Zatsepin Laboratory

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Start date – September 2016

Research in Zatsepin laboratory are classified by three main directions:

1) Targeted delivery of modified antisense/siRNA/sgRNA in vivo.

We are working on the development of RNA-based therapeutics with improved efficacy, biodistribution and stability in vivo. We design and synthesis of heavily modified RNA for gene silencing and CRISPR-Cas9 gene editing to improve potency, efficacy and specificity. Then modified oligonucleotides are either packed in lipid nanoparticles or directly conjugated to the ligands of cellular receptors to enhance targeted delivery in vivo. We succeeded in synthesis and use of GalNAc-RNA conjugates for hepatocyte-specific delivery to the liver and now work with small molecules that bind to mannose, PSMA and folate receptors in macrophages, breast cancer cells and prostate cancer cells.

2) Functional studies of new targets for liver cancer/fibrosis therapy:

–  Regulation of antitumor response via modulation of Ubr-ubiquitin ligases in vivo
This project is focused on the development of a new approach that allows regulation of the activity of the N-end rule in clinically relevant settings by liver-specific delivery of Lipid NanoParticles loaded with highly potent siRNA probes against key components of the N-end rule pathway.

- Role of DDX3 helicase in the translation process
Application of the RNA interference method will provide us a stable DDX3 knockdown system to perform ribosomal profiling and deep RNA sequencing in vivo. The results of sequencing will allow us to reveal target mRNAs for DDX3 RNA helicase, hence, define and describe the exact role of DDX3 in translation in the mouse liver.

- Role of LL35 lncRNA in the liver
Using bioinformatic analysis we found a possible functional analog of the ncRNA DEANR1 in mouse – LL35 ncRNA and confirmed its expression in the mouse liver. Based on the published data we assume that ncRNA LL35 may be involved in the transcription regulation in the liver and can affect metabolic processes and various liver diseases in mice.

- Mouse long non-coding RNA Gm14005 as a potential functional analog of human long non-coding RNA CYTOR
Deeper insight into mechanism of CYTOR lncRNA action, as well as identification of its potency as an anti-cancer therapeutic target, require reliable animal models and further in vivo studies. To make a transfer from in vitro to in vivo research we identify the potential functional analog of CYTOR lncRNA in mice – lncRNA Gm14005. Investigation of Gm14005 functional roles and interactions both in vivo and in vitro will describe its potential application as a CYTOR analog in vivo.

3) Novel fluorescent oligonucleotide probes for DNA/RNA detection.

We are working on the novel design of oligonucleotide probes for qPCR/ RT-qPCR. Currently we start a project devoted to evaluation of bladder cancer by droplet digital PCR (joint study with MSU and Institute of Urology).

  • Non-coding RNA in liver regeneration – from molecular mechanisms to clinical implications. Sergeeva O, Sviridov E, Zatsepin T.  Seminars Liver Dis., 2019.

 

Research grants/Industry funded research

Cancer cell-specific RNA interference in vivo
Novel chemical modifications in guide RNAs for improvement of genome editing by CRISPR-Cas9
lncRNA LL35 as a regulator of Foxa 2 expression in vitro and in vivo - a probable target for diagnostics and therapeutics

Olga Sergeeva

Date: 02.08.2017

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Next Generation Program: Skoltech – MIT Joint Projects

Regulation of Antitumor Response via Modulation of Ubr‐Ubiquitin Ligases In Vivo

Skoltech Biomedical Initiative

Magnetic nanoparticles and carbon nanotubes as enhancers for targeted RNA delivery in vivo
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“Targeted RNA delivery in vivo for therapy by RNAi and genome editing” and “Regulation of Antitumor Response via Modulation of Ubr‐Ubiquitin Ligases In Vivo” Prof. Daniel Anderson, Massachusetts Institute of Technology

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“Novel RNA conjugates for targeted and functional RNA delivery” Prof. Vadim ShmanaiLaboratory of Bioconjugate Chemistry

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“Mechanisms of hepatocyte polarization in vivo” Prof. Marino ZerialZerial Lab

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​”Cancer cell – specific RNA interference in vivo” Prof. Dr. Andriy MokhirFriedrich-Alexander-Universität Erlangen-Nürnberg 

2018
Instrumental Methods in Molecular Biology
RNA Biology
This course is devoted to the knowledge on the structures of RNA and RNA-protein complexes as well as their functioning in cells. The aim of this course is to provide an explanation of fundamental mechanisms such as translation, splicing and gene expression regulation based on the structural viewpoint. Thus the role of RNA in the maintenance of cell identity and cell metabolism will be defined. By focusing on modern techniques for RNA and RNA-protein structure and RNA modifications analysis, students will get aquainted with the approaches to study RNA input into cellular processes in vitro and in vivo.
The students will apply obtained knowledge and skills in presentations and a written exam. An examination commission, consisting of CTB faculty and of invited members, will conduct final evaluation of the overall product design completeness, quality of the results achieved, and of the presentations delivered.