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Department of Pharmacology

 

 

Dr Delphine Larrieu – Group leader

University Assistant Professor

E-Mail:
Tel: +44 (0) 763882

Lab website: www.larrieulab.com

 

Keywords

Nuclear envelope, lamins, premature ageing, ageing, nuclear ruptures, rare diseases, translation, synthetic rescue

Investigator biography

Dr Delphine Larrieu completed her Master's degree in Integrative and Cell Biology at the University of California, Irvine (UCI) and at the University of Grenoble, France. She then carried out her PhD at the Institute for Advanced Biosciences in Grenoble, working on tumour suppressor genes and their involvement in DNA replication and repair. In 2011, she moved to the University of Cambridge for her postdoctoral research in the Steve Jackson Laboratory, with personal funding from EMBO and from the Medical Research Council (MRC). During her time as a postdoc, Delphine developed a strong interest in understanding nuclear envelope function and its links with disease, more specifically premature ageing. In 2017, Delphine was awarded a Wellcome Trust Sir Henry Dale fellowship, to set up her own lab at the Cambridge Institute for Medical Research to pursue her research in the field of nuclear envelope. In 2022, she was appointed as an Assistant Professor at the Department of Pharmacology, University of Cambridge.

Delphine also has a strong interest in translational research. In 2020, she co-founded Adrestia Therapeutics, whose aim is to restore the biological balance in disease. She is also a scientific advisor for Shift Bioscience, whose mission is to discover new cellular rejuvenation pathways.

Research summary

Our lab is studying the nuclear envelope (NE), a crucial structure surrounding the cell nucleus. The importance of the NE is highlighted by the catastrophic diseases caused when it is dysfunctional. These include several cancers, muscular diseases, neurodegenerative syndromes and premature ageing syndromes (progeria). Importantly, NE dysfunction also occurs in physiological ageing but the mechanisms driving this remain unknown.

In the lab, we have implemented cutting-edge approaches, including whole genome CRISPR/Cas9 screens, to identify new players regulating NE function in ageing. This has led to the identification of new genes and pathways that can restore NE defects in progeria. Our lab is currently investigating the mechanisms behind this “synthetic rescue”. This work has also opened-up potential new therapeutic avenues for progeria that we are currently pursuing, and that could also benefit diseases associated with physiological ageing.

 

Lab members

Dr Anne Janssen – Alex Fleet – George Han – Denny Yang

 

Key publications

 

  • The BAF A12T mutation disrupts lamin A/C interaction, impairing robust repair of nuclear envelope ruptures in Nestor–Guillermo progeria syndrome cells. Anne F. J. Janssen, Agathe Marcelot, Sophia Y. Breusegem, Pierre Legrand, Sophie Zinn-Justin and Delphine Larrieu Nucleic Acids Research, Aug 2022, gkac726, https://doi.org/10.1093/nar/gkac726
  • Current Methods and Pipelines for Image-Based Quantitation of Nuclear Shape and Nuclear Envelope Abnormalities. Anne F. J. Janssen, Sophia Y. Breusegem and Delphine Larrieu. Cells, Jan 2022, 11(3), 347; https://doi.org/10.3390/cells11030347 2019
  • Abnormal microtubule dynamics disrupt nucleocytoplasmic transport in tau-mediated frontotemporal dementia. Francesco Paonessa, Lewis Evans, Ravi Solanki, Delphine Larrieu, Selina Wray, John Hardy, Stephen P Jackson, Frederick J Livesey. Cell Reports, Jan 2019 P582-593.E5
  • Inhibition of acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the Transportin-1 nuclear import pathway. Delphine Larrieu*, Emmanuelle Viré, Samuel Robson, Sophia Y. Breusegem, Tony Kouzarides and Stephen P. Jackson*. * Co-corresponding. Sci Signal. 2018 Jul 3;11(537).
  • Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome. Gabriel Balmus*, Delphine Larrieu*#, Ana C Barros, Casey Collins, Monica Abrudan, Mukerrem Demir, Nicola J Geisler, Christopher J. Lelliott, Jacqueline K. White, Natasha A Karp, James Atkinson, Andrea Kirton, Matt Jacobsen, Dean Clift, Raphael Rodriguez, Sanger Mouse Genetics Project, David J Adams, Stephen P Jackson#. *Co-authorship, #Co-corresponding. Nat Commun. 2018 Apr 27;9(1):1700.
  • A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome. Bar DZ, Arlt MF, Brazier JF, Norris WE, Campbell SE, Chines P, Larrieu D, Jackson SP, Collins FS, Glover TW, Gordon LB. J Med Genet. 2017 Mar;54(3):212-216.
  • Prelamin A impairs 53BP1 nuclear entry by mislocalizing NUP153 and disrupting the Ran gradient. Cobb AM, Larrieu D, Warren DT, Liu Y, Srivastava S, Smith AJ, Bowater RP, Jackson SP, Shanahan CM. Aging Cell. 2016 Jul 27
  • CRISPR-Cas9D10A nickase-based genotypic and phenotypic screening to enhance genome editing. W Chiang*, C le Sage*, D Larrieu, M Demir and Stephen P. Jackson. Sci Rep. 2016 Apr 15;6:24356.
  • Chemical inhibition of NAT10 corrects defects of laminopathic cells. Larrieu D, Britton S, Demir M, Rodriguez R, Jackson SP. Science. 2014 May 2;344(6183):527-32

 

Funding

Wellcome Trust – Leverhulme – Cambridge Gates