The progression of cancer is driven by mutations and errors in the cell that promote the "hallmarks of cancer". These are a set of distinct behaviours that cells in tumours possess, enabling the survival and growth of the cancer. A longstanding observation in cancer cells is the Warburg effect; the switch away from oxidative phosphorylation to anaerobic glycolysis. Recent evidence has shown that metabolic reprogramming- large scale modification of how the cells process energy- is achieved by mutations in oncogenes including KRAS. This enables cancer cell survival in the tumour. Furthermore mutations in individual metabolic enzymes, such as fumarate hydratase, can affect a transition from epithelial to a mesenchymal morphology. Both the links between individual metabolites and cell behaviour, and the role of the metabolic network in cancer development however remains unclear. Knowledge of both of these are necessary to interpret metabolic changes in cancer and to identify new drug targets that are robust to network effects. Computational modelling offers the opportunity to formalise the relationships between elements in the network and to address this issue. However, conventional approaches based on ordinary differential equations (ODEs) and flux balance analysis (FBA) are not suitable. ODE models require precise physico-chemical parameters that are not available for human metabolism. FBA does not have this requirement but is not capable of modelling the accumulation of metabolites that can occur in response to mutation. I propose to use an "executable" modelling approach to construct models of the metabolic network and link them to cellular behaviour. Executable modelling approaches do not require detailed physical parameters, and can model accumulation events. They have the further advantage that they are amenable to a class of model analysis known as formal verification. Here mathematical proofs are used to offer guarantees of cell properties that are encoded in formal logic. These guarantees can apply over all possible states of the system and so offer a uniquely powerful way to test model correctness. This is particularly useful for highly robust systems such as the metabolic network, but also in taking account of rare events. This latter issue is particularly important when considering how rare events determine the development of cancer. Model building will be guided by the use of machine learning approaches (t-SNE, decision forests) to address publicly available expression data and metabolomic datasets shared with us by AstraZeneca. Finally, these models will be used to make novel predictions about the metabolism can change cell phenotype. The development of these models will allow us to understand how metabolic networks drive cancer progression and help us identify novel oncogenes and drug targets.

Musculoskeletal conditions are the most common cause of severe long term pain in the EU and lead to significant healthcare and social support costs. The prevalence increases with ageing, and as the lifespan of individuals is increasing and skeletal health is decreasing due to lifestyle factors such as obesity and lack of physical activity, the burden of bone pain on individuals and society is expected to further increase in the coming decades. Bone pain is notoriously difficult to treat with the available analgesics and there is a huge need for mechanism-based treatments. Therefore, it is pertinent to train highly skilled researchers to promote frontline research, innovation and education within bone pain. In BonePainIII we bring together 3 industrial beneficiaries, 4 academic beneficiaries, two industrial partners and three academic partners in a highly interdisciplinary and intersectoral network encompassing bioengineering, neuroscience, pharmacology, drug discovery and clinical medicine. BonePainIII will train a new generation of 10 creative, entrepreneurial and innovative early stages researchers (ESR), who in a doctoral programme will achieve research specific and transferable competences. The transferable skills program consists of workshops and courses covering essentials skills for a successful career in academic or non-academic sectors and includes entrepreneurship, knowledge transfer, open science, coding and artificial intelligence, communication, self-marketing, outreach, intellectual property rights, and environmental practices. A strong participation of the non-academic sector committed to hosting ESRs and to train through secondments and workshops ensures that the ESRs will be exposed to both academia and industry, and a gender balanced supervisor group will counteract gender-related barriers. Two major obstacles hamper drug discovery in bone pain: 1) the lack of understanding of the underlying molecular and cellular mechanisms of bone pain, and 2) a translational gap to the clinic. In BonePainIII, we will address these challenges through four integrated and ambitious, yet achievable research work packages.

