Influenza infections each year cause a major burden of sickness and death (greater than 250,000 deaths each year world wide). The most effective means of reducing illness caused by influenza is by vaccination. The influenza virus evolves by changing its surface proteins each year in response to selective pressure from the human antibody response. The World Health Organisation coordinates a massive effort to monitor the evolution of influenza around the world to try and identify the viruses that are most likely to cause infections in the coming years, and select the best candidates for manufacture into a vaccine. The methods used to do this are both new, by sequencing virus genes to monitor genetic changes, and old, by testing the antibodies that ferrets make to candidate vaccine viruses for cross-reactivity with circulating strains. Ferret antibodies are traditionally used because these animals are susceptible to influenza infections in a way similar to humans. Overall the effectiveness (reduction in risk of becoming ill with influenza) of the vaccines selected by these methods is quite poor at ~54%, so there is room for improvement. Recent technical developments have provided a new method to analyse the evolution of influenza that uses human monoclonal antibodies. It is these human antibodies that are thought to be driving the evolution of influenza in nature. We have shown that human antibodies isolated from vaccinated or infected individuals can detect changes in the virus that the ferret antibodies miss. In addition the changes that human antibodies detect frequently correlate with the changes that are appearing in the influenza viruses currently circulating in the human population. We propose to develop panels of human monoclonal antibodies that can help predict the future evolution of the virus, which will be distributed to the WHO Collaborating Centres around the world, for comparison to the standard ferret antibodies to see if this new technology can improve vaccine selection.

The gastrointestinal tract is a vital organ that converts our diet into useful digestible nutrients, contributes to the maintenance of water balance and protects our body from pathogenic microorganisms that are present within the lumen of the gut, along with large numbers of beneficial bacteria. In order for the gut to carry out its essential functions, it contains exquisitely specialised cells, including epithelial cells, immune cells, nerve cells and muscle cells. Intestinal epithelial cells are tightly connected to each other to form a sophisticated gatekeeping system that allows the selective transport of nutrients and water but keeps away harmful toxins or pathogenic bacteria. Immune cells constantly monitor the lumen and the wall of the gut and respond in case the essential intestinal barrier is breached. Finally, complex networks of nerve cells within the gut wall are responsible for generating intestinal movements that are essential for proper digestive function by activating the musculature of the gut wall. Since the intestinal epithelium is constantly exposed to harmful substances and pathogenic microorganisms, it is quite vulnerable and is often damaged. Normally this does not have detrimental consequences for an organism since all cells of the intestinal epithelium are continuously replenished by stem cells that are dedicated to producing constantly fresh epithelial cells. Although the continuous regeneration of the intestinal epithelium is essential for maintaining it in good working order, other cell types play a major role in keeping them healthy. In particular, glial cells, which normally accompany and support nerve cells in all parts of the nervous system, are also found in the vicinity of intestinal epithelial cells and release substances that are essential for maintaining the intestinal epithelial barrier; if these enteric glial cells are eliminated in experimental conditions, the barrier breaks down and animals die from acute inflammation of the small intestine. In addition, several studies have suggested that the inflammation that accompanies common gut diseases, such as Crohn's disease or ulcerative colitis, may also involve the abnormal interaction of glial cells with intestinal epithelial cells and immune cells. These observations support the idea that despite their specialised functions, the different cell types that make up the gut wall (and indeed any organ) need to work in concert in order to support its physiological roles. Despite the important roles of the intestinal glial cells in supporting the critical functions of the nerve cells and the epithelium of the gut, very little is known about their biology in healthy individuals and in disease situations. In this proposal we will aim at filling this knowledge gap by building on some of our own recent observations. In particular, we will identify and characterise the properties of the gliogenic stem cells which generate new glial cells throughout life. We will also identify conditions and signals that modulate the behaviour of intestinal glial cells. Finally, we plan to characterise molecules which are located within the nucleus and are important for these cells to maintain their properties and continue to generate new glial cells throughout adult life. Normal digestive function depends on the fine balance between the loss of old and the production of new cells in the different gut tissues and the optimal cross talk between the different cell types. Breakdown of such an equilibrium results in uncontrolled growth of cells (cancer), severe inflammation of the gut wall (inflammatory bowel disease-IBD) or inability of the gut wall to protect the internal environment of an organisms from toxic substances or pathogenic bacteria. Understanding how local glial cells contribute to the integrity and normal function of gut tissues, we can ultimately use these cells as a means to alter the course of common debilitating gastrointestinal disorders.

