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  • 2018-2022
  • Wellcome Trust
  • 2019

  • Funder: WT Project Code: 219912

    The dominantly inherited spinocerebellar ataxias (SCAs) are rare neurodegenerative disorders which primarily affect the cerebellum, the area of the brain responsible for motor coordination. Patients suffering from SCAs experience a progressive loss of coordination as the cerebellum degenerates. Key cerebellar cells known as Purkinje cells (PCs) are particularly affected, but not enough is known about the disease mechanisms and there is currently no cure. This project aims to investigate the role of two key proteins – TRPC3 and mGluR1 – in the molecular pathways underlying these disorders. mGluR1 is a cell-surface membrane protein which responds to the neurotransmitter glutamate at synapses and leads to activation of TRPC3, an ion channel which allows positively charged ions such as calcium into the cell. Mutations in both proteins have been identified in different subtypes of SCA; these mutations lead to increased protein activity and a subsequent toxic increase of intracellular calcium. Using computational techniques, in vitro studies, and a novel mGluR1 mutant mouse model, I will investigate the impact of mutant TRPC3 and mGluR1 on PCs, as well as the effects of novel TRPC3 inhibitors, to better understand the molecular mechanisms underlying SCAs and work towards new therapeutic approaches.

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  • Funder: WT Project Code: 220066

    Antibiotic resistance is a global health issue that threatens modern medicine and how we treat bacterial infections. Investigating how bacteria live is important to fight against antibiotic resistance as it can lead to new approaches for dealing with bacterial infections, and new targets for antibiotics. The research project we are proposing aims to further our understanding of a system called Tol-Pal in a class of bacteria called Gram negatives. Tol-Pal has been shown to have a role in cell division and is important for the growth of Gram-negative bacteria. At the moment, we do not fully understand how the components of Tol-Pal work together to carry out this function. In this project we hope to use structural biology techniques to see what a complex of three of the proteins in the Tol-Pal system, TolQRA, look like. We hope that finding out what TolQRA looks like will help us to investigate the mechanism of TolQRA within the Tol-Pal system, and further our understanding of Gram-negative bacteria and how they work.

    more_vert
  • Funder: WT Project Code: 212885
    Funder Contribution: 896,850 GBP

    This core facility at King’s College London (KCL) will form the hub of a multi-institution consortium of leading UK molecular imaging researchers and their clinical and biomedical collaborators. It will provide radiochemists and radiobiologists with a unique, comprehensive range of radioanalytical equipment for development and characterisation of the next generation of radiopharmaceuticals for whole-body molecular imaging, cell tracking and targeted radionuclide therapy. The objectives are to: 1. enable chemical synthesis and analysis, and biological evaluation, of new radiochemical platforms and radiopharmaceuticals, and develop radiosynthetic protocols for their clinical translation; 2. develop a new generation of radiotracers, building on recent innovations to help develop and support the clinical use of new advanced therapies: novel molecular, cell-based, nano and radio therapies; 3. use radionuclide molecular imaging to understand disease environment, pathology and resistance to treatment. The facility will enable a consortium of chemists, biologists, pharmacists and clinicians to pursue these objectives across cancer, immunology, neurology, cardiovascular disease, infection, regenerative medicine and transplant therapies, through collaboration with the applicants and through direct access. The requested equipment will complement existing KCL research facilities including whole-body preclinical imaging PET/CT and SPECT/CT scanners funded by a previous Wellcome Multi-User Equipment Grant (2008 – 2013). Scientists have recently discovered how cells such as stem cells and immune cells can cure disease, leading to new therapies based on cells rather than drugs. For this knowledge to benefit patients, it is important to understand how these cells behave in the body: Where do they go? Do they survive? Scientists have also discovered that particular disease cell “markers” can be used to predict whether or not a disease will respond to therapy. Detecting these markers by imaging the whole body with radiotracers will enable better disease monitoring and treatment. We propose to establish a research facility that will house equipment to enable doctors, chemists and biologists to develop new radiotracers which can bind to therapeutic cells or disease “markers” to map their location in living subjects across the whole body, enabling doctors to use new cell-based therapies and cell marker diagnostics safely and efficaciously.

