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678 Projects

  • 2018-2022
  • Wellcome Trust
  • OA Publications Mandate: Yes
  • 2019

10
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  • Funder: WT Project Code: 212246
    Funder Contribution: 990,352 GBP

    Membrane proteins destined for lysosomal degradation are ubiquitinated within the endosome and then sorted into intralumenal vesicles (ILVs), to form the multivesicular body (MVB). This critically important process is exemplified by the sorting of EGF receptor (EGFR). MVB sorting requires ESCRTs (Endosomal Sorting Complexes Required for Transport). ESCRTs collectively recognise ubiquitinated EGFR on the cytoplasmic face of the endosome and capture it within ILVs, whilst they escape. Towards understanding how ESCRTs overcome this topological problem, we will reconstitute the process. We have identified all those ESCRTs that drive EGFR sorting, and how they bind each other. We will now reconstitute MVB sorting, using proteoliposomes containing EGFR and exploiting our full complement of baculovirus-expressed ESCRTs. We will use site-directed photo-crosslinking to map the entire process biochemically, and will complement this with further in vitro analysis of the molecular architecture within the developing ILV. Key conclusions will be verified in cells. Current ideas suggest ubiquitination is the determining factor for EGFR sorting. However, we believe instead that EGFR signalling-dependent activation of ESCRTs is decisive. We will systematically identify ESCRT post-translational modifications (PTMs) that map with MVB sorting, and test using both reconstituted proteoliposomes and in cells how these PTMs control the pathway. Plasma membrane proteins destined for degradation are internalised, enter the endosome, and then transit to the lysosome. Many crucial proteins follow this pathway, with epidermal growth factor receptor (EGFR) an exemplar because of its biological and biomedical importance. EGFR transport to the lysosome requires a crucial event; the receptor is ubiquitinated and then enters membrane vesicles that bud into the lumen of the endosome, to form the multivesicular body. The molecular machinery that drives multivesicular body formation must overcome a complex topological problem: it recognises ubiquitinated EGFR on the cytoplasmic face of the endosome, generates vesicles that capture EGFR inside the endosome, but escapes itself. How this works remains mysterious, but we aim to solve it. We will reassemble the machinery from its component parts on artificial endosomes, and dissect biochemically how it envelops EGFR. We will also examine how the machinery is activated by EGFR, ensuring EGFR’s efficient capture.

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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.

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  • Funder: WT Project Code: 219914

    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.

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  • Funder: WT Project Code: 216006
    Funder Contribution: 27,200 GBP

    India is home to more than half the global population at risk of cholera. While cholera is significantly under-reported, there is recognition that sanitation and water interventions alone are insufficient to control disease in highly endemic areas, with significant environmental reservoirs and, during disasters and population displacements. Affordable killed oral cholera vaccines are available, but in limited quantities. A novel single strain whole cell killed oral cholera vaccine (Hillchol) has been developed by Hilleman Laboratories and evaluated for immunogenicity in a phase I/II clinical study. The further testing of this vaccine for efficacy is likely to be challenging for several reasons, including the need for large field trials, and the complexity of regulatory processes when a licensed cholera vaccine is available in India. A cholera human infection model, would permit evaluation of efficacy in adults in endemic areas, and would follow a pathway to licensure that has already resulted in one cholera vaccine (Vaxchora) being approved by the US FDA. The Christian Medical College, Vellore is already putting in place the infrastructure and processes for a human infection model of typhoid and will transfer the cholera model from Centre for Vaccine Development, Maryland, which was responsible for the Vaxchora study.

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  • Funder: WT Project Code: 220025

    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.

