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.

Developments in our scientific understanding of biological systems highlight the complexity and interconnected nature of such systems. When integration of biological systems fails, disease can result. Thus, to advance both our understanding of these fundamental mechanisms, scientists from different fields are working together to address these biological challenges, and in turn develop better treatments for a range of diseases. This project will integrate cell biology with biophysics, artificial intelligence, chemistry, computational modeling and physiology, termed a convergent or trans-disciplinary approach, to problem-solve the fundamental question: how do hormones act on the female ovary- a complex organ of distinct interconnected cells. The ovary is a hub of female reproduction. Within the ovary, each egg is encapsulated in a highly organized group of cells, termed the follicle. Different cell types within the follicle respond to hormonal cues, communicating with the egg to ensure a single mature egg is released each month for fertilisation. A key hormone that develops the egg, causes its release and provides the hormones critical in early pregnancy if the egg is fertilized, is luteinising hormone (LH). LH coordinates these functions by binding to its specific receptor on the surface of the cell, the LHR. LHR is part of a large family of receptors called G protein-coupled receptors (GPCRs) with more than 800 different types that respond to light, smells, taste, chemical transmitters in the brain and a variety of different hormones. Thus, GPCRs are a popular drug target, however, there is high demand for new drugs that are more specific, have fewer side effects, and that are active for longer. Such developments require an in-depth understanding of the molecular mechanisms from complex biological systems to control receptor activity in a highly controlled manner. One important way receptors can modify how they communicate is by associating with each other. Our previous BBSRC-funded studies have dissected how LHR signalling is altered via its association with itself (homomers) and another important reproductive hormone receptor, the follicle stimulating hormone (FSHR) as heteromers. We have visualised LHR homomers and LHR/FSHR heteromers by employing a form of microscopy called super resolution imaging- a technique called photoactivated dye localisation microscopy (PD-PALM), which provides the ability to image single receptors on the surface of the cell. Our work has revealed that LHR receptors exist as monomers and a range of size of homomers/heteromers. Altering the pattern of these receptor-receptor association can change the type, duration and magnitude of signals generated inside cells. An outstanding and important question that remains is how the organization of LHR complexes contributes to LHR's multiple functions in the follicle. We will use our single molecule microscopy technique of PD-PALM with machine learning technology to create a novel automated platform to visualize LHR molecular complexes (receptor with it's signaling machinery) in the different follicle cell types and 'open' follicles that retains the communication with the egg. Combining PD-PALM images from follicle cells with computational simulations will unpick how LHR engages with each other, and employ novel chemical, small molecule and antibody tools to disrupt or manipulate these interactions to understand their role in regulating multiple ovarian functions via biophysical, biochemical and genetic methods. We anticipate that in the future, the information generated can be directly applied to improve the quality of life of women with conditions such as polycystic ovarian syndrome, hormone-dependent cancer, infertility, premature ovarian failure, and potentially applied to other diseases that involve GPCRs.

The 2019 World Health Organisation (WHO) report on Antimicrobial Resistance (AMR) identifies it as: "one of the greatest threats we face as a global community." The evolution of drug-resistant bacteria, our over-use of antibiotics and failure to develop new methods for tackling infection could leave us without viable treatments for even the most trivial infections within the next 3 decades. There have been significant efforts by the WHO and national agencies to raise awareness of AMR and reduce the use of antibiotics, but there is still an urgent need to intensify these efforts and, crucially, to develop alternatives. The aim of the programme is to address this need. The programme will consist of 4 interlinked work packages focussed on the core research objectives: (1) The development of human organoid models for studying interactions between bacteria and the tissue microenvironment and larger scale interactions with the host microbiome. (2) New microscopy methods to complement the organoid models and to facilitate rapid characterisation of bacteria for improved diagnosis. (3) New antimicrobial therapeutics and targeted delivery techniques to improve the use of existing antibiotics and provide viable alternatives. (4) "Drug-free" methods for treating infections and promoting immune function thereby further reducing the use of antibiotics and providing methods suitable for large scale environmental/industrial use. These will be supported by 2 parallel translational activities to enable development of the translational pathway and wider engagement with clinical and industrial stakeholders, policy-makers and the public.