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  • Funder: WT Project Code: 216075
    Funder Contribution: 485,385 GBP

    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.

    more_vert
  • Funder: WT Project Code: 214286
    Funder Contribution: 1,305,660 GBP

    We found that production of new oligodendrocytes (OLs) is stimulated by, and required for, motor skill learning in mice. New OL production was required within 2-3 hours of mice engaging with the motor task, seemingly too soon for full myelin wrapping. We will therefore investigate how, at the cellular level, OLs contribute to early-stage learning, by interfering genetically with pre-myelinating functions of OLs including process outgrowth and ensheathment, or metabolic coupling between OLs and axons. We will also investigate signalling between axons and OLs to ask whether AMPA receptor-mediated synaptic input to OLs selects electrically active axons for myelination over their inactive or less-active neighbours, and whether this contributes to learning. Recently, we found that active OL generation is required for non-motor, "cognitive" learning in a T-maze test, which relies on short-term working memory and longer-term reference memory in a spatial context. We will use additional maze tests to dissociate working and reference memory and test the hypothesis that adult OL genesis is a general requirement for goal-directed learning and memory processes. We will also perform a genetic test of the idea that myelinating OLs, which are extremely long-lived, are required for preserving long-term memories. How we learn and retain skills and abilities is a major unanswered question in neuroscience. For a long time attention has been focussed on neurons, the brain’s electrically active cells. During learning, communication among neurons becomes strengthened at “synapses”, the tiny physical and electrical contacts between one neuron and another. This allows learned patterns of activity to be preserved and re-activated (remembered) more easily in the future. Another way of strengthening communication among neurons is to insulate and protect their “axons” – the long thread-like extensions of neurons that allow them to reach out to one another across the brain. The insulation is provided by “myelin”, spiral wraps of fatty membrane made by "oligodendrocytes", another type of brain cell. We will study how oligodendrocytes detect and respond to electrical activity in axons during learning, and how this modifies myelin and changes the properties of neural circuits – so-called “adaptive myelination”.

    more_vert
  • Funder: WT Project Code: 215943
    Funder Contribution: 300,000 GBP

    The neuropathological hallmark of the two closely related neurodegenerative diseases, ALS and FTD, is the presence of poorly soluble intracellular protein aggregates consisting of low-complexity domain-bearing RNA-binding proteins (RBPs). Intriguingly, these proteins are also key components of liquid-like ribonucleoproteins (RNPs) mediating diverse physiological processes, including transporting mRNAs to distal neurites to promote local protein synthesis (LPS). Interestingly, LPS in disease-affected neurons is often perturbed raising the possibility that the phase transition property of RBPs is critical for regulating the local supply of proteins that promote axon maintenance. Using the ALS/FTD-associated protein FUS as an example, I will investigate the effects of liquid-liquid phase separation and liquid-to-solid phase transition on axonal mRNA localisation, LPS and axon maintenance. Xenopus retinal neurons and mouse cortical neurons will be used as complementary models, in combination with optogenetic tools to achieve precise spatiotemporal control of localised FUS phase transition. A major goal is to understand the mechanisms by which aberrant intra-axonal phase transition of FUS leads to impaired LPS and axon degeneration. As effective treatments for ALS/FTD are currently unavailable, identifying differential mRNA interactors of physiological and pathological FUS and determining their translational status in axons may provide insights for clinical therapeutic options for ALS/FTD. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases leading to behavioural and cognitive impairments. Many essential proteins are produced locally in axons (neuronal extensions), and in disease-affected axons, protein aggregation interferes with local protein synthesis and causes neuronal death. However, it remains unclear whether these aberrant aggregates are the direct cause of defective protein synthesis and axon death. I will investigate this question using a light-controlled tool to induce protein assemblies in one of the two forms, stable aggregates found in disease cells, or less stable granules present in normal cells. I will compare the differences in local protein synthesis and axon survival in neurons carrying different forms of protein assemblies. I also intend to identify novel disease-associated proteins, the synthesis of which is affected by the presence of aggregates. My findings will potentially provide new opportunities for the development of effective treatments, which is currently unavailable.

    more_vert
  • Funder: WT Project Code: 216606
    Funder Contribution: 642,214 GBP

