The problem: Sepsis is a common, out-of-control immune response to infection which often causes people to become critically ill and require admission to intensive care. Sepsis is a leading cause of death world-wide. Red blood cells carry oxygen around the body through small blood vessels. Sepsis causes blood flow through the blood vessels to become abnormal, so that some areas may not receive enough blood flow and hence not enough oxygen. Without oxygen, cells in the body stop working and die, causing vital organs, such as the kidneys and heart, to fail. Ultimately, this organ failure leads to critical illness and death. Sepsis also causes damage to special cells, called endothelial cells, which form the inner lining of blood vessels. As a result, the blood vessels become "leaky", allowing fluid to move from the blood vessels into surrounding areas. This leaked fluid causes swelling of the areas surrounding the blood vessels, making it even harder for oxygen to reach the cells where it is needed. A key treatment for sepsis is to give fluids intravenously, that is directly into a vein, in order improve blood flow around the body. However, there is evidence that too much fluid may be harmful, perhaps even making patients with sepsis more likely to die. Giving fluid may cause more damage to the lining of blood vessels, thereby making swelling worse. This additional swelling makes it even more difficult for oxygen to be delivered to where it is required, resulting in the failure of multiple organs. It is clearly very important to establish the effects of intravenous fluid on blood vessels and blood flow in people with sepsis, as it may be either helping or causing harm. It is also important to find out if any drugs can protect the blood vessels from damage in the first place or control the immune response to infection. The Research Proposal: We will give healthy volunteers a substance derived from bacteria, known as lipopolysaccharide (LPS), by injection into a vein. LPS has been safely and reliably given to hundreds of people over several decades. It causes a predictable and very mild sepsis-like state for a few hours, similar to a mild flu. Symptoms can be treated with Paracetamol, although this is usually not required. People who are given LPS recover fully within 24 hours or less. This will be carried out in a fully equipped medical research centre with trained intensive care doctors. We will use a specialised camera that will allow us to see the small blood vessels under the tongue. We will measure blood flow and look at blood vessels before and up to 24 hours after giving LPS. We will also take blood samples at intervals to look at the immune response to receiving LPS. After giving LPS, some volunteers will be given intravenous fluids, and some not. By comparing the two groups, we can see what effect, if any, intravenous fluid has on blood flow, on small blood vessels and on the immune system. As well as intravenous fluids, we also plan to investigate the effect of a drug called imatinib, a very safe drug used for decades to treat a type of leukaemia. A number of studies have shown that imatinib may also help protect endothelial cells from damage. Some of the volunteers will be given imatinib and some will not. Again, by comparing the blood flow, blood vessels and blood markers of the immune response, we will be able to see if imatinib has any beneficial effects. Applications and Benefits: Through this study, we hope to establish the effects on small blood vessels and on the immune system by giving LPS to healthy human volunteers in order to produce a mild sepsis-like state. We also aim to understand the effects of intravenous fluid and imatinib treatment in people with this sepsis-like condition. Our findings will help us to design future clinical trials to see if different ways of giving fluid, or imatinib, can help real world patients with sepsis. This project will lead to better treatment of sepsis.

DIALECT aims to combat diabetic foot disease through personalised medicine, by establishing an innovative, international, interdisciplinary and intersectoral research and training effort that will deliver the next generation of leading, entrepreneurial and creative scientists to reinforce the European innovative workforce. This is both timely and urgent, illustrated by that the burden of diabetic foot disease is in the top-10 of all medical conditions, and emphasized by the fact that every 20 seconds someone in the world loses a leg because of foot disease. Currently, we lack success in delivering the right treatment to the right person at the right time to prevent foot ulceration and amputation. We will provide unique world-class interdisciplinary and intersectoral training to a new generation of high-achieving early stage researchers in the areas of biomechanics, activity behaviour and footwear related to diabetic foot disease. A well-balanced consortium of academic, industry, healthcare and implementation partners will deliver the carefully designed DIALECT training network, comprising training through research, structured network-wide training events, intersectoral secondments and future work skills training. This will result in a paradigm shift towards personalised medicine that goes beyond state-of-the-art, by developing new personalised risk stratifications, biomechanical foot models, innovative activity and adherence profiles, wearable technology systems for biomechanical and activity monitoring, and personalised optimised footwear intervention products. DIALECT will provide ESRs with a comprehensive skillset capable of delivering high-quality scientific and industry solutions to develop into leading innovators in the European healthcare sector, who are highly employable and ready to engage and lead the next European generation of scientists-entrepreneurs to expedite progress in reducing the patient, societal and economic burden of diabetic foot disease.