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  • 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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  • Funder: WT Project Code: 219880

    The world around us is complex, but at the same time full of meaningful regularities. We can detect, learn and exploit these regularities automatically in an unsupervised manner, i.e. without any direct instruction or explicit reward. For example, we effortlessly estimate the average tallness of people in a room, or the boundaries between words in a language. These regularities, once learned, can affect the way we acquire and interpret new information to build and update our internal model of the world for future decision-making processes. Despite the ubiquity of passively learning from the structured information in the environment, the mechanisms that support learning from real-world experience are largely unknown. By combining sophisticated cognitive tasks in human and rats, neuronal measurements and perturbations in rat and network modelling, we aim to build a multi-level description of how sensory history is utilised in inferring regularities in temporally extended tasks. The ability to use sensory statistics to update the internal models may be impaired in individuals with dyslexia or with neurodevelopmental disorders, such as autism, or psychosis, such as schizophrenia. Our findings can have immediate application in better understanding and designing more accurate treatments for these disorders.

    more_vert
  • Funder: WT Project Code: 216293
    Funder Contribution: 6,898.79 GBP

    Introduction: The Ugandan National Biorepository was set up in September 2016 out of a need to store human biological specimens to promote low-cost public health and academic research. The National Biorepository is owned by the Government of Uganda under the custodianship of Central Public Health Laboratories (CPHL). For the last two years, National Biorepository has sought informed consent for long term storage and use of remnant clinical samples mainly from the centralized reference HIV early infant diagnosis (EID), viral load and isolates of antimicrobial drug resistance surveillance and disease outbreak investigations. Objectives: To evaluate the knowledge, attitudes, and perceptions of broad consent for bio-specimen and associated data in Uganda Methods: A cross-sectional study design will be carried out. This study will be performed in 14 Regional referral Hospitals. A multiple-choice questionnaire will be used for data collection. One thousand patients seeking health care at selected Health facilities will be enrolled in this project. A multiple-choice questionnaire will be used(1) (2). The questionnaire comprises 23 items, including 11 Likert scale items, 3 statement items, 2 open items, and 6 demographic questions. The information brochure and Broad consent form will be read and understood[DW1] by the participant before the questionnaire is administered.

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  • Funder: WT Project Code: 215553
    Funder Contribution: 2,215,270 GBP

    Bacterial secretion systems release effectors into the extra-cellular milieu or directly into foreign cells. They represent fundamental mechanisms by which bacteria modulate their environment and induce human infection. Here we study two related and complementary secretion systems, the bacterial type II secretion system (T2SS) and the Tad secretion system (TdSS). The T2SS secretes effectors and toxins involved in cell adherence, biofilm formation and host cell death. The TdSS drives cell adherence and colonization through extra-cellular pilus formation. Both secretion systems constitute multi-component complexes with many shared components that span the cell envelope of Gram-Negative bacteria. The overall goal is to determine the molecular mechanism underlying T2SS and TdSS operation. Key aims for the T2SS include showing how substrate is recruited, how inner membrane components are organised, and how pseudo-pilus assembly is coordinated. The repertoire of K. pneumoniae T2SS virulence factors will also be expanded. For the TdSS, key aims include structure-function studies on the outer membrane secretin with its associated pilotin and pilus. Comparison of T2SS and TdSS structures will reveal common mechanistic and evolutionary principles. By understanding how the T2SS and TdSS function and promote pathogenesis, this research has the potential to facilitate drug development and combat anti-microbial resistance. Some bacteria cause infections in humans that kill millions of people annually. To trigger the infection, the bacteria contain nanomachines within their cell surface that act like miniature pumps. These are secretion systems. One role of secretion systems is to deliver harmful proteins from inside the bacteria to outside environments like your cells. These harmful proteins act as molecular weaponry in many ways. They can form grappling hooks to help the bacteria attach to environments like your intestine or as molecular malware that maliciously reprogram your cells. We use a powerful technique called cryo-electron microscopy, which allows us to visualize the precise position of the atoms within the secretion systems. In this way we can learn the 3D structure and chemistry of the secretion systems. By understanding how the secretion systems work we have a much greater chance of developing medicines that stop the secretion systems from causing human illness.

    more_vert
  • Funder: WT Project Code: 218247
    Funder Contribution: 616,706 GBP

