In addition to the genome, precise regulation of the proteome is now recognised to be a major contributor to organismal health and disease. Proteins of the proteome are regulated by various chemical modifications that together make up the epiproteome. One of the most important regulatory modifications of the epiproteome is made by the small conserved protein ubiquitin. Attachment of ubiquitin to substates serves many signalling roles, including regulation of substrate stability, cellular localisation, activity and conformation. Consequently, dysfunction of the ubiquitin system causes severe cellular stress and is a leading cause of developmental defects across different eukaryotes, including human pathologies such as neurodegenerative diseases, autoimmunity, cardiomyopathy, and genetic disorders like cystic fibrosis. So how does ubiquitin control so many different processes? Ubiquitin can be attached to substrates as a monomer or as an interlinked chain of ubiquitin molecules. In nature there are eight different ways in which ubiquitin can be attached to itself. These eight different topologies each serve as a platform for cellular signalling by associating with specific ubiquitin-binding domain proteins (UBDPs). Thus, distinct ubiquitin chain topologies can regulate different cellular processes. The importance of ubiquitin to health and disease has made it a major target for intervention strategies in biomedicine, pharmacology and in agricultural biotechnology. Consequently, synthetic ubiquitin variants and synthetic ubiquitinated proteins with novel properties have been engineered. However, engineering novel ubiquitin chain topologies that do not exist in nature has not yet been considered, yet offers the potential to generate completely new synthetic signalling platforms in vivo. Here we propose to build synthetic ubiquitin chain topologies that are completely novel and thus can be utilised as a unique cell signalling platform. To that end we will also use intelligent design to build new UBDPs that specifically recognise these synthetic chain topologies. Taken together, our approach has the potential to create new cellular signalling platforms to engineer solutions to combat disease in biomedicine and pharmacology, and mitigate the effects of climate change in agricultural biotechnology.

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.

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.

Malaria mosquitoes mate in swarms. They use their antennal ears to detect the mating partners through their flight tones. Because the swarm is noisy, and the mosquito flight tones faint, mosquito auditory organs are highly sensitive and complex. We discovered a few years ago that the mosquito ear is innervated by a complex neuromodulatory network of neurotransmitters that are released from the brain, what is called an efferent system. This system is unique as mosquitoes are the only insect where auditory efferent activity has been described. Because mosquito hearing is necessary for mosquito reproduction, we hypothesize that disrupting the efferent system could be an innovative target for mosquito control. In the initial fellowship period, we focused on studying two of there neurotransmitters, octopamine and serotonin, to analyse their auditory roles in the swarm context and the implications for mosquito mating. For the second fellowship period, we would like to build on these results and provide a better understanding of the underlying fundamental biology mechanisms and explore implications for malaria control. We will also study the auditory role of the inhibitory neurotransmitter GABA, which extensively innervates the auditory nerve. We aim at providing a comprehensive understanding of the role of individual neurotransmitters modulating mosquito audition and swarming behaviour and of the emergent properties of the system. We will also explore specific tools to disrupt mosquito audition and swarming behaviour and model the effects on malaria transmission.

To achieve Net Zero, we require a complete understanding of the climate impacts of Near-Term Climate Forcers (NTCFs). Aviation NOx emissions (ANE) represent a major uncertainty in aviation's NTCF climate impacts. Using new in situ constraints of observations of NOx, a series of state-of-the-art coupled chemistry-climate models, state-of-science emission inventories and by developing a range of new possible future emission scenarios we will constrain and reduce this uncertainty in REVEAL-NOx. In doing so we will address Themes 1.2, 2.1 and 2.2 of the Jet Zero call, enabling solutions for a reduction in aviation's non-CO2 climate impacts to be delivered through a better understanding of the need for any trade-offs. It is unlikely that we will get to zero NOx emissions from aviation, so it is paramount we fully constrain ANE radiative impacts in order to successfully deliver Net Zero aviation emissions.