    I will use routine healthcare data to undertake feasibility work to inform novel clinical trial design and trial populations in heterogeneous populations. There is an unmet need for this in intensive care research. I will frame this around critically ill patients with CVD following on from my PhD, however this will be applicable to other disease/pathologies with heterogeneous populations. I hypothesise that critically ill patients with co-existing CVD may benefit from higher oxygen delivery to the myocardium during critical illness, preventing myocardial infarction and subsequent cardiovascular mortality. Key goals: 1. Identification of current outcomes for critically ill patients with CVD. I will link high quality Scottish routine healthcare datasets for all admissions to Scottish ICUs 2010-2018. I will characterise cardiovascular and non-cardiovascular outcomes and healthcare trajectories for these patients. 2. Identification of patients in whom CVD has the highest attributable mortality. This group would be the target population for a cardiovascular intervention trial. I will use prediction modelling, latent variable analysis and propensity score analysis to address this. 3. Identification of intermediate short-term outcomes using both routinely collected time series ICU physiological data, national datasets and existing trial datasets. 4. Development of efficient trial methodology, including Bayesian adaptive trial designs. Novel clinical trial design is needed to reduce the burden of research on patients, reduce costs, and improve efficiency. High quality routine healthcare data can help identify at risk groups and quantify important outcomes. This work is framed around critically ill patients with cardiovascular disease (CVD), following on from my PhD. Patients with CVD have a vulnerable heart muscle at risk of damage due to lack of oxygen. Interventions to increase oxygen delivery may benefit these patients. I will describe critically ill patients with CVD using data routinely collected in all Scottish hospitals. I will explore rates of cardiovascular events and mortality, and identify groups where the cardiovascular risk is greatest, and therefore where cardiovascular interventions are most likely to be beneficial. I will explore the relationship between routinely collected "vital-signs" data in ICU and longer-term outcomes, and I will develop my expertise in efficient trial methodology.

    visibility191
    visibilityviews191
    downloaddownloads120
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  • Funder: WT Project Code: 214607
    Funder Contribution: 48,478 GBP

    This qualitative pilot study aims to provide insight into an under-developed area by exploring health inequalities amongst substance users from different class position living in the north east of England. This study will develop a theoretical approach which offers a way of conceptualising the connection between social inequality, health inequality and substance use practices drawing on Bourdieu (1990) and other relevant theorists. This involves challenging public health doxa which frames health inequalities as structural or caused by individual risk behaviours. The importance of this research is linked to an agenda for social justice and a government priority in England to reduce inequalities to allow everyone to have the same opportunities to lead a healthy life (PHE, 2017). Illicit substance users come from a range of social class backgrounds and genders; yet, we do not know how a substance users’ place in society impacts on their health or their drug use. Using qualitative semi-structured interviews this study will firstly, explore the relational connection across class, gender and substance use by providing insight into the experiences of a diverse range of individuals’ and their everyday lives, and secondly, identify emerging health inequalities and how they are (re)produced.

    more_vert
  • Funder: WT Project Code: 219988

    Our understanding of how the immune system shapes the development of cancer is constantly improving as we continue to employ better experimental models. In particular, we are interested in how cytotoxic T cells, known as “resident killer” cells of the immune system, are capable of entering tumour tissues to suppress malignant cell growth. Acquisition of mutations allows tumour cells to become insensitive to soluble molecules called cytokines, which function within the vicinity of the tumour to promote T cells to recognize and attack tumour cells. Inflammatory cytokines further activate professional antigen presenting cells which can in turn initiate T cells specific for the tumour to proliferate and persist. However, it is not known whether insensitivity to cytokines due to tumour mutations will alter the function of immune cells. We propose to explore this biology using a murine model of melanoma which best replicates immune cell activity in the tumour. We aim to better understand how these mutations dampen anti-tumour immunity, and hope that our results can provide the basis for novel therapies which work to re-shape immune responses against tumours.

    more_vert
  • Funder: WT Project Code: 215471
    Funder Contribution: 3,378,480 GBP

