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Stress and aging in the Nuclear Pore Complex and associated cytoskeleton: a 3D super-resolution light and electron microscopy study


   Department of Biosciences

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  Dr M Goldberg, Prof B Obara, Dr I Karakesisoglou, Dr T Davies, Dr J Marles-Wright  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Introduction: the nuclear pore complex (NPC) is the gateway into and from the nucleus. It has a barrier function, preventing non-specific leakage of macromolecules, as well as specific transport functions (e.g. import/export of transcription factors and mRNA). NPCs are physically linked to the cytoskeleton, the nucleoskeleton and chromatin. NPCs are thought to be critical during aging because many nucleoporins are “extremely long-lived proteins” which in post-mitotic tissue (e.g. nerves) have no turnover. Nucleoporins, therefore, accumulate damage, such as carbonylation (oxidative damage), during aging. Chemical and physical stresses may also cause related damage. NPCs then become leaky and inefficient, upsetting cellular homeostasis, leading to pathologies.

Aim: to test the hypothesis that NPC perturbations during stress and aging cause structural and functional dis-organisation of intestinal cells leading to loss of cellular homeostasis. To test this, we will determine how NPCs and cyto/nucleoskeletal interactions and functions are altered in response to aging/stress and what the consequences are.

Methodology: this is an imaging project. Imaging is at the forefront of much of bioscience and biomedical research and this is a fantastic opportunity to learn a unique combination of many of the most exciting methods in imaging, molecular/cell techniques and image analysis. We will use as a model system, the C. elegans intestine. This consists of just 20 post-mitotic cells, and worms have a life span of only 2-3 weeks. It is therefore possible to study the whole tissue at the molecular and cellular level, with no cell division, hence no nucleoporin turnover, allowing us to study chronological aging in a short time, as well as stress. We will use super resolution light microscopy techniques, of live and fixed worms, to determine the structural organisation of NPCs and cytoskeleton throughout the intestine. We will then see how this changes during aging and in response to chemical and physical stresses. The project will involve a role in developing image analysis software to quantify changes. We will then use state-of-the-art 2D, and 3D volume, electron microscopy. To test which proteins are important in aging or stress responses, we will use an induced degradation system to delete specific nucleoporins in the intestine and look for effects that correspond to aging or stress phenotypes.

Conclusion: this will appeal to scientists who are interested in cell biology with biomedical and industrial applications and want to be involved at the forefront of the imaging revolution, learning  cutting-edge techniques in molecular biology, imaging and computer science. 

HOW TO APPLY

Applications should be made by emailing [Email Address Removed] 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 [Email Address Removed]. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.

Informal enquiries may be made to [Email Address Removed]

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


Funding Notes

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.

References

Entry into the nuclear pore complex is controlled by a cytoplasmic exclusion zone containing dynamic GLFG-repeat nucleoporin domains. J Cell Sci. 2014 127:124-36. doi: 10.1242/jcs.133272.
Cell-intrinsic and -extrinsic mechanisms promote cell-type-specific cytokinetic diversity. Elife. 2018 7:e36204. doi: 10.7554/eLife.36204.
The intestinal intermediate filament network responds to and protects against microbial insults and toxins. Development. 2019 146:dev169482. doi: 10.1242/dev.169482. PMID: 30630824.
Three-dimensional data capture and analysis of intact eye lenses evidences emmetropia-associated changes in epithelial cell organization. Sci Rep. 2020 10:16898. doi: 10.1038/s41598-020-73625-9.
Culturing Keratinocytes on Biomimetic Substrates Facilitates Improved Epidermal Assembly In Vitro. Cells. 2021 10:1177. doi: 10.3390/cells10051177.
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