Multiple sclerosis (MS) is the most common inflammatory disease of the brain, affecting more than 130,000 people in the UK alone. One of the most prevalent and debilitating symptoms of MS is cognitive impairment, which affects attention and memory. During their lifetime, more than half of people with MS will experience an accelerated ageing of the brain and develop disabling cognitive deficits, whose causes have yet to be fully elucidated. One of the possible drivers of brain damage and ageing in MS is the malfunctioning of microglia, the immune cells that reside in the brain and spinal cord. Normally, microglia function as the brain's clean-up crew by removing damaged cells and fine-tuning the activity of nerve cells (or neurons). However, recent data has shown that in MS, microglia become chronically overactive because of the way they produce and consume energy (i.e., their metabolism). This overactivity contributes to a persistent state of inflammation that may impede the correct functioning of neurons and their connections. With this research fellowship, I aim to test the hypothesis that specific metabolic pathways in microglia affect how these cells respond to and modulate the activity of surrounding neurons. By understanding how different microglial metabolic states affect brain functions, we will be able to develop new strategies to combat cognitive decline in MS and possibly other brain disorders. In this fellowship, I will focus on three key objectives: 1. Identify metabolic regulators of microglial activation. I will use a mouse model of MS-like disease to identify the metabolic factors that influence microglial activation in adult and aged mice. To do so, I will use a combination of brain imaging and pathological analysis to investigate how microglial and neuronal activation change in different brain regions during chronic inflammation. I will then study how microglial metabolism is correlated to changes in the functional connections between neurons and related cognitive dysfunction. 2. Understand the effects of modifying microglial metabolism to modulate neuronal functions. I will use 2D and 3D human cellular models to understand how manipulating precise metabolic pathways in microglia affects the function of human neurons grown with microglia in a dish. I will study metabolic pathways that I previously discovered in microglia, as well as new metabolic targets identified during the prior objective. This setup will establish a direct link between microglial metabolism and its effect on neuronal functionality. 3. Develop strategies to target microglial metabolism and slow cognitive decline. Based on the combined findings from the first two objectives, I will identify precise metabolic targets to modulate microglial activation in vivo. My goal will be to find new ways to reprogram microglia from their chronic, overactive, inflammatory state to acquire protective functions that will sustain proper neuronal fitness and slow down cognitive decline. While the journey toward effective treatments for cognitive impairment is still long, this research fellowship represents a novel step forward in our understanding of the mechanisms involved. By investigating the relationship between microglial metabolism and neurons, we may be able to develop drugs and interventions that can reduce chronic inflammation in the brain and protect its delicate functioning. Importantly, findings from this research will have broad applicability to other neurodegenerative diseases that are characterised by chronic inflammation and cognitive decline, such as Alzheimer's and Parkinson's diseases.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Time is the quantity, which can be measured to the highest precision of all metrological quantities. We all benefit from this extraordinary precision in our everyday lives, as precision time enables synchronization of data packets in ultrafast broadband communication and the determination of our position by computing the flight times of radiofrequency signals in Satellite Navigation to nanosecond precision. These economically important applications rely on microwave atomic clocks, which in their commercial form are precise to 1 part in 10^14. We are currently facing a revolution in timing accuracy due to the invention of optical clocks and accessible ways of counting optical frequencies, which has already been recognised by the Nobel Price in Physics in 2005. These novel clocks already reach stabilities beyond 1 part in 10^18, more than 4 orders of magnitude beyond the state-of-the art. However, while the clock technology is progressing rapidly, there is still a lot to learn about how such a precision can be transferred to the user community in a practical and efficient way. Microwave links, such as used in current satellite time transfers, are impractically slow for such precision, while optical fibre links need expensive dedicated fibre connections and are limited to a few 100 km, making intercontinental connections impractical. In addition, at 10^-18 precision, effects such as general relativity coupling gravity to frequency are coming into play and make the transfer dependent on deformation of the continental plates in Earth tides and larger rain falls. ICON brings together world leading transportable optical clocks and world leading optical link space infrastructure to explore the limits of precision time transfer. Including work on making transportable clocks more compact and robust with world-leading atom chip concepts, we are aiming at bringing precision time to everyone - first researchers relying on precision oscillators and later in commercial applications for the benefit of wider society.