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Early diagnosis of cancer is important for improved survival and patient experience. Reaching a diagnosis needs correct and timely collection of information from consultations, tests and follow-up of results. However, diagnosis can be difficult as non-cancerous conditions are common and cancer is quite rare. The use of tests forms a very important part in diagnosis, but this may also increase the time to cancer diagnosis. It is likely that what and when tests are done and how results are communicated can vary for different patients with the same cancer. These differences may represent missed diagnostic opportunities in some cases. In this project, I will explore how patients with kidney and bladder cancer are diagnosed. Bladder and kidney cancer will be studied together as patients usually present with blood in the urine or other urinary symptoms, and similar tests are done to look for both types of cancer. Despite the increasing trends and gender differences in how quickly these cancers are diagnosed, there is little information on how they are diagnosed. Therefore, studying this and whether there are delays in the use of tests is important to understand how we can improve early diagnosis of these cancers.

As summarised in the extracted text below from our full application (page 5 "Proposed work") in Section 10 of this application form (and described in more detail on pages 5-16 of Section 10). During the next 5 years, it is intended to: - Extend cohort-wide linkage to primary care health records, while maintaining and updating health outcome data from existing linkages to death, cancer and hospital records (and explore the added value of linkages to additional healthcare datasets); - Further develop and implement large-scale identification and characterization of many different types of health outcome; - Streamline the research access systems, and improve methods for processing, presenting and providing linked healthcare data to researchers; - Maintain the sample resource, and make increasing amounts of different types of genotype and biomarker data available; - Conduct imaging assessments in 100,000 participants, and develop and implement further enhancements (such as cardiac monitoring and further sample collection and assays). Efforts will continue to be made to ensure that researchers from around the world are suitably well informed about the resource so that the effective use of it increases substantially, leading to novel findings that have a major impact on human health.

Osteoarthritis (OA) is the most common cause of physical disability in adults, affecting millions of people worldwide. It is associated with the breakdown of cartilage, causing pain and joint stiffness. However, other than pain management and surgery, treatments capable of changing the course of this disease and slowing down its progression are not available. Previously, the Meng lab discovered a temperature-responsive body clock in cartilage cells that tracks time and controls important physiological processes, namely tissue repair. This clock becomes deregulated as we age and in the joints of people suffering from OA, playing an important role in disease progression. In this project, we will take a multidisciplinary approach to better understand how the periodic application of heat to the joint affects the clock at the molecular level. To do so, we will use cartilage from mice and patient samples to establish the ideal conditions to restore clock function by testing different temperatures and treatment durations/frequencies. Then, we will study whether repair mechanisms in cartilage have been strengthened by analysing global gene expression patterns and identifying possible therapeutic targets. These studies will help us investigate the potential of using a body clock-based heat treatment to slow down OA progression.

Neutrophils are the most abundant white blood cell, and a key first responder to infection. They are particularly interesting as, unlike other cells in the body, they work primarily in tissues where oxygen and nutrient availability are limited. We have observed that the local environment that a neutrophil works in dictates its function. For example, in chronic obstructive pulmonary disease where both tissue (lung) and whole body oxygen levels may be reduced, neutrophils persist inappropriately resulting in further tissue damage. Similarly, in diabetes where there is excess sugar, neutrophils suffer a number of changes which impair the body’s defence. Not just a short-term effect, we have discovered that changes in oxygen availability are able to imprint long-term changes to neutrophil function, even after return to normal oxygen levels. How this is regulated is unknown but we believe changes in cellular metabolism are critical. We are now interested to explore whether glucose also regulates short and long term neutrophil behaviour and investigate the mechanisms by which this occurs. To do so, we will use a variety of techniques including a mouse model of diabetes and investigate the mechanisms by which neutrophils adapt to their environment.

Many greenhouse gas mitigation actions also benefit air quality and health. However, progress incorporating co-benefits assessments into climate mitigation planning has been limited. Over the next several years, C40 Cities is working with city governments to develop climate action plans. We aim to develop methods to integrate PM2.5 and associated health co-benefits into the climate action planning tool these cities will use, thereby building a bridge between the scientific evidence on co-benefits to the largest urban climate action planning effort worldwide. Specifically, we will: 1) Develop, evaluate, and integrate a screening-level air quality model (focusing on fine particulate matter, PM2.5) into C40’s climate action planning tool, Pathways, for at least three pilot cities; 2) With local partners, test the tool to explore air quality and health co-benefits of climate action pathways in the pilot cities; and 3) Assess the potential for quantifying additional health co-benefits in Pathways, such as changes in ozone, nitrogen dioxide, physical activity, noise, and green space. Data and tools will be publicly available to support additional research into climate/health linkages. C40 will maintain Pathways beyond the project’s end, creating a platform to study more cities and enabling long-term integration of co-benefits into city climate action planning. Many actions cities can take to reduce greenhouse gas emissions would also improve air quality and therefore also human health. This project develops a decision-support tool that helps cities explicitly recognize the nexus between climate action and air quality and public health benefits. We will add a new screening-level air quality and health assessment capability to an existing greenhouse gas planning tool that is maintained by C40 Cities and used in cities worldwide. We will then work with local officials in three pilot cities to test the tool to explore the air quality and health implications of specific climate action pathways that these cities can take. We will also assess the potential for including additional health co-benefits such as from increased physical activity and green space.