Our bodies are made up of trillions of cells, each of which contains an array of specialised compartments, known as organelles. Each type of organelle has its own important job to do, but must also cooperate with other types of organelles to form an integrated network that keeps cells alive and healthy. Efficient inter-organelle teamwork is particularly critical in the brain, where the unique properties and functions of nerve cells (neurons) place extra demands on organelles. Indeed, dysfunctional organelle cooperation has been implicated in many neurological and neurodegenerative diseases, which are a major socio-economic burden in the UK and beyond. One way organelles within a network 'talk' to each other is by sharing information, signals and resources at points of physical contact called 'membrane contact sites'. Orchestrated cooperation between organelles at membrane contact sites is vital for cell function and survival. Despite this, how most organelles communicate at contact sites, and for what purposes, is still unclear. Because we do not yet understand this, we do not know which processes are compromised during disease, or how to correct these using medical treatment. This research project seeks to identify and characterise the machinery that mediates organelle communication, and reveal the cellular processes that benefit from this cooperation. This knowledge will significantly advance our understanding of cell biology and provide new insights into how detrimental changes in organelle communication cause disease, and might one day be targeted for new treatments. Given the immense social cost of declining brain function in ageing populations, my research will focus on nerve cells, where my aim is to explain: the mechanisms and functions of inter-organelle communication within nerve cells how faulty organelle communication leads to disease how organelle communication can be therapeutically targeted to improve nerve cell health I will use my existing expertise to concentrate on two organelles, namely peroxisomes and mitochondria. Peroxisomes act as factories within the cell, making and breaking-down important cellular molecules, while mitochondria are 'power-houses' that generate most of the cell's energy. Both are essential for cell survival and play crucial roles in healthy brain function, with inherited defects in either organelle causing devastating diseases that are frequently associated with neurological decline. Peroxisomes and mitochondria are closely linked because they act in concert to 1) process fat molecules within the cell and 2) control levels of potentially harmful 'free-radical' molecules that can damage cellular components. Peroxisome-mitochondria communication appears to be particularly important in the brain since nerve cells contain more peroxisome-mitochondria contacts than other cell types. Despite this, membrane contact sites between peroxisomes and mitochondria, their roles in nerve cell function, and their contribution to disease, are poorly understood. I will use my expertise in a variety of cutting-edge cell biology, microscopy and large-scale screening techniques to address three specific objectives: How do mitochondria and peroxisomes physically interact? What is the function of peroxisome-mitochondria communication in nerve cells? Can modulating peroxisome-mitochondria communication improve nerve cell health? The insights generated will fundamentally advance our understanding of organelle communication in health and disease, and inform future studies on other crucial organelle interactions. Furthermore, in conjunction with my collaborators in the pharmaceutical industry, this knowledge will ultimately drive the development of treatments that improve nerve cell health in a variety of diseases where these processes are dysregulated.

DNA methylation (DNAm) is an epigenetic mechanism that plays a central role in gene regulation. It helps to define how cells respond to genetic and environmental signals and, ultimately, contributes to whole system health and disease status. Levels of DNAm differ from one person to another. However, it is unclear how much of the variation in DNAm levels is caused by genetic or environmental factors and if such effects also relate to human phenotypes. Understanding the relationships between DNAm, genetics and environment is essential for both understanding pathways of health and disease and disease consequences. Prior research has been limited to populations of European ancestry, restricting understanding of DNAm variation to limited contexts. This is a crucial knowledge gap because there are known genetic and environmental differences in drug response and disease risk factors across population groups worldwide which may be attributable to DNAm variation. Evaluating DNAm variation in diverse population groups allows comparison across varying genetic and environmental exposure profiles. Identification of disease pathways common to all populations will represent mechanisms of health and disease that are common across all humans. This allows identification of drug targets that will be effective in any population group. Identification of disease pathways restricted to specific genetic and/or environmental exposure profile will reflect adaptation to environmental and genetic context. This will allow identification of molecular mechanisms that underpin the disease discordance that we observe across global populations and highlight opportunities for targeted treatments. Our first project aim is to map genetic and environmental determinants of human DNAm variation to understand mechanisms of DNAm variability. We will generate a catalog of genetic associations with DNAm across populations worldwide. This catalog will be used to assess which of the identified genetic associations with DNAm are also associated with human complex traits. This is important because the findings can inform the functional role of phenotype-associated genetic variation, and ultimately - our understanding of the mechanisms underlying human phenotype variation. The second aim of the project is to understand mechanisms of disease and disease discordance observed between population groups for childhood and cardiometabolic disease related phenotypes. This project focusses on childhood and cardiometabolic disease for which there is substantial disease discordance and health disparity across populations. For example, diabetes risk is substantially higher in individuals of South Asian origin even after accounting for known genetic and environmental risk factors. Identification of DNAm variation associated with type 2 diabetes that is context specific will contribute to explaining excess type 2 diabetes risk in the South Asian population group. In doing so, Identification of disease pathways restricted to specific genetic and/or environmental exposure profiles brings the opportunity to target treatment or intervention where it is effective. This research builds a global partnership of teams to bring together genetic and epigenetic data collected from individuals worldwide. A key aspect of this proposal is building equitable partnerships between these teams. This is essential in order to build capacity for research in genetically diverse datasets and to provide internationally relevant research on cardiometabolic and child health phenotypes Identification of common and context specific mechanisms of health and disease mediated by DNAm is of high health impact because it will enable actions to reduce global health disparity and inequity via targeted interventions or treatments.