This project seeks to solve the challenge of making complex '3 dimensional' molecules (here heterocycles) that are of interest and of use to the pharmaceutical industry. The proposed solution is to transform flat '2-dimensional' aromatic compounds into stereochemically and functionally diverse target molecules in just one step. The route that will be developed to transform readily available aromatic compounds into complex heterocycles uses catalysis to promote a dearomatisation (essentially here a reduction) reaction. This approach will revolutionise the way that such complex targets are made and give rapid access to molecules that were hitherto unobtainable. Here, the utilisation of very low loadings of a metal catalyst to allow an otherwise impossible or extremely difficult transformation is in itself a valuable and worthwhile goal that reduces the environmental impact of synthetic chemistry and is clearly of great interest to both academia and industry. We have plans to optimise the processes that are developed further so that they can use smaller amounts of easily available metal catalysts. This project will study all aspects of the catalytic dearomatisation reaction and in so doing will understand and exploit it fully. A team of academic collaborators and an industrial project partner (AstraZeneca) has been assembled and this will ensure that the work can expand to follow all worthwhile directions and also retain a focus on producing industrially relevant outputs. For example, we have the possibility to collaborate with specialist academic chemists as well as having access to the enormously diverse set of expertise found in the chemical industry.

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 the realm of oncology, immunotherapy has evolved as a powerful modality to treat several cancer types. Yet, heterogeneity in response and the problem of resistance remain critical challenges especially in pancreatic ductal adenocarcinoma (PDAC). Transforming Growth Factor-beta (TGF-beta) and Activin, members of the TGF-beta superfamily, are pivotal signalling pathways implicated in tumorigenesis, immune regulation, and therapy resistance. However, the precise roles these pathways play in mediating immune escape and immunotherapy resistance are still poorly understood. This research proposal aims to delineate the interplay between TGF-beta and Activin signalling pathways in the tumour microenvironment (TME) and explore how they modulate response to immunotherapy in PDAC. We propose to: 1) Investigate the role of TGF-beta and Activin in immune cell recruitment and function within the TME. 2) Characterize how alterations in these pathways correlate with immunotherapy resistance. 3) Evaluate the therapeutic efficacy of targeted inhibitors against TGF-beta and Activin pathways in combination with immunotherapy, using in vitro and in vivo cancer models. Methodologies to be employed include mouse models of PDAC, multiplex immunofluorescence, single-cell RNA sequencing using 10X Genomics, CRISPR/Cas9 gene editing, NanoString GeoMx technology for comprehensive spatial profiling and multimodal intersection analysis. These cutting-edge techniques will provide a multi-dimensional view of the cellular and molecular complexities involved. The study is designed to foster collaborative interdisciplinary research, engaging with both academic institutions and industry partners like AstraZeneca. Insights from this research could open new avenues for rational drug design and combination therapies with the potential to increase the effectiveness of current immunotherapeutic regimens. Ultimately, the findings aim to facilitate more effective treatment paradigms for cancer patients.

Diabetes affects close to 5 million people in the UK, a number that is likely to increase in the next decade due to an increasing rate of obesity. People with diabetes are unable to regulate their blood sugar levels, which are normally controlled by the hormone insulin. High blood glucose as a result of decreased uptake into cells can result in serious medical complication, including blindness, strokes, and necrosis of limbs. Insulin is produced in the pancreas, and induces cells of the body, primarily muscle cells, to take up glucose and re-balance sugar levels following meals. However, in people developing type-2 diabetes, skeletal muscle no longer responds properly to insulin - a condition known as insulin resistance. While diabetes can be treated with insulin injections, in type-2 diabetes, the most common form of diabetes, insulin resistance renders this therapy ineffective over time. Therefore, a more thorough understanding of the molecular pathways involved in insulin resistance would greatly facilitate the development of new treatments of diabetes. Culturing human cells in a dish provides an ideal platform for finding new drugs, as this avoids issues with species differences, ethical considerations and high costs associated with experimental animals. Cultured skeletal myofibers would be an ideal for studying glucose metabolism, because this tissue is responsible for ca. 80-90% of glucose uptake following meals. However, to date, their use in diabetes modelling has been hampered by the fact that they are contractile, and detach quickly from rigid plastic surfaces in conventional cell culture. In addition, myofibers require innervation by nerve cells called motor neurons to mature into the equivalent of adult human muscle. Researchers have used fat cells to model diabetes instead, but these cells differ in how they control glucose uptake, in particular with regards to cellular trafficking of the glucose transporter GLUT4, a key factor in the regulation of blood sugar by insulin. Here, we propose to fill this technological gap in diabetes research by adapting a 3D-coculture system developed by members of our team for neuromuscular disease studies to investigate insulin responses in muscle. The culture system combines motor neurons and myofibers derived from human induced pluripotent stem cell (hiPSCs) into a multi-well device suitable for high content imaging, a technology commonly used for drug screens. In the devices, muscle fibres are stabilized by a scaffold of aligned elastic nanofibers, which guide uniform growth of myofibers and prevent collapse. We will equip culture wells with nanofiber-based glucose biosensors to directly measure changes in glucose levels. We will incorporate genetic probes to aid the analysis: Motor neurons will be genetically engineered such that their activity can be controlled by light. Myofibers will carry a fusion gene of GLUT4 and red fluorescent protein, which will allow us to track the movement of GLUT4 in live cells in response to insulin and/or exercise. Our proposal combines microdevice manufacturing, hiPSC-derivation of tissue, and analysis of metabolic pathways into a new neuromuscular culture model of diabetes. By the end of the project, we will have established the neuron/myofiber co-culture system, shown that innervated skeletal muscle myofibers take up glucose and mimic insulin responses, and recapitulate the failure of these processes in diabetes. We will have carried out a proof-of-principle screen with potential pharmacological treatments to show the suitability of the system for future drug discovery.

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.