Our research
Health and wellbeing
Circadian (24-hour) rhythms are essential for all lifeforms, allowing physiology and behaviour to be optimally aligned to light and dark cycles. Our health and wellbeing depend on appropriately timed circadian rhythms with disruption contributing to:
- ageing
- obesity
- diabetes
- cancer
- addiction
- depression
- psychotic and cardiovascular disease
Around 30% of people experiencing sleep disorders and insomnia cost around 2% UK-GDP, equalling £40 billion a year. Furthermore, our population is getting older having wider medical and socio-economic consequences with ageing dampening daily rhythms in physiology and behaviour causing poor health in the elderly.
About half of the elderly population experience chronic circadian and sleep disturbances with Alzheimer’s (AD) and Parkinson’s disease (PD) causing more pronounced circadian deficits, with poor sleep contributing to disease pathology.
The Nobel prize was awarded to Drosophila researchers determining the fundamental mechanisms of circadian rhythms conserved from flies to humans. This molecular clock consists of clock genes which are rhythmically expressed in clock neurons controlling the circadian expression of genes encoding ion channels and receptors that drive daily changes in electrical activity.
This so-called membrane clock is vital for synchronising the molecular clock in different clock cells and communicating time-of-day information to the rest of the brain and body. The molecular clock is well-understood, but there is a lack of research on the membrane clock. We will address this crucial knowledge gap and the effect of ageing on both clocks.
Objectives
Our hypothesis is the membrane and molecular clock become synergistically weaker during the lifespan compromising circadian rhythms and the individual’s health during ageing. This predicts that disrupted molecular and membrane clocks significantly contribute to ageing.
The key objectives are to determine the conserved components and mechanisms of the membrane clock and how it ages by defining:
- The role of clock neuron excitability in circadian rhythms
- The mechanism of the membrane clock and effect of ageing
- The relationship between the membrane and molecular clocks
- How known ageing and senescence signalling pathways interact with the molecular and membrane clock
- If interventions designed to reverse age-dependent decline in the molecular and membrane clock can promote healthy ageing
Deciphering the membrane clock
Deciphering the membrane clock is important because it is composed of receptors and channels which are the first and third biggest targets for therapeutic drugs, therefore we will generate knowledge facilitating the development for chronotherapies and ageing.
In contrast to previous studies that are limited to certain aspects of the clocks, we address how the clock works as a whole spanning multiple levels from mathematical models to whole organisms across their lifetime.
To achieve this, we will take a unique interdisciplinary approach and leverage our prior work and world-leading expertise in:
- Harnessing the genetic tractability, and short-lived diurnal Drosophila to efficiently address the circadian objectives; quickly providing results that will inform computational models generating key hypotheses to test causality in aged nocturnal mice and for the first-time a diurnal rodent Rhabdomys, making our results more translatable to diurnal humans.
- Frontier bioscience tool development including:
- cutting-edge clock neuron electrophysiology incorporating computational modelling, AI and a new technology called dynamic clamp (DC).
- clock neuron and glia live cell-imaging and optogenetics, including developing novel subcellular ion and ageing reporters.
We will identify evolutionary conserved interventions to rejuvenate rhythms and behaviour improving health during ageing, potentially allowing our ageing population to continue to live well and independently.
CircadiAgeing research programme overview
Our team investigates the impact of ageing on circadian rhythms and vice versa (‘CIRCADIAGEING’), and whether interventions can reverse ageing.
Our holistic approach uses an extensive range of transdisciplinary techniques from the molecular to the organismal level across multiple timescales.
Organisms
Our behavioural studies in flies and rodents will test the effects of interventions on the ageing phenotypes.
Circuits, networks and synapses, and the molecular clock
Circadian clocks are entrained by the environment (light) and generate circadian behaviour. We will use imaging and optogenetics to measure and manipulate these neuronal networks, the molecular clock and interactions with glia in the mouse SCN and fly clock.
The membrane clock
We will determine the relationship between the molecular and membrane clock using electrophysiology and calcium imaging to study the signalling pathways responsible.
Pathways
We will investigate crucial intracellular metabolic and energetic pathways converging on the mitochondria.
Modelling
Mathematical models will test and inform experiments on the molecular, cellular and electrophysiological mechanisms of the clock, which will then be tested using dynamic clamp.