In all animals, the sense of smell (olfaction) is fundamental for sensing the outside world with roles including for feeding, avoiding predators, social interactions, and reproduction. Much of the information for these smell associated behaviours is imprinted during early-life and in humans smell dysfunction is an early indicator of various behavioural disorders, including autism. The ways (mechanisms) through which smell develops in early life to influence subsequent animal behaviours, however, are largely unknown. Recently, we discovered that oestrogens (which are steroid hormones) regulate olfactory development in the embryo brain via a novel cell type which we have named oestrogen responsive olfactory bulb (EROB). In this project we will apply highly novel ways (so called CRISPR-Cas9 methods), developed by our industry partner (AstraZeneca), to remove (knock out) the key oestrogen receptor (called esr 1) in a highly controlled cell-specific and precisely-timed manner. This will help us to identify the role of esr1 in the development of smell and smell-mediated behaviour. The CRISPR-Cas9 methods we will develop will also allow other researchers to study other genes with much greater precision in the zebrafish model. In this work we will first knock out esr1 in zebrafish in specific brain cells (called glia, which include EROB) in a highly controlled and timed manner to provide the required zebrafish study models. We will then use these zebrafish models to establish what happens to the anatomy of the brain and the neural circuits in a key region of the brain involved in smell (the olfactory bulb) when esr-1 is knocked out. We will do this by analysing brain sections and measuring the different brain cell types, their structural arrangements and the neural circuits they form. We will then cross breed our esr1 knock out zebrafish with another genetically modified zebrafish in which brain neural activity can be visualised via imaging. With this new zebrafish model we will assess the effects of the glial-specific knock out of esr-1 during embryo development on brain activity in response to selected smells using imaging, and in subsequent juveniles and adults through studies on sections of the brain. Finally, we will use behavioural assessments to determine the consequences of knocking out esr1 in EROB cells on smell-mediated behaviours in larval stages, and on social-interaction in both larval and adult animals. We provide significant pilot data supporting our approach that includes showing that esr1 specifically affects the number of EROB cells during development. As a major step in creating a brain cell- specific conditional esr 1 knock out we have also already incorporated key genetic elements into a zebrafish line to facilitate this. Furthermore, we have established an imaging system which allows us to image neural activity in the whole brain, in real time. Our research will be of significant interest to a diverse audience including academic and industry researchers, and the medical profession, by providing new models to study smell and the roles of oestrogens in brain development and function. Our project will advance genomic editing tools for the research community relevant to anyone studying genes and their function in the zebrafish model. It will also be of great interest to industry and government regulatory bodies, as the models developed, for example, could be applied for advancing the risk assessment of chemicals with oestrogenic activity, supporting evidence-based decision-making for those chemicals. The wider public will benefit also from this research from improved understanding of basic life processes associated with smell, a sense fundamental to animal (including human) life.

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

Parkinson's disease (PD) is a devastating neurological condition. It affects over 10million people worldwide and UK data shows that the number of people affected will increase by 28% by 2020. The most obvious symptoms are altered motor functioning, although many patients experience non-motor symptoms. Up to half experience psychosis during the course of the disease. Visual hallucinations (seeing things that are not there) and delusions can be extremely distressing resulting in poorer quality of life and increased caregiver burden. Existing treatments for Parkinson's disease replace lost dopamine (a brain chemical) in the brain, but do not help with psychosis symptoms. Existing treatments for psychosis (as would be given to patients with schizophrenia) are ineffective or come with troubling side effects (sedation, heart and liver function) and regular monitoring visits. Brain imaging studies have shown that another brain chemical, serotonin, is involved in psychosis symptoms. We have gathered evidence to indicate that serotonin signalling through a particlar pathway in brain cells called the src-kinase pathway may be responsible for PD psychosis symptoms. If we can reduce activity in this pathway patients may see improvements in their symptoms and quality of life. A drug from cancer called saracatinib has been made available that reduces activity in the src-kinase pathway of the brain. Studies so far have shown that it can affect brain function and is well-tolerated. We wish to test this drug in patients with PD psychosis to show that this drug can reduce or normalise brain function in the brain areas that are associated with visual hallucinations and other disturbances. We will test the effects of 10 days of saracatinib against a dummy drug (or placebo) in 20 patients with PD psychosis and compare the effects to those without PD psychosis to see if it normalises brain function. We will use two brain measurements that are safe and well-tolerated for this study and ask patients to perform visual recognition tests or just rest while we take these measurements. If successful, this study will provide the basis to test the drug in larger samples which is necessary to develop a new treatment.