    Our long-term vision is that AVATAR therapy is optimised for delivery in clinical settings, with the impact that a novel effective treatment for distressing voices is readily adopted in UK and international clinical settings. As a result of the current study we expect the impact to be: - Software platform tested and optimised for use in NHS settings - Further evidence of effectiveness and the relative cost effectiveness of two therapy levels, including a further elaboration of the participants for whom the simpler phase 1 approach would be sufficient. The advantage of this being that the therapy would be more rapidly disseminated as the more straightforward skills needed for this phase are widely available and at lower cost both in the UK and internationally compared to the specialised psychological therapy skills necessary for phase 2 - Clarity about optimal therapy content and training, with published therapy operational and clinical manuals - Evidence sufficient for a NICE recommendation of AVATAR as a treatment in the NHS. This is a key next step in the wider dissemination of this therapy in the UK and will also be helpful data for similar clinical guideline and policy recommendations in the US and elsewhere AVATAR therapy is a brief intervention aimed at reducing the frequency of auditory verbal hallucinations (AVH, henceforth ‘voices’). It involves the use of a digital simulation (avatar) of the entity the person believes is the source of the voice in a three-way discussion between participant, avatar and therapist, focussing initially on managing anxiety and helping the participant to stand up to the avatar (phase 1) followed by a realistic enactment of the ascribed character of the voice, targeting processes that are specific to an individualised formulation (phase 2). The first fully powered RCT found AVATAR therapy resulted in a rapid and substantial fall in frequency and associated distress of voices that was superior to a supportive counselling control condition at 12 weeks. In the current study we have four main goals. First, a multicentre RCT to examine the effects of high and low intensity AVATAR therapy (where high intensity involves both phases and low intensity only phase 1) by comparing each to a treatment as usual comparator, and to identify who would be likely to benefit from the high intensity therapy versus those for whom low intensity alone would be sufficient. Second, to examine the relative cost-effectiveness of the two levels of AVATAR therapy and routine treatment. Third, to broaden the availability of AVATAR therapy by expanding the number of staff trained in geographically dispersed NHS settings. Finally, to provide the evidence on effects and cost-effectiveness necessary to take AVAVAR therapy to recommendation by guideline bodies such as NICE.

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Advanced search in
Projects
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arrow_drop_down
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  • Funder: WT Project Code: 219912

    The dominantly inherited spinocerebellar ataxias (SCAs) are rare neurodegenerative disorders which primarily affect the cerebellum, the area of the brain responsible for motor coordination. Patients suffering from SCAs experience a progressive loss of coordination as the cerebellum degenerates. Key cerebellar cells known as Purkinje cells (PCs) are particularly affected, but not enough is known about the disease mechanisms and there is currently no cure. This project aims to investigate the role of two key proteins – TRPC3 and mGluR1 – in the molecular pathways underlying these disorders. mGluR1 is a cell-surface membrane protein which responds to the neurotransmitter glutamate at synapses and leads to activation of TRPC3, an ion channel which allows positively charged ions such as calcium into the cell. Mutations in both proteins have been identified in different subtypes of SCA; these mutations lead to increased protein activity and a subsequent toxic increase of intracellular calcium. Using computational techniques, in vitro studies, and a novel mGluR1 mutant mouse model, I will investigate the impact of mutant TRPC3 and mGluR1 on PCs, as well as the effects of novel TRPC3 inhibitors, to better understand the molecular mechanisms underlying SCAs and work towards new therapeutic approaches.

    more_vert
  • Funder: WT Project Code: 220066

    Antibiotic resistance is a global health issue that threatens modern medicine and how we treat bacterial infections. Investigating how bacteria live is important to fight against antibiotic resistance as it can lead to new approaches for dealing with bacterial infections, and new targets for antibiotics. The research project we are proposing aims to further our understanding of a system called Tol-Pal in a class of bacteria called Gram negatives. Tol-Pal has been shown to have a role in cell division and is important for the growth of Gram-negative bacteria. At the moment, we do not fully understand how the components of Tol-Pal work together to carry out this function. In this project we hope to use structural biology techniques to see what a complex of three of the proteins in the Tol-Pal system, TolQRA, look like. We hope that finding out what TolQRA looks like will help us to investigate the mechanism of TolQRA within the Tol-Pal system, and further our understanding of Gram-negative bacteria and how they work.

    more_vert
  • Funder: WT Project Code: 212885
    Funder Contribution: 896,850 GBP

