Tatyana Shelkovnikova Lab

RNA metabolism in health and disease: mechanisms and drug discovery

RESEARCH

We have several fundamental and translational projects falling into three main themes

1) Molecular mechanisms of amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders 2) Regulation of stress granules and paraspeckles under stress and in disease states 3) Therapeutic targeting of RNA

Amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease, is a severe and inevitably fatal neuromuscular condition which currently has no cure. Disease-modifying therapies are urgently needed. To be able to find such therapies, we need better understanding of disease mechanisms, especially those applicable across different disease subtypes. Our research is focusing on the components of cellular RNA metabolism dysregulated in ALS, including lncRNA NEAT1 and RNA-binding proteins such as FUS and TDP-43.

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Stress granules and paraspeckles are prototypical RNP granules localised in the nucleus and cytoplasm, respectively. Recently, we found that despite their spatial separation, these two RNP granules are intimately linked. Our aim is to dissect molecular mechanisms behind paraspeckle-stress granule crosstalk.

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Many RNA molecules represent attractive drug targets. However, RNAs are traditionally thought to be difficult to target using small molecules. It is now increasingly appreciated that despite linearity and limited structural complexity, most RNAs contain complex 3D motifs in their structure that can serve as platforms for small molecule binding. We are exploring the possibility of using small molecules for targeting of protein-coding and non-coding RNAs to expand the boundaries of the druggable genome.

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Who are we?

Meet the team

Dr Tatyana Shelkovnikova

Group Leader

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Funding
Our work is/was kindly supported by:

  • Motor Neurone Disease Association
Senior Non-Clinical Fellowship: “Long non-coding RNA NEAT1 in motor neurone physiology and pathophysiology” (2018-2022)

  • BBSRC
Research grant: “Understanding the crosstalk between spatially separated RNP granules during cellular stress responses” (2021-2024)

  • MND Scotland
PhD Studentship: "Small molecule modulators of stathmin-2 splicing as a novel ALS therapy"(2022-2025)

  • MRC
Research grant: "Mechanistic studies of ALS-causative mutations and RNP-focussed drug discovery using in vitro reconstitution of RNP complexes" (2022-2025)


Previous funding:

  • Medical Research Foundation
MRF fellowship: “Dissecting the role of the paraspeckle in amyotrophic lateral sclerosis” (2015-2018)
  • Academy of Medical Sciences
AMS Springboard Award: “Developing tools to monitor expression of lncRNA NEAT1 isoforms for basic research and drug discovery” (2019-2021)
  • ISSF Wellcome Trust
ISSF Translational Kickstart Award “Identification of chemotypes selectively binding to a structured motif of lncRNA NEAT1 as templates for novel drugs” (2019-2021)
  • Welsh Government 
Sêr Cymru III – Tackling COVID-19 grant (2020-2021)

Read about our work

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Stay tuned with our latest achievements


5 April 2022
TS and Guillaume Hautbergue were awarded a 3-year MRC research grant to establish a biochemical assay for analysis of ALS-linked RNP complexes, suitable for screening of small molecules. The recruitment on this grant (3-year postdoctoral position, full time) to begin soon (will be posted here).

4 February 2022
TS and Kurt De Vos have been awarded a PhD studentship to identify drugs that modulate STMN2 splicing, by MND Scotland. Needless to say that we are honored and excited to be selected within this completive scheme. The project is currently advertised on Findaphd, until 6th May:
https://www.findaphd.com/phds/project/small-molecule-modulators-of-alternative-splicing-as-a-novel-therapy-for-amyotrophic-lateral-sclerosis-als/?p143014

6 September 2021
Lab has moved to SITraN, Sheffield. Exciting times!!

5 May 2021
Tatyana has been awarded a BBSRC grant, together with Nicolas Locker from Surrey, to look into the molecular mechanisms of stress granule - paraspeckle crosstalk.

16 March 2021
MND Research blog about our work was published, check it here: https://mndresearch.blog/2021/03/16/flexible-molecules-and-droplets-researching-and-targeting-rna-protein-complexes-in-mnd/

02 March 2021
Our study on the analysis of FUS aggregate composition is now available as a preprint: https://www.biorxiv.org/content/10.1101/2021.03.02.433611v1 

11 January 2021
The paper with our collaborators in Tokyo, Nevada and Moscow has been accepted for publication at the RNA Biology journal.

08 December 2020
Tatyana is this year's winner of the ENCALS Young Investigator Award!

07 October 2020
The lab has received a grant from the Welsh Government for a COVID-19 drug discovery project. Can't wait to start it!

04 May 2020
Our paper on neurological phenotypes in Neat1 knockout mice (previously available as preprint), with Haiyan, Camille and Tatyana as authors, has been accepted for publication in the Translational Psychiatry journal.

30 April 2020
Our paper on the effect of FUS frameshift mutations, with Haiyan, Camille and Tatyana as authors, has been accepted for publication in the Molecular Brain journal.

12 February 2020
Tatyana presented at CU School of Dentistry seminar: “Therapeutic targeting of RNA – expanding the boundaries of the druggable genome?”

14 January 2020
Tatyana invited to give a talk on paraspeckle regulation by stress granules at the RNA UK 2020 meeting
https://www.rnauk2020.org/

21 November 2019
Invited commentary on our J Cell Biol paper was published in Cell Stress
check free text: https://www.cell-stress.com/researcharticles/2019a-an-microbial-cell/

23 October 2019
Haiyan had her PhD viva – only minor corrections! Congratulations!!!

23 September 2019
The very first lab’s preprint, with Haiyan, Camille and Tatyana as authors, published on bioRxiv: https://www.biorxiv.org/content/10.1101/773333v1

Contact information

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  • SITraN, The University of Sheffield, 385a Glossop Road, Broomhall, Sheffield S10 2HQ, UK
 

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