For regenerative medicine to fulfil its potential, we must understand how cells form functional tissues. Currently it remains elusive how cells integrate mechanical and biochemical signals into a coherent response. The cell tensegrity model proposes that cells’ stability is provided by actomyosin-mediated tension being balanced by tension-resisting structures, such as adhesions. Cell tensegrity predicts that as localised forces are applied to cells, stress is distributed, modulating disparate mechanoreceptors providing an integrated response. By developing a cell culture system where forces can be applied via ferromagnetic beads to specific cell locations, such as the apical surface, I aim to examine if stresses are indeed distributed to distant regions within cells. I will assess if stress distribution is mediated by myosin II activity, as predicted by cell tensegrity. Furthermore, by utilising the mechano-sensitive Hippo pathway, which is also regulated by biochemical signals, I will assess if stress distribution influences a cells response to chemical cues. This will aid in developing a cellular in silico model of stress distribution that will be employed to examine the integration of signals during tissue formation. Ultimately, the hope is that this work will provide important insights that will contribute to advances in regenerative medicine. Regenerative medicine, where damaged tissues are replaced with artificially grown healthy copies, promises to provide major benefits to human health. To make this a reality, we need to understand how cells, the building blocks of life, behave appropriately, and not wildly like cancer cells. Biologists know that cells can sense their surroundings and change their behaviour accordingly. For instance, if cells are stretched they will make more cells to reduce the amount they themselves are stretched However, in tissues cells exist in environments where they get mixed signals, telling them to do different things. It remains a mystery how cells are able to process all of these messages into a coherent response, such as whether to grow or die. I aim to grow cells in an environment were I can give them conflicting signals to see how they respond. I will stretch cells and see if they produce a signal indicating they are growing, and then see what happens if I give them the opposite message, telling them not to grow. The aim is to build a computer model allowing us to understand and predict how cells would behave in different environments, hopefully helping to make regenerative medicine a reality.

During development, pattern formation and tissue growth must be coordinated, suggesting that feedback mechanisms exist between these two processes. Indeed, in some systems, the signals that control pattern formation have been found to be required for growth. Tissue growth is also regulated by dedicated - local and systemic - signals that convey information about tissue architecture and nutritional status. We propose to investigate how these pro-growth signals are integrated. As a first step, we will uncover how patterning signals link molecularly with the cellular growth control machinery. As a model system, we will use Drosophila wing imaginal discs. To overcome the delays associated with traditional genetic analysis, we will develop optogenetic and thermo-sensitive means of controlling signal transduction, focusing on Wingless, a Wnt, and Dpp, a TGF-ß. These tools will be used to identify the patterning signals’ immediate early targets that promote growth, perhaps through regulation of known transducers of systemic signals. In addition, we will investigate whether the activity of patterning signals might be affected by the growth rate, as this could account for scaling. These experiments will uncover, in molecular detail, how various signals are integrated to ensure that tissues grow in a timely and proportionate manner.

Gametocytes are the only stage of the malaria lifecycle that can be transmitted from humans to mosquitos to sustain disease transmission. Prior to being taken up by mosquitos, immature gametocytes sequester to the bone marrow where they extensively remodel the host cell in which they reside. For example, gametocytes can infect nucleated erythrocyte precursors, leading to a delay in erythroblast maturation. There is also evidence that parasite proteins exported onto the host cell surface are critical for mediating cell- cell interactions leading to the secretion of cytokines involved in angiogenesis, leading to remodelling of the bone marrow microenvironment. However, the parasite effectors responsible for these critical remodelling events remain to be identified. The aim of this proposal is to describe the mechanisms underlying the key remodelling events in gametocyte infected host cells and determine which parasite effector proteins are responsible for mediating them. Using state-of-the-art single-cell approaches I will identify what erythroblast developmental pathways are perturbed upon gametocyte infection. I will also use a combination of reverse genetics and mass spectrometry to identify which effectors are responsible for host cell subversion and mediating cell-cell interactions. Overall, this work will identify key regulators of host cell remodelling required for malaria parasite transmission.

Tissue maintenance and repair depend on stem cells that replenish cellular compartments reduced by physiological turnover or disease. Despite the essential function and unavoidable attrition of the enteric nervous system, a major branch of the peripheral nervous system that controls digestive physiology and gut homeostasis, the mechanisms controlling its cellular integrity and regeneration remain unknown. We will test the hypothesis that mammalian enteric glial cells (EGCs) exhibit neural stem cell activity and determine whether this is a property of a defined EGC sublineage or can be exhibited by a wider population of EGCs. As a first step, we will define the transcriptional hetrogeneity of EGCs and uncover the dynamic behaviour of moleculary defined supopulations during homeostasis or in response to gut pathology. Quantitive analysis and intavital imaging will inform the dynamics of EGCs within the gut microenvironment. The generation and functinal integration of enteric neurons into intestinal neural circuits will also be analysed.Finally, we will characterise niche signals and cell intrinsic transcriptional programmes that control fate decisions of EGCs, namely their choice to remain quiescent, enter the cell cycle and differentiate into neurons. Our work will advance the fields of neural stem cells, glia cell biology and gastroenterology. The gastrointestinal system is essential for digestive function and health. Not surprisingly, the complex physiological processes of digestive function are controlled by intricate regulatory systems, including vast neural networks that are embedded within the wall of the entire gastrointestinal tract. As in other parts of the nervous system, it is expected that the neural networks of the intestines are very dynamic and at least some of their cells are lost due to normal attrition or disease. Nevertheless, we know very little about the mechanisms that maintain the nervous system of the gut in good functional order and the cell types that are likely to be mobilised to replace potential intestinal neural cell losses. In our studies we will use a range of experimental approaches to characterise the dynamic behaviour of neural cell networks of the gut and understand the biological mechanisms that control their maintenance and regeneration in adult life.