    This core facility at King’s College London (KCL) will form the hub of a multi-institution consortium of leading UK molecular imaging researchers and their clinical and biomedical collaborators. It will provide radiochemists and radiobiologists with a unique, comprehensive range of radioanalytical equipment for development and characterisation of the next generation of radiopharmaceuticals for whole-body molecular imaging, cell tracking and targeted radionuclide therapy. The objectives are to: 1. enable chemical synthesis and analysis, and biological evaluation, of new radiochemical platforms and radiopharmaceuticals, and develop radiosynthetic protocols for their clinical translation; 2. develop a new generation of radiotracers, building on recent innovations to help develop and support the clinical use of new advanced therapies: novel molecular, cell-based, nano and radio therapies; 3. use radionuclide molecular imaging to understand disease environment, pathology and resistance to treatment. The facility will enable a consortium of chemists, biologists, pharmacists and clinicians to pursue these objectives across cancer, immunology, neurology, cardiovascular disease, infection, regenerative medicine and transplant therapies, through collaboration with the applicants and through direct access. The requested equipment will complement existing KCL research facilities including whole-body preclinical imaging PET/CT and SPECT/CT scanners funded by a previous Wellcome Multi-User Equipment Grant (2008 – 2013). Scientists have recently discovered how cells such as stem cells and immune cells can cure disease, leading to new therapies based on cells rather than drugs. For this knowledge to benefit patients, it is important to understand how these cells behave in the body: Where do they go? Do they survive? Scientists have also discovered that particular disease cell “markers” can be used to predict whether or not a disease will respond to therapy. Detecting these markers by imaging the whole body with radiotracers will enable better disease monitoring and treatment. We propose to establish a research facility that will house equipment to enable doctors, chemists and biologists to develop new radiotracers which can bind to therapeutic cells or disease “markers” to map their location in living subjects across the whole body, enabling doctors to use new cell-based therapies and cell marker diagnostics safely and efficaciously.

    visibility25
    visibilityviews25
    downloaddownloads41
    Powered by Usage counts
    more_vert
  • Funder: WT Project Code: 216075
    Funder Contribution: 485,385 GBP

    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.

    more_vert
  • Funder: WT Project Code: 214286
    Funder Contribution: 1,305,660 GBP

    We found that production of new oligodendrocytes (OLs) is stimulated by, and required for, motor skill learning in mice. New OL production was required within 2-3 hours of mice engaging with the motor task, seemingly too soon for full myelin wrapping. We will therefore investigate how, at the cellular level, OLs contribute to early-stage learning, by interfering genetically with pre-myelinating functions of OLs including process outgrowth and ensheathment, or metabolic coupling between OLs and axons. We will also investigate signalling between axons and OLs to ask whether AMPA receptor-mediated synaptic input to OLs selects electrically active axons for myelination over their inactive or less-active neighbours, and whether this contributes to learning. Recently, we found that active OL generation is required for non-motor, "cognitive" learning in a T-maze test, which relies on short-term working memory and longer-term reference memory in a spatial context. We will use additional maze tests to dissociate working and reference memory and test the hypothesis that adult OL genesis is a general requirement for goal-directed learning and memory processes. We will also perform a genetic test of the idea that myelinating OLs, which are extremely long-lived, are required for preserving long-term memories. How we learn and retain skills and abilities is a major unanswered question in neuroscience. For a long time attention has been focussed on neurons, the brain’s electrically active cells. During learning, communication among neurons becomes strengthened at “synapses”, the tiny physical and electrical contacts between one neuron and another. This allows learned patterns of activity to be preserved and re-activated (remembered) more easily in the future. Another way of strengthening communication among neurons is to insulate and protect their “axons” – the long thread-like extensions of neurons that allow them to reach out to one another across the brain. The insulation is provided by “myelin”, spiral wraps of fatty membrane made by "oligodendrocytes", another type of brain cell. We will study how oligodendrocytes detect and respond to electrical activity in axons during learning, and how this modifies myelin and changes the properties of neural circuits – so-called “adaptive myelination”.

    more_vert
  • Funder: WT Project Code: 215943
    Funder Contribution: 300,000 GBP

