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Sexual dimorphism in nucleolar function: consequences for metabolism and ageing

Primary Supervisor: Dr Cathy Slack, Life & Health Sciences

Secondary supervisor: Dr Zita Balklava

PhD project title : Sexual dimorphism in nucleolar function: consequences for metabolism and ageing

University of Registration: Aston University

Project outline:

Sex is a key determinant of almost all aspects of animal physiology. Fundamental biological differences between males and females result in sexually dimorphic responses across a diverse array of phenotypes including metabolism and ageing. Furthermore, sexual dimorphisms impact on the pathogenesis of most, if not all, diseases, including metabolic disorders such as obesity and diabetes. However, despite the prevalence of sexual dimorphisms on phenotype, sex has historically been ignored in basic and preclinical research and so the underlying mechanisms that lead to many sex-specific effects are not well understood. As such, there is an urgent priority to redress this gap in the knowledge particularly where sex differences could impact on clinical outcomes.

The fruit-fly, Drosophila melanogaster, is a well-established and powerful model for the in vivo study of genes that influence both metabolism and ageing. More recently, as a sexually dimorphic species, Drosophila have been successfully used to further understand sex differences on these phenotypic outputs. We have recently identified the nucleolus as an important sexually dimorphic organelle in Drosophila. The nucleolus is the largest structure in the eukaryotic nucleus and as the primary site of ribosome biogenesis, plays a key role in cellular metabolism. Our preliminary data suggest that sex-specific differences in nucleolar function may be a major contributing factor to sexually dimorphic metabolic responses.

This project aims to further characterise the interplay between sex and nucleolar function to reveal fundamental new insights into how metabolic systems are co-ordinately yet differentially regulated in the two sexes. A full characterisation of the sex-specific differences in nucleolar structure and function across different tissues over the life-course of the fly will be performed. This information will be used to identify key regulatory pathways that could be mediating sexually dimorphic metabolic responses within the nucleolus during ageing. We will then use genetic tools to manipulate their activity to test whether sex-specific differences in nucleolar function are related to sexually dimorphic lifespan responses. Evolutionary conservation of sexual dimorphisms in nucleolar function will be examined using the nematode worm C.elegans. Collectively, these studies will help us to better understand the complex relationship between sex, cellular metabolism and ageing.

Key references:

  1. Tiku, V and Antebi, A (2018). Nucleolar Function in Lifespan Regulation. Trends in Cell Biology, 28: 662-672.
  2. Slack C, Alic N, Foley A, Hoddinott M, Cabecinha M, Partidge L (2015). The Ras-Erk-ETS pathway is a drug target for longevity. Cell 62:72-83.
  3. Slack C and Partridge L (2013) Genes, pathways and metabolism in ageing. Drug Discovery Today: Disease Models 10: e87-e93.

BBSRC Strategic Research Priority: Integrated Understanding of Health: Ageing

Techniques that will be undertaken during the project:

  • Genetic manipulations using transgenic technologies in Drosophila.
  • Drosophila physiological and behavioural analyses e.g. survival assays.
  • Gene expression analysis by quantitative real-time PCR.
  • Molecular biology e.g. PCR, cloning, genomic engineering.

Contact: Dr Cathy Slack, Aston University