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.

We propose a new phase of the successful Mathematics for Real-World Systems (MathSys) Centre for Doctoral Training that will address the call priority area "Mathematical and Computational Modelling". Advanced quantitative skills and applied mathematical modelling are critical to address the contemporary challenges arising from biomedicine and health sectors, modern industry and the digital economy. The UK Commission for Employment and Skills as well as Tech City UK have identified that a skills shortage in this domain is one of the key challenges facing the UK technology sector: there is a severe lack of trained researchers with the technical skills and, importantly, the ability to translate these skills into effective solutions in collaboration with end-users. Our proposal addresses this need with a cross-disciplinary, cohort-based training programme that will equip the next generation of researchers with cutting-edge methodological toolkits and the experience of external end-user engagement to address a broad variety of real-world problems in fields ranging from mathematical biology to the high-tech sector. Our MSc training (and continued PhD development) will deliver a core of mathematical techniques relevant to all applied modelling, but will also focus on two cross-cutting methodological themes which we consider key to complex multi-scale systems prediction: modelling across spatial and temporal scales; and hybrid modelling integrating complex data and mechanistic models. These themes pervade many areas of active research and will shape mathematical and computational modelling for the coming decades. A core element of the CDT will be productive and impactful engagement with end-users throughout the teaching and research phases. This has been a distinguishing feature of the MathSys CDT and is further expanded in our new proposal. MSc Research Study Groups provide an ideal opportunity for MSc students to experience working in a collaborative environment and for our end-users to become actively involved. All PhD projects are expected to be co-supervised by an external partner, bringing knowledge, data and experience to the modelling of real-world problems; students will normally be expected to spend 2-4 weeks (or longer) with these end-users to better understand the case-specific challenges and motivate their research. The potential renewal of the MathSys CDT has provided us with the opportunity to expand our portfolio of external partners focusing on research challenges in four application areas: Quantitative biomedical research, (A2) Mathematical epidemiology, (A3) Socio-technical systems and (A4) Advanced modelling and optimization of industrial processes. We will retain the one-year MSc followed by three-year PhD format that has been successfully refined through staff experience and student feedback over more than a decade of previous Warwick doctoral training centres. However, both the training and research components of the programme will be thoroughly updated to reflect the evolving technical landscape of applied research and the changing priorities of end-users. At the same time, we have retained the flexibility that allows co-creation of activities with our end-users and allows us to respond to changes in the national and international research environments on an ongoing yearly basis. Students will share a dedicated space, with a lecture theatre and common area based in one of the UK's leading mathematical departments. The space is physically connected to the new Mathematical Sciences building, at the interface of Mathematics, Statistics and Computer Science, and provides a unique location for our interdisciplinary activities.

I have a long-standing interest in the intestine as a major source of signals that maintain whole-organism homeostasis and drive adaptive change. We recently discovered that the intestine engages in bidirectional communication with reproductive organs, revealing a novel gut-gonad axis that impacts food intake and gametogenesis. During the course of these experiments, we observed intriguing adjacency between organ regions that communicate with one another, raising the possibility that inter-organ communication is confined in space as well as time. In this proposal, I explore the idea that there is a spatial logic to how internal organs are arranged within the body cavity of animals, and that their geometry can both enable and confine inter-organ signalling. Using 3D images of adult Drosophila, we will gather volumetric data, building detailed 3D maps of the intestine and neighbouring organs. This will enable us to develop new quantitative methods to describe gut geometry and its inter-organ contacts, studying their stereotypy, variation amongst individuals and relationship with internal state. We will then use the powerful genetic toolkit available in Drosophila to identify the molecular mechanisms that make and maintain 3D intestinal geometry. With this multipronged approach, we will unpick this previously unrecognised level of organisation, and establish its roles in enabling and/or confining interorgan communication. Finally, we will apply our methodologies to investigate contributions of the intestine and its geometry to the viviparity of tsetse flies: an under-investigated form of reproduction in a biomedically relevant and economically damaging disease vector. By revealing a previously unrecognised level of biological complexity, we will help resolve current paradoxes in inter-organ signalling, shed new light on the physiology of organs and organisms, and explore the potential of gut-gonad communication as a novel population control strategy.