Protecting cells from mechanical stress, A novel role of cell-surface receptor LRP1 in extracellular matrix- nuclei communication

Description

This project will generate insight into fundamental processes of cellular mechano-adaptation, which plays a critical role in formation, maintenance, and regeneration of our body. Our exciting recent discoveries in this rapidly evolving field have led us to establish new collaborations with Aarhus University (Denmark), Ri.MED Foundation (Italy) and Newcastle University. These collaborations will ensure that we can successfully complete the project and exploit these new developments.

Cellular adaptation to mechanical strain (mechano-adaptation) is increasingly understood to be conferred by Lamin intermediate filament proteins located within the nuclear lamina. Upon mechanical stress, expression levels of Lamin-A and -C change rapidly to minimise nuclear damage and defects in a cell cycle, which could otherwise lead to diseases such as chronic inflammation, cancer and Alzheimer’s disease. However, the molecular mechanisms behind this regulation remained elusive until our recent discovery showing that the cell-surface receptor protein LRP1 is a rapid mechano-responder and regulates Lamin-A/C expression in cells.

We hypothesise that LRP1 senses extracellular mechanical loading, transmits these signals intracellularly and protects the cell nucleus from aberrant mechanical force by regulating Lamin-A/C abundance. This project will use biochemical, biophysical, proteomics, transcriptomics, imaging analysis and mouse models to investigate this hypothesis and to understand molecular basis for mechano-transduction via LRP1 and its biological significance. The specific aims are to:

1. Identify the proteins that LRP1 interacts with inside the cell.

2. Determine the role of LRP1 in stiffness and shape of cell and nuclear membranes upon local (single cell) and global (tissue) mechanical stimulation.

3. Elucidate the impact of LRP1 loss on the transcriptomic landscape upon mechanical stimulation.

4. Delineate the role of LRP1 on mechano-adaptation in mouse in vivo.

The student will be supervised by: Dr Kazuhiro Yamamoto (primary supervisor, https://www.liverpool.ac.uk/life-course-and-medical-sciences/staff/kazuhiro-yamamoto/) at Institute of Life Course and Medical Sciences, University of Liverpool (UoL)(https://www.liverpool.ac.uk/life-course-and-medical-sciences/) providing expertise in analysis of LRP1 and Lamin-A/C using biochemistry, cell and molecular biology, and histological analysis; Dr Riaz Akhtar (secondary supervisor, https://www.liverpool.ac.uk/engineering/staff/riaz-akhtar/) at the Department of Mechanical, Materials and Aerospace Engineering, UoL (https://www.liverpool.ac.uk/engineering/departmentofmechanicalmaterialsandaerospaceengineering/) providing expertise in biomechanics and nano-scale analysis of biological tissues; and Dr Louise Reynard (third supervisor, https://www.ncl.ac.uk/medical-sciences/people/profile/louisereynard.html) at Newcastle University Biosciences Institute (https://www.ncl.ac.uk/medical-sciences/research/institutes/biosciences/) providing expertise in genetics and epigenetics. The student will visit Dr Reynard in Newcastle, Prof Jan Enghild in Denmark and Dr Simone Scilabra in Italy to learn transcriptomics, proteomics and multiple data analysis, respectively, with access to the training courses including bioinformatics and mass-spectrometry practical.

HOW TO APPLY

Applications should be made by emailing  with:

·        a CV (including contact details of at least two academic (or other relevant) referees);

·        a covering letter – clearly stating your first choice project, and optionally 2nd ranked project, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University;

·        copies of your relevant undergraduate degree transcripts and certificates;

·        a copy of your IELTS or TOEFL English language certificate (where required);

·        a copy of your passport (photo page).

A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE AT https://www.nld-dtp.org.uk/how-apply. Applications not meeting these criteria may be rejected.

In addition to the above items, please email a completed copy of the Additional Details Form (as a Word document) to . A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.

Informal enquiries may be made to 

The deadline for all applications is 12noon on Monday 9th January 2023. 

Availability

Open to students worldwide

Funding information

Funded studentship

Studentships are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) for 4 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

Supervisors

References

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2) Heterogenous strain in tissue collagen show that high strains locally suppress degradation by collagenase. bioRxib (2021)
3) Lymphocyte DNA methylation mediates genetic risk at shared immune-mediated disease loci. J Allergy Clin Immunol (2020) 145(5):1438-1451. PMID: 31945409
4) Nano-Scale Stiffness and Collagen Fibril Deterioration: Probing the Cornea Following Enzymatic Degradation Using Peakforce-QNM AFM. Sensors (2021) 21:1629
5) Inhibition of shedding of low-density lipoprotein receptor-related protein 1 reverses cartilage matrix degradation in osteoarthritis. Arthritis Rheumatol (2017) 69(6):1246-1256