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).
Supervisor – Timofei Zatsepin
|Team:||Katerina Nagornova||Oxana Kovaleva||Svetlana Dukova|
|Olga Sergeeva||Arsen Mikaelyan||Tatiana Abakumova||Tatyana Prikazchikova|
|Ilya Aparin||Valentina Farzan|
|PhD Students:||Dominique Leboeuf||Anna Fefilova||Denis Melnik|
|Adelya Gabdulkhakova||Renata Ialchina|
i-Clamp phenoxazine for the fine tuning of DNA i-motif stability. Tsvetkov V, Zatsepin T, Belyaev E, Kostyukevich Y, Shpakovski G, Podgorsky V, Pozmogova G, Varizhuk A, Aralov A. Nucleic Acids Res. 2018, 10, 1093 121.
Research grants/Industry funded research
Next Generation Program: Skoltech – MIT Joint Projects
Skoltech Biomedical Initiative