    The neuropathological hallmark of the two closely related neurodegenerative diseases, ALS and FTD, is the presence of poorly soluble intracellular protein aggregates consisting of low-complexity domain-bearing RNA-binding proteins (RBPs). Intriguingly, these proteins are also key components of liquid-like ribonucleoproteins (RNPs) mediating diverse physiological processes, including transporting mRNAs to distal neurites to promote local protein synthesis (LPS). Interestingly, LPS in disease-affected neurons is often perturbed raising the possibility that the phase transition property of RBPs is critical for regulating the local supply of proteins that promote axon maintenance. Using the ALS/FTD-associated protein FUS as an example, I will investigate the effects of liquid-liquid phase separation and liquid-to-solid phase transition on axonal mRNA localisation, LPS and axon maintenance. Xenopus retinal neurons and mouse cortical neurons will be used as complementary models, in combination with optogenetic tools to achieve precise spatiotemporal control of localised FUS phase transition. A major goal is to understand the mechanisms by which aberrant intra-axonal phase transition of FUS leads to impaired LPS and axon degeneration. As effective treatments for ALS/FTD are currently unavailable, identifying differential mRNA interactors of physiological and pathological FUS and determining their translational status in axons may provide insights for clinical therapeutic options for ALS/FTD. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases leading to behavioural and cognitive impairments. Many essential proteins are produced locally in axons (neuronal extensions), and in disease-affected axons, protein aggregation interferes with local protein synthesis and causes neuronal death. However, it remains unclear whether these aberrant aggregates are the direct cause of defective protein synthesis and axon death. I will investigate this question using a light-controlled tool to induce protein assemblies in one of the two forms, stable aggregates found in disease cells, or less stable granules present in normal cells. I will compare the differences in local protein synthesis and axon survival in neurons carrying different forms of protein assemblies. I also intend to identify novel disease-associated proteins, the synthesis of which is affected by the presence of aggregates. My findings will potentially provide new opportunities for the development of effective treatments, which is currently unavailable.

    more_vert
  • Funder: WT Project Code: 216606
    Funder Contribution: 642,214 GBP

    I will use routine healthcare data to undertake feasibility work to inform novel clinical trial design and trial populations in heterogeneous populations. There is an unmet need for this in intensive care research. I will frame this around critically ill patients with CVD following on from my PhD, however this will be applicable to other disease/pathologies with heterogeneous populations. I hypothesise that critically ill patients with co-existing CVD may benefit from higher oxygen delivery to the myocardium during critical illness, preventing myocardial infarction and subsequent cardiovascular mortality. Key goals: 1. Identification of current outcomes for critically ill patients with CVD. I will link high quality Scottish routine healthcare datasets for all admissions to Scottish ICUs 2010-2018. I will characterise cardiovascular and non-cardiovascular outcomes and healthcare trajectories for these patients. 2. Identification of patients in whom CVD has the highest attributable mortality. This group would be the target population for a cardiovascular intervention trial. I will use prediction modelling, latent variable analysis and propensity score analysis to address this. 3. Identification of intermediate short-term outcomes using both routinely collected time series ICU physiological data, national datasets and existing trial datasets. 4. Development of efficient trial methodology, including Bayesian adaptive trial designs. Novel clinical trial design is needed to reduce the burden of research on patients, reduce costs, and improve efficiency. High quality routine healthcare data can help identify at risk groups and quantify important outcomes. This work is framed around critically ill patients with cardiovascular disease (CVD), following on from my PhD. Patients with CVD have a vulnerable heart muscle at risk of damage due to lack of oxygen. Interventions to increase oxygen delivery may benefit these patients. I will describe critically ill patients with CVD using data routinely collected in all Scottish hospitals. I will explore rates of cardiovascular events and mortality, and identify groups where the cardiovascular risk is greatest, and therefore where cardiovascular interventions are most likely to be beneficial. I will explore the relationship between routinely collected "vital-signs" data in ICU and longer-term outcomes, and I will develop my expertise in efficient trial methodology.

    visibility191
    visibilityviews191
    downloaddownloads120
    Powered by Usage counts
    more_vert
  • Funder: WT Project Code: 214607
    Funder Contribution: 48,478 GBP

