Doktorské studium

Studijní obor Bio-omika

Název práce: Non-Coding RNAS and Microenvironmental Interactions of B-Cell Leukemias and Lymphomas

Školitel: doc. MUDr. Mgr. Marek Mráz, Ph.D.

Oficiální zadání:
The objective of the laboratory is to study the biology of hematological malignancies with a focus on molecular pathways that regulate malignant immune cells’ microenvironmental interactions. It is now understood that pathways like the B-cell receptor (BCR) signaling are deregulated during the onset of most B cell leukemias and lymphomas. The BCR pathway is considered the most promising target for therapy in B cell malignancies. For numerous pathological processes the principal deregulation takes place at the level of such non-coding RNAs in B cell malignancies (Mraz et al., Leukemia, 2009; Mraz et al., Blood, 2012; Musilova and Mraz, Leukemia, 2015). We have recently performed studies which revealed that microRNAs regulate the B-cell receptor signaling which represents the essential pathway for the fate of normal and malignant B cells (Mraz et al., Blood, 2014; Mraz and Kipps, 2013). However, the role of non-coding RNAs in microenvironmental interactions of immune cells is largely unclear. The PhD candidate will perform integrated analysis of coding and non-coding RNAs in the regulation of fundamental microenvironmental interactions of B cell, namely adhesion and BCR signalling. The project will focus on short non-coding RNAs (microRNA) and identification of their targets, but also on long-noncoding RNAs. This will be performed using NGS technics (Illumina) in collaboration with the Genomics Core Facility of CEITEC MU, and experts in NGS data analysis (Uni Torino, CEITEC, EMBL). The candidate will use our in vitro models for microenvironmental interactions, and artificial activation/inhibition of BCR signalling to decipher the regulatory loops that involve coding and non-coding RNAs in primary leukemia cells and in lymphoma cell lines. He will utilize genome editing technics in B cells (using the Crispr/Cas9 technology) to delete miRNAs and test their effect on BCR signalling, activation of kinases and transcription factors. Project will also utilize co-culture of malignant B cells with stromal cells, and/or scaffold materials that mimic human bone marrow, and various other technics of molecular and cell biology (western blotting, cell transfection with miRNA mimics, siRNAs, flow cytometry, cloning etc). Overall, the understanding of microenvironmental interactions is of great interest since it drives the discovery of combinatorial therapy. We will further use the knowledge of gene expression networks to reveal molecular inhibitors that should be used clinically. The interactions within the immune niches are the basis for relapse, persisting minimal residual disease, failure of the immune system to target cancer cells, cell resistance to therapy and, in principle, the incurability of many hematological malignancies. To apply please contact the supervisor and submit a CV by email to: marek.mraz@email.cz (Subject: PhD School). Information about the laboratory at ceitec.cz/mrazlab


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