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 www.rcuk.ac.uk/StudentshipTerminology. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

This project is rooted in Ergodic Theory and Dynamical Systems, but also aims to have significant impact on Geometry. The main novelty will be to exploit techniques from Ergodic Optimization, a relatively new branch of Ergodic Theory and Dynamical Systems, to prove Optimal Hitting results in a symbolic dynamics context, and certain conjectures in Optimal Packing.

Pro-senescence therapies trigger a cell cycle arrest halting tumour growth. The lack of targeted therapies for Basal-like breast cancer (BLBC) makes this aggressive cancer an excellent candidate for pro-senescence approaches. We have used 2D, high-throughput phenotypic screening to discover pro-senescence therapeutics for BLBC combined with genome-wide siRNA screening [1] to identify pro-senescence targets. We aim to use 3D cell systems that mimic the tumor microenvironment to probe the mechanism of action of these novel compounds, to explore the consequences of pro-senescence within the tumour microenvironment and neighbouring healthy cells, and to further develop 3D screening platforms for pro-senescence therapies. Pro-senescence therapies are an exciting route to targeted therapy for cancers with an unmet clinical need such as BLBC [2]. The recent advent of 3D bioprinting has revolutionised the research and drug discovery landscape [3]. These 3D systems can: 1. faithfully recapitulate native cellular physiology; 2. provide invaluable mechanistic insights into cancer biology, e.g. by determining how drugs influence normal and diseased cells; and 3. enable scientists to unite this amenable technology with powerful screening platforms for drug discovery. This ambitious and multidisciplinary PhD programme is made up of three, interwoven aims. Aim 1. Determine the mechanism of action of pro-senescence compounds using 3D BLBC models Phenotypic screening for drug discovery has uncovered novel pro-senescence compounds. We will determine the efficacy of these compounds in 3D BLBC models and probe how the top compounds act to trigger cancer cell senescence, exploiting our candidate pro-senescence targets in mechanistic studies. Aim 2. Determine the impact of senescent cancer cells on the tumour microenvironment and surrounding healthy cells Senescent cells secrete a cocktail of pro-inflammatory molecules, termed the senescence secretory phenotype (SASP) [4], which could potentially 'uncloak' cancer cells and trigger anti-tumour defenses. However, the SASP of senescent cancer cells is virtually unexplored. Therefore, we will investigate the consequence of cancer cell SASP factors within the tumour microenvironment and, importantly, their impact on surrounding healthy mammary fibroblasts and epithelial cells in 3D bioprinted co-culture models using matrigel. Aim 3. Build a high-throughput 3D co-culture screening platform for pro-senescence drug discovery In parallel, 3D bioprinting approaches will be expanded to generate high-throughput co-culture models of cancer and healthy cells for translational research. This will develop a phenotypic screening platform which simultaneously enables drug discovery (in cancer cells) and drug safety testing (in healthy fibroblast and epithelial cells) using human 3D co-culture models.

Unlike conventional electron microscopy (EM), cryo-EM samples are neither dehydrated nor stained and so the structure of samples remain close to the shape for the hydrated structure in the native environment. Large macromolecules and subcellular structures are proving to be excellent targets for cryo-EM. We are applying for funds for the acquisition of a cryo-electron microscope (cryo-EM) to transform the impact of our research in structural molecular biology and cell biology. Recent advances, which include direct electron detectors and data processing to correct for molecular movement in the electron beam, have revolutionised cryo-electron microscopy making it possible to determine atomic resolution structures of macromolecules and nano-machines. The results will be transformative for research in structural biology and cell biology at Queen Mary University of London. This proposal is especially timely as we have recently employed structural biologists who need access to cryo-EM (Darbari, Garnett, Milanesi), just secured access to a Titan Krios for high-resolution data collection (Pickersgill co-I), and we have a number of active and of developing projects in healthy ageing through the lifecourse, combating antimicrobial resistance, synthetic biology and bioenergy for which cryo-EM will provide a step-change in understanding the biology of the systems. We also have several existing staff who need to access cryo-EM, both single particle analysis and cryo-tomography to allow ultrastructural imaging. Finally, we have four further appointments to make in these areas in 2017/18. The equipment will also transform our ability to train the next generation of researchers, both our undergraduate students (MSci) and PhD students including those from the BBSRC LIDO DTP.