Prenatal development may influence childhood and even adult disease (Barker-Hales hypothesis). In the lung, airway smooth muscle (ASM) surrounds developing airways and may participate both in fetal lung development and also childhood asthma. Given both asthma and disordered lung development (e.g. related to prematurity or birth defect) are common, there is international consensus that greater study of prenatal ASM is required to improve chances to treat such diseases. We recently showed prenatal lung harbours pacemakers whose rhythmic ASM contractions spread via the fetal airways and appear related to lung growth. The latter relationship is supported by the observations that (i) developing ASM produces a factor essential for lung growth and (ii) specific disruption of calcium signalling in ASM halts both airway contractions and prenatal lung growth. We will investigate how the ASM pacemaker emerges and how ASM contractions relate to lung growth using cell and lung culture, calcium imaging and techniques to screen gene expression. Given the information currently available, the present project can expect to extend our knowledge of ASM development considerably. We may therefore discover new approaches to not only improve prenatal lung growth but also ameliorate ASM dysfunction in asthma.

Progression of a disease or condition as it develops over time can be monitored in many ways, which can be collectively referred to as biomarkers. Some of these are very familiar, such as blood pressure and cholesterol levels. Others are used to convert the results of tests and examinations into numerical scores, such as the stage of a cancer or a performance index of activity. Still others are the results of psychological questionnaires used to describe intangibles like mental health or quality of life. This proposal aims to develop statistical methods to investigate how the patterns over time in biomarkers relate to prognosis for the patient and in particular the timing of clinically significant events. For example, we all know that a high cholesterol level leads to an increased risk of a heart attack, but is the risk for someone whose cholesterol level has risen gradually over several years the same as for someone whose cholesterol has increased to the same level in a much shorter time? And what about someone whose cholesterol has stayed constant at the same high level for many years? To answer questions like this we need to develop statistical models to describe the complex relationship between the biomarker and the clinical events. The models need to take into account errors in the measurement of the biomarker and the variability observed between people, so as to be able to detect genuine patterns in the type of data observed in practice. The models will be used to exploit biomarker data in providing accurate prognostic forecasts of clinical events, enabling identification of individuals in whom early intervention may be warranted to prevent adverse events. They will help the patient and their doctor to make the best treatment choice. The models can allow researchers to assess indirectly, but very quickly, the effect of a new drug or therapy, by examining its effect on biomarker patterns rather than waiting for the clinical event to occur. The proposal is built around three important medical areas: epilepsy treatment, cardio-thoracic surgery and renal transplantation. The multidisciplinary research team includes clinical specialists in each medical area as well as experienced statisticians from Liverpool and Lancaster Universities. Although there are currently no plans for direct communication to the public of the high level research methodology to be developed, specific medical results will be disseminated by collaborators through relevant Patient Association groups.

One of the specific United Nations Sustainable Development goals is to end epidemics of neglected tropical diseases by year 2030. Some of the most devastating of these diseases are caused by trypanosomatid parasites that are transmitted to humans via the bites of infected insects from the order Diptera (Flies). While most natural fly vectors pose a challenge to study under laboratory conditions, Drosophila melanogaster, with its well-established molecular, genetic and genomic toolkit and a vast amount of prior knowledge of its biology, is a proven model for experimental studies. Because D. melanogaster is host to several natural parasites that belong to the trypanosomatid group, it can also serve as a model for studying fly-parasite interactions. In this project, we propose to take advantage of the Drosophila melanogaster Genetic Reference Panel (DGRP) to investigate the genetic basis of fly susceptibility to trypanosomatid infection. First, we will perform a genome-wide association study (GWAS) for natural susceptibility to trypanosomatid parasite using a well-developed DGRP mapping resource to map genetic variation in susceptibility. Further, we will also test for differences in gene expression associated with infection susceptibility, using RNA sequencing, and validate the candidate genes identified with GWAS and RNA sequencing. Together, along with the well-annotated Drosophila genome, these data will reveal functional pathways affecting susceptibility to trypanosomatid infection. The established Drosophila-trypanosomatid system can serve as a functional model for insect-vectored diseases in medically and economically relevant species of Diptera.

The Cockcroft Institute will be an international centre of excellence in Accelerator Science and Technology. It will provide the intellectual focus and the essential scientific and technological facilities in Accelerator Science and Technology Research and Development, so that UK scientists and engineers are able to take a global lead in accelerator design, construction, and operation. It will assume the central role in organising, coordinating and sustaining the contributions of the UK to accelerator facilities worldwide, such as to the next electron-positron linear collider and a neutrino factory. It will facilitate and underpin the development of new technologies in UK industry to enable the nation to take full advantage of the substantial commercial opportunities which arise in the construction of such global accelerator projects. The Institute's mission is summarised in the following deliverables: 1. generic research and development (R&D) in Accelerator Science and Technology; 2. project specific R&D in Accelerator Science and Technology (e.g. a linear collider and a Neutrino Factory); 3. leadership and management of national deliverables to international facilities (which may be UK-situated); 4. competence in crucial and specific technologies; 5. technology transfer to industry both nationally and regionally; 6. staff complement of internationally acknowledged expertise; 7. seamless involvement of the HEI and CCLRC sectors; 8. education and training to ensure a flourishing staff supply side. The Institute's role and impact in delivering its mission is greatly enhanced by the coordination and focus provided by its location in a purpose-built centre with convenient links to nearby HEIs.

In order to survive human cells must continuously release and internalize both soluble and membrane bound factors. The most common method by which cells release factors such as serum proteins, peptide hormones and antibodies is called ?exocytosis?. In human cells exocytosis can happen in three ways. Every cell in our body is constantly producing small vesicles, which fuse to the plasma membrane. This is how we replenish the external membrane around our cells. In addition some specialized cells like neurons and secretory cells posses a population of specialized vesicles or granules, which only fuse with the plasma membrane when the cell is stimulated. It is very important that this form of exocytosis is tightly controlled as neurons must only transmit signals at the appropriate time, and the level of molecules like peptide hormones released into the circulation must be carefully controlled. Because exocytosis is an essential process, it is not surprising that defects in this process can result in different forms of human diseases including neuronal and immunological disorders, reproductive problems and diabetes. Although we now have a fairly good understanding of how exocytosis works in human cells there are still many things that we do not understand. To increase our understanding of this important process we plan to use a range of complementary technologies to build maps that show which proteins interact at different stages of exocytosis. We also intend to use new techniques to study these interactions in living cells. By building these ?living maps? we will have a much better understanding of how exocytosis is controlled in different human cells. This information could then help us to develop rational strategies for regulating the release of factors from specific cell in the body.