Sergey Prykhozhij

Research Associate

sergey.prykhozhij@dal.ca

Sergey studied biology and biotechnology for 3 years at the Belarusian State University in Minsk, Belarus, and then moved to the University of Edinburgh, Scotland, to specialize  in molecular, cell and structural biology during the last 2 years of university studies (BSc Honours in Molecular Biology). His main research interest during this time was the mechanisms of cell cycle regulation and cell division processes, which resulted in projects aimed at characterizing kinetochore protein complexes in the lab of Dr. Kevin Hardwick. Following his interest in developmental and cell biology, Sergey joined the lab of Carl Neumann at the European Molecular Biology Laboratory and University of Heidelberg to study the functions of Sonic Hedgehog signaling pathway in fin bud and retinal development. These projects provided a very good opportunity to pursue both of his interests in cell cycle regulation and developmental biology in an integrated manner. After his PhD, Sergey could stay at EMBL for one year as a post-doctoral fellow in the lab of Francesca Peri and worked on the response of microglia and macrophages to apoptotic cells in the developing neural tissues. This work led to a number of intriguing observations about dynamics of macrophage and microglia recruitment to dying cells in the nervous system and resulted in several transgenic tools to investigate these processes. For his first post-doc position, Sergey moved to Berlin, Germany, where he worked with Sebastiaan Meijsing from October 2010 to May 2012 on the tissue-specificity of Glucocorticoid Receptor (GR) signaling, where he developed zebrafish GR reporter transgenes to study general patterns of GR target gene induction and the strong negative influence of adjacent AT-rich sequences on the strength of GR reporter induction. During this time, Sergey had a lot of exposure to bioinformatics research and developed ZEOGS website (http://zeogs.scienceontheweb.net/) allowing zebrafish researchers to gauge the expression pattern features of their expression profiling results.

During the time in Berman laboratory, Sergey has worked on generating and characterizing zebrafish morphants mutants in genes, whose defects cause human diseases identified in the course of IGNITE (Identifying Genes and Novel Therapeutics to Enhance Treatments) project. The main purpose of using mutants in this project is to establish the basis to test candidate substances and existing drugs for their potential to ameliorate the phenotypes of zebrafish mutants, perform unbiased chemical screens to eventually pave the way for therapies of these diseases in humans. An example success story from characterizing zebrafish disease models based on mutations identified in IGNITE project is investigation of the sideroblastic anemia model resulting from knock-down of slc25a38a and slc25a38b genes, whose down-regulation in zebrafish results in profound anemic phenotype and can be rescued by treatment with glycine and folate. Another ongoing project in this research program is generation of a zebrafish model for cutis laxa, a mitochondrial disease due to aberrant proline synthesis. In addition, based on the original work by Sergey in zebrafish on fzd4, whose loss in humans results in the familial exudative vitreoretinopathy, we have expanded into several different projects on FEVR disease models in zebrafish.

Another area of Sergey’s work is development and application of new tools for CRISPR/Cas9 genome editing. This work includes development of a website for design of sgRNA for specialized targeting experiments: http://multicrispr.net/, several review and methodology discussion articles as well as a recent paper on a method for screening, sequencing and reporter verification of engineered frameshift mutations in zebrafish. A more recent project on introducing point mutations into the zebrafish genome using oligos is also gaining traction as we managed to strongly enhance the efficiency of the process (manuscript in preparation). Sergey oversees much of genome editing work in the lab, is watching and contributing to new developments in this space to further make genome editing easier, more powerful and more specific.

Sergey is currently mainly involved in the Li-Fraumeni Syndrome project and the Atlantic Innovation Fund (AIF) Muscular Dystrophy project, where advanced genome editing techniques are being used to facilitate creating of zebrafish disease models for finding new therapeutic leads against cancers and muscular dystrophies, respectively. The AIF project is a partnership of Dalhousie University with AGADA Biosciences biotechnology company and the details of the project are to be treated as confidential at this stage. Here is a more detailed description of the Li-Fraumeni Syndrome project:

Li-Fraumeni Syndrome project

Li-Fraumeni syndrome (LFS) is a hereditary disorder characterized by early age of onset of a diverse spectrum of cancers. Most patients with LFS carry mutations of a gene called TP53 that predisposes them to cancer development. Zebrafish provide a useful preclinical animal model in which to study Li-Fraumeni Syndrome and factors that contribute to the development of cancers. Zebrafish have previously been created that have mutations in the TP53 gene that develop tumours and have other features in keeping with patients with Li-Fraumeni Syndrome, but these fish models have not been based on mutations commonly found in human Li-Fraumeni Syndrome. We will genetically modify zebrafish to contain mutations in TP53 that are frequent in human Li-Fraumeni Syndrome (Li-Fraumeni Syndrome zebrafish). We will use genetic techniques to create similar mutations in the Li-Fraumeni Syndrome zebrafish. Normally TP53 protects cells from factors that can damage the DNA in those cells, resulting in death of damaged cells. When TP53 is mutant, it can no longer signal damaged cells to die and those cells can go on and become cancerous. We will examine how these additional abnormalities affect the survival and behaviour of cells in Li-Fraumeni Syndrome zebrafish. It is important to confirm that these mutations found in patients cause abnormal cell survival and behaviour in an animal system. We will then screen these fish with collections of drugs to find a particular drug that restores normal cell death after damage from radiation. These drugs may represent drugs that could be given to patients with Li-Fraumeni Syndrome to prevent the development of cancers.

Publications:

Please use the following link for the complete list of Sergey’s publications:

https://www.ncbi.nlm.nih.gov/pubmed/?term=prykhozhij+s

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