    This qualitative pilot study aims to provide insight into an under-developed area by exploring health inequalities amongst substance users from different class position living in the north east of England. This study will develop a theoretical approach which offers a way of conceptualising the connection between social inequality, health inequality and substance use practices drawing on Bourdieu (1990) and other relevant theorists. This involves challenging public health doxa which frames health inequalities as structural or caused by individual risk behaviours. The importance of this research is linked to an agenda for social justice and a government priority in England to reduce inequalities to allow everyone to have the same opportunities to lead a healthy life (PHE, 2017). Illicit substance users come from a range of social class backgrounds and genders; yet, we do not know how a substance users’ place in society impacts on their health or their drug use. Using qualitative semi-structured interviews this study will firstly, explore the relational connection across class, gender and substance use by providing insight into the experiences of a diverse range of individuals’ and their everyday lives, and secondly, identify emerging health inequalities and how they are (re)produced.

    more_vert
  • Funder: WT Project Code: 219988

    Our understanding of how the immune system shapes the development of cancer is constantly improving as we continue to employ better experimental models. In particular, we are interested in how cytotoxic T cells, known as “resident killer” cells of the immune system, are capable of entering tumour tissues to suppress malignant cell growth. Acquisition of mutations allows tumour cells to become insensitive to soluble molecules called cytokines, which function within the vicinity of the tumour to promote T cells to recognize and attack tumour cells. Inflammatory cytokines further activate professional antigen presenting cells which can in turn initiate T cells specific for the tumour to proliferate and persist. However, it is not known whether insensitivity to cytokines due to tumour mutations will alter the function of immune cells. We propose to explore this biology using a murine model of melanoma which best replicates immune cell activity in the tumour. We aim to better understand how these mutations dampen anti-tumour immunity, and hope that our results can provide the basis for novel therapies which work to re-shape immune responses against tumours.

    more_vert
  • Funder: WT Project Code: 215471
    Funder Contribution: 3,378,480 GBP

    Our long-term vision is that AVATAR therapy is optimised for delivery in clinical settings, with the impact that a novel effective treatment for distressing voices is readily adopted in UK and international clinical settings. As a result of the current study we expect the impact to be: - Software platform tested and optimised for use in NHS settings - Further evidence of effectiveness and the relative cost effectiveness of two therapy levels, including a further elaboration of the participants for whom the simpler phase 1 approach would be sufficient. The advantage of this being that the therapy would be more rapidly disseminated as the more straightforward skills needed for this phase are widely available and at lower cost both in the UK and internationally compared to the specialised psychological therapy skills necessary for phase 2 - Clarity about optimal therapy content and training, with published therapy operational and clinical manuals - Evidence sufficient for a NICE recommendation of AVATAR as a treatment in the NHS. This is a key next step in the wider dissemination of this therapy in the UK and will also be helpful data for similar clinical guideline and policy recommendations in the US and elsewhere AVATAR therapy is a brief intervention aimed at reducing the frequency of auditory verbal hallucinations (AVH, henceforth ‘voices’). It involves the use of a digital simulation (avatar) of the entity the person believes is the source of the voice in a three-way discussion between participant, avatar and therapist, focussing initially on managing anxiety and helping the participant to stand up to the avatar (phase 1) followed by a realistic enactment of the ascribed character of the voice, targeting processes that are specific to an individualised formulation (phase 2). The first fully powered RCT found AVATAR therapy resulted in a rapid and substantial fall in frequency and associated distress of voices that was superior to a supportive counselling control condition at 12 weeks. In the current study we have four main goals. First, a multicentre RCT to examine the effects of high and low intensity AVATAR therapy (where high intensity involves both phases and low intensity only phase 1) by comparing each to a treatment as usual comparator, and to identify who would be likely to benefit from the high intensity therapy versus those for whom low intensity alone would be sufficient. Second, to examine the relative cost-effectiveness of the two levels of AVATAR therapy and routine treatment. Third, to broaden the availability of AVATAR therapy by expanding the number of staff trained in geographically dispersed NHS settings. Finally, to provide the evidence on effects and cost-effectiveness necessary to take AVAVAR therapy to recommendation by guideline bodies such as NICE.

    download4
    downloaddownloads4
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