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Regulation of BCR signalling by DNA damage response and P53 protein


Faculty of Medicine

About the Project

Supervisor: Miroslav Boudný, Ph.D.

Co-supervisor: assoc. prof. Marek Mráz

PROJECT:

We are looking for a motivated PhD student that would like to work on the following project  funded by the ERC (European Research Council) Starting grant. The variable clinical course of several B cell malignancies largely depends on p53 functionality and B-cell receptor (BCR) signalling propensity; however, it is unclear if there is any crosstalk between these pathways. We showed for the first time that there is a connection between p53 pathway and regulation of BCR signaling (Cerna et al…Mraz, Leukemia, 2018). We described that DNA damage response (DDR) activation leads to down-modulating the transcriptional factor FOXP1, which functions as a positive BCR signalling. It seems that the low FOXP1 levels limit BCR signalling partially via allowing for upregulation of a CD22 cell-surface, whose intracellular part serves as a docking site for phosphatases that limit BCR activation on the cell membrane. The student will further explore the connection between DNA damage response and the BCR signalling regulation. Additionally, the p53 aberration could also affect the basal levels of CD22/phosphatases, and thus contribute to the “tonic” BCR signalling, and general aggressiveness of the B cells. In vitro studies using Crispr technology and inducible shRNAs for p53 will be conducted. Additionally, we have collected over 100 samples obtained during the administration of chemo-immuno therapy in B-cell chronic lymphocytic leukaemia (CLL) patients, and these can be used to validate the in vitro observations.

WHAT DO WE OFFER:

Modern laboratories, project funded by the prestigious ERC grant = high risk and high gain, state-of-the-art instrument, stable funding, competitive scholarship
You will work in a team of young investigators that challenge some long standing problems in the field of hematology. We do basic science, but with the objective to help patients in the future (we have access to primary samples with hem. malignancies, and we suggest novel clinical trials)

WHAT WILL YOU LEARN/DO:

How to think and work independently as a scientist
Writing of abstracts and papers (and course in grant writing and presentation of data)
How to present data and will attend conferences to present your research
You will spend 1-2 months visit(s) in collaborating labs in Europe or US
Collaboration with experts in wet lab research and bioinformatics
Novel methods such as Next Generation Sequencing (Illumina) and genome editing (Crispr).
How to critically analyze scientific data (regular journal clubs)
Classical methods of molecular biology (e.g. immunoblotting, flow cytometry, qRT-PCR, cell cultures, cloning), and you will use our in vitro models for microenvironmental interactions, and artificial activation/inhibition signalling pathways to decipher the gene regulatory loops.
You can supervise bachelor and diploma students if interested
WHO ARE WE LOOKING FOR:

Motivated smart people that have the “drive” to work independently, but also willing to learn from other people in the lab and collaborate.
Candidates should have a master’s degree in Molecular biology, Biochemistry, or similar field and have deep interest in molecular biology and cancer cell biology.

HOW TO APPLY:

To apply please contact the co-supervisor and submit a CV by email to:  and  (Subject: PhD School).
Information about the laboratory at: ceitec.cz/mrazlab; The PhD will start approx. Feb 2021

OTHER INFO:

The research is funded by ERC grant, and will be conducted at CEITEC MASARYK UNIVERSITY (campus Bohunice). Our laboratory extensively collaborates with the University Hospital Brno in the same campus to obtain primary samples from patients. The campus provides a vibrant, multidisciplinary and highly collaborative scientific environment. The lab is located in Brno, the second-largest city in Czech Republic that has the biggest concentration of biomedical research in the region. Brno is one of the major cultural hubs, with a vibrant and lively atmosphere housing ~60.000 students. The city has a very good public transport and plenty of interesting places to visit within the reach of trains (within small distance of several major cities such as Prague, Vienna, Bratislava, Budapest) and close to international airports.

Keywords: B-cell receptor, BCR signaling inhibitors, DDR, FOXP1, CD22, chronic lymphocytic leukemia, CLL, NGS technology, genome editing

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