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How do healthy cells age - a worm's tale into the decline of DNA replication and the structure of the nuclear membrane.
Secondary Supervisor(s): Dr Zita Balklav, Dr Alice Rothnie
University of Registration: Aston University
BBSRC Research Themes:
- Integrated Understanding of Health (Ageing)
Project Outline
Background:
DNA replication is the fundamental process of all life, and maintaining accuracy in this process protects against development of disease. Onset of DNA replication requires formation of an intact nuclear membrane. Indeed, components of the nuclear membrane interact with DNA replication machinery, but the importance of these interactions is still unclear.
As healthy cells age, DNA replication accuracy decreases, while the integrity of the nuclear membrane also deteriorates [1, 2]. Such changes have never been studied together however and so the aim of this project is to determine which occurs first in ageing - defects in DNA replication or deterioration of the nuclear membrane?
For this project, we will use the C. elegans (nematode worm) model organism, which ages within 2-3 weeks and is highly conserved with humans. The project combines my expertise in DNA replication with that of Dr Zita Balklava (C. elegans expert) and Dr Alice Rothnie (expert in co-polymers for nuclear membrane analyses).
Objectives:
1. Monitor the health of DNA replication and the structure of the nucleus over the life span of the worms.
2. Isolate nuclei from cells at different stages of the life span. Extract sections of the nuclear membrane with co-polymers [3] and analyse the proteome of the nuclear membrane through mass spectrometry.
3. Determine the cellular localisation of a key component of the nuclear membrane, Lamin 1, as worms age, and also analyse its interactions with DNA replication factors.
This project will enable us to characterise how fundamental aspects of cell biology decline with age, and could potentially lead to the development of treatments to protect the accuracy of DNA replication in healthy ageing, reducing the occurrence of ageing-related diseases.
References:
1. Pathak, R.U, et al. Ageing Research Reviews, 2021.
2. Flach, J, et al. Nature, 2014.
3. Hawkins, O.P, et al. Biochim Biophys Acta Biomembr, 2021.