory experience in molecular biology and/or biochemistry techniques
Prior experience in flow cytometry, NGS, and/or working with animal models (mouse or zebrafish), as well as basic programming skills would be an advantage although not essential
Ability to communicate fluently in English and has a collaborative attitude

Number of positions available: 1

Contact: This email address is being protected from spambots. You need JavaScript enabled to view it.

For more information please follow:

Recruitment 2020/21

1.

2.

Title: Elucidating the epigenetic contribution to cardiovascular lineage specification

Title: Lysine deserts as a universal mechanism to escape premature proteins degradation

Title: The impact of cytoplasmic polyadenylation on local translation in neurons

3.

Research projects for admissions 2020/2021-3:

1. Title: Rac1 contribution to brain connectivity impairments and neuropsychiatric disorders in Tuberous Sclerosis Complex (NCN/OPUS)

2. Title: Identification of novel vulnerabilities of VPS4B-deficient cancer cells (NCN/OPUS)

3. RNA-Protein Interactions in Human Health and Disease (NCN/DIOSUCRI)

4. Title: Cellular adaptation to cold (NCN/GRIEG)

5. Title: Elucidating the epigenetic contribution to cardiovascular lineage specification (NCN/OPUS)

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