For our brain and spinal cord to work properly, allowing us to move, see, hear, feel and think quickly, fast electrical communication between different parts of the nervous system is essential. This is achieved by surrounding the nerve cells with an insulating layer called myelin; accordingly, significant mental or physical impairment occurs when myelin is damaged in disease. However, despite the importance of myelin, we have a limited understanding of how myelination is regulated. Throughout life stem cells in our brain called oligodendrocyte precursor cells (OPCs) differentiate into myelinating oligodendrocytes, and recent work implicates new myelinating cells as a mechanism for learning. In this project, I will study chemical signals, neurotransmitters, that neurons send to OPCs to instruct them to produce new myelinating oligodendrocytes during development and learning. I will focus on G protein-coupled receptors (GPCRs), a family of receptors that OPCs express and that are activated by neurotransmitters. Indeed, a number of drugs acting on GPCRs regulate experience-dependent myelin, and promote the formation of new myelin following injury. However, there is little understanding of the mechanism of action of these receptors. Thus, studying these signals in OPCs will give us a better understanding of myelination, brain function, and learning.

The goal of my research is to develop novel biomedical technologies that will enable quantitative investigation of gene expression within live tissues and animals. By developing a set of new molecular imaging techniques, I seek to understand how gene expression is regulated at the RNA level in the neural networks. One of the fundamental questions in neuroscience is how neural activities modulate the connectivity. Activity-dependent transcription and local protein synthesis are critical events involved in the formation and alteration of neural circuits. However it is still unclear how de novo gene expression occurs in response to neural activities in real time at a single cell level. My research will be based on a multifaceted systems approach combining genetic engineering, RNA biology, neuroscience, and quantitative single-molecule analysis. I will pursue my research in three directions: 1) understanding the real-time dynamics of transcription in the network of neurons in the brain, 2) investigating the activity-dependent transport and localization of mRNA, and 3) developing novel RNA labeling methods to facilitate non-invasive imaging of transcription in live animals. The International Research Scholars grant will allow me to expand my research programs in creative directions with a long-term stability and flexibility.

Blood vessels, including arteries and capillaries, are equipped to constrict and dilate in response to changes in their environment. Importantly, vessels are known to respond to pH. A key example is in the lungs, where lung damage prevents these regions from taking up oxygen, making the area hypoxic and acidic. This causes vessels in the damaged area to constrict, reducing blood flow. However, the ways by which vessels respond to pH are not fully understood. Recently, the gene encoding a pH-sensing protein named PAC has been identified. PAC is an ion channel, forming a gated pore in cell membranes which opens in response to acidic pH and allows movement of chloride ions. Here we propose that PAC is important for vessels to respond to acidity. We will investigate this by measuring chloride currents in vascular cells, and by using a technique called myography which allows us to observe vessel constriction. We will apply these techniques to study channel structure, and explore potential drugs which target the channel. Overall, this will further our understanding of how blood vessels respond to pH. The long-term goal is enabling PAC to become a target for diseases of the lungs and other organs.

How and why proteins aggregate is an important fundamental question. It also has far-reaching biomedical importance given the increasing prevalence of amyloid-diseases in today’s ageing population. Whilst some amyloid precursors are intrinsically disordered, others are natively folded. Each must undergo major conformational changes to form amyloid fibrils. Defining these changes is key to developing therapeutic strategies. This proposal aims to achieve this by focusing on two overarching questions: 1. What is the nature of the protein-protein interactions that initiate amyloid formation; 2. Can we use this knowledge to develop molecules able to control aggregation in vitro and in vivo? The challenges in answering these questions lie in the heterogeneity of aggregating species, their transient/weak interactions, and the fact that amyloid precursors adopt non-native, dynamic structures. We will meet these challenges: exploiting cutting edge structural methods to map the protein-protein interactions that commit proteins to aggregate and will use the knowledge gained to inform the design of small molecules/artificial proteins able to control aggregation by targeting these surfaces. Focusing on islet-amyloid-polypeptide (involved in type II diabetes) and β2-microglobulin (involved in systemic amyloidosis) the goal is to enhance our fundamental understanding of protein aggregation and to inspire new strategies for intervention in disease.

The transcription of almost all genes occurs via random transitions between active and inactive gene states. The net mRNA production is determined by the frequency and size of the resulting random bursts of mRNA synthesis, making gene expression a stochastic process. As a consequence, responses of individual immune cells upon bacterial infection are highly variable, resulting in different infection outcomes. For example, only a subset of innate immune macrophages may accurately recognize and kill invading bacteria. In this project, using mathematical modelling of transcriptional bursting, inference of single-cell genomics and live-cell imaging data, I aim to understand mechanisms involved in coordination of the innate immune responses to pathogen stimulation. In particular, I will study how the foodborne Listeria monocytogenes manipulates the host cell’s gene expression and signalling responses in order to establish a successful infection. I hypothesise that modulation of transcriptional bursting characteristics is a key control mechanism that allows the host to fine-tune its response to pathogen infection, and in turn enables the pathogen to implement its infection strategy. Mechanistic understanding of transcriptional dynamics induced by bacterial infection will inform strategies to improve infection outcomes in the future.