Project Outline

Maintaining metabolic function is key to lifelong health. Changes in metabolism that disrupt cellular energy balance are now considered causative factors for multiple human diseases including diabetes, cancer and neurodegeneration.

For successful metabolic homeostasis, nutrient intake must be coordinated to the energy demands of the organism across multiple tissues of the body. Such signals are coordinated through highly conserved cell signalling networks, the concerted actions of which are essential to produce a balanced phenotypic response to changes in the nutritional environment. Yet many of these signals and their downstream targets remain poorly understood.

The core metabolic pathways that regulate energy homeostasis have been remarkably well conserved through evolution not only at the molecular level but also at the level of physiological output. For example, the highly conserved insulin/IGF-like signalling (IIS) pathway functions across diverse species to orchestrate the allocation of nutrients amongst different tissues to coordinate growth, metabolism and cellular maintenance. However, the cellular mechanisms by which this is achieved are not well understood. In this project, we will use Drosophila as a model system to study the role of such cell signalling mechanisms in metabolic regulation.

We will use a combination of genetic approaches alongside pharmacological inhibitors (where available) to manipulate the activity of key cell signalling nodes within the IIS pathway. We will then test how changes in signalling modulate the physiological responses to dietary changes and elucidate their downstream targets. Identifying the molecular mechanisms that drive metabolic homeostasis will be a key focus of this research. Other techniques used in the project may include gene expression analysis by qRT-PCR, behavioural assays, immunohistochemistry & confocal microscopy.

References

Laskovs M, Partridge L, Slack C. Molecular inhibition of RAS signalling to target ageing and age-related health (2022). Disease Models & Mechanisms 15 (10): dmm049627.

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.

Slack C and Partridge L (2013) Genes, pathways and metabolism in ageing. Drug Discovery Today: Disease Models 10: e87-e93.

Techniques

• 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.
• Immunohistochemistry and confocal microscopy