    We request funds to purchase an Illumina NovaSeq 6000 DNA Sequencing System. This will enable the University of Exeter to sequence DNA from humans and other species relevant to human health with the best possible efficiency, throughput, speed, and flexibility. Our current Illumina HiSeq 2500 system is approaching the end of its useful lifespan. Replacing it with the NovaSeq 6000 will reduce running costs by ~75%. Local accessibility to the most up-to-date DNA sequencing technology is critical to many researchers, especially those translating research into the NHS, and underpins several “flagship” Exeter research programmes. The current equipment is routinely used by groups in the Medical School and Biosciences, and existing demand exceeds capacity. Local access to DNA sequencing has enabled Exeter researchers to drive world leading studies identifying the genetic basis of diseases including diabetes, obesity, dementia and schizophrenia, and enabled us to establish internationally-renowned projects in epigenomics and transcriptomics. The sequencer will be managed and operated as a Research Facility within the University, by an experienced sequencing team established more than 10 years ago, to provide a key resource for the biomedical research community in Exeter and beyond that is critical to our continued innovation and leadership in genomics. The last decade has seen tremendous advances in our understanding about the role of genetic variation in health and disease, driven by developments in technology for sequencing the genome. Genes involved in a spectrum of debilitating disorders and health-related traits have been identified, including many by researchers at the University of Exeter. We are requesting funds to purchase the most high-throughput and economical genetic sequencer currently available. Local access to the most up-to-date DNA sequencing technology is critical to many researchers, especially those translating research into the NHS, and underpins several “flagship” Exeter research programmes. For example, it will enable Exeter researchers to continue to drive world leading studies identifying the genetic basis of diseases including diabetes, obesity, dementia and schizophrenia. Given the considerable matched funding from the University, the funds requested here represent outstanding value for money, enabling Exeter to further drive innovation and excellence in UK genomics research.

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Advanced search in
Projects
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Searching FieldsTerms
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arrow_drop_down
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arrow_drop_down
678 Projects
  • Funder: WT Project Code: 212246
    Funder Contribution: 990,352 GBP

    Membrane proteins destined for lysosomal degradation are ubiquitinated within the endosome and then sorted into intralumenal vesicles (ILVs), to form the multivesicular body (MVB). This critically important process is exemplified by the sorting of EGF receptor (EGFR). MVB sorting requires ESCRTs (Endosomal Sorting Complexes Required for Transport). ESCRTs collectively recognise ubiquitinated EGFR on the cytoplasmic face of the endosome and capture it within ILVs, whilst they escape. Towards understanding how ESCRTs overcome this topological problem, we will reconstitute the process. We have identified all those ESCRTs that drive EGFR sorting, and how they bind each other. We will now reconstitute MVB sorting, using proteoliposomes containing EGFR and exploiting our full complement of baculovirus-expressed ESCRTs. We will use site-directed photo-crosslinking to map the entire process biochemically, and will complement this with further in vitro analysis of the molecular architecture within the developing ILV. Key conclusions will be verified in cells. Current ideas suggest ubiquitination is the determining factor for EGFR sorting. However, we believe instead that EGFR signalling-dependent activation of ESCRTs is decisive. We will systematically identify ESCRT post-translational modifications (PTMs) that map with MVB sorting, and test using both reconstituted proteoliposomes and in cells how these PTMs control the pathway. Plasma membrane proteins destined for degradation are internalised, enter the endosome, and then transit to the lysosome. Many crucial proteins follow this pathway, with epidermal growth factor receptor (EGFR) an exemplar because of its biological and biomedical importance. EGFR transport to the lysosome requires a crucial event; the receptor is ubiquitinated and then enters membrane vesicles that bud into the lumen of the endosome, to form the multivesicular body. The molecular machinery that drives multivesicular body formation must overcome a complex topological problem: it recognises ubiquitinated EGFR on the cytoplasmic face of the endosome, generates vesicles that capture EGFR inside the endosome, but escapes itself. How this works remains mysterious, but we aim to solve it. We will reassemble the machinery from its component parts on artificial endosomes, and dissect biochemically how it envelops EGFR. We will also examine how the machinery is activated by EGFR, ensuring EGFR’s efficient capture.

    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: 219914

    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.

    more_vert
  • Funder: WT Project Code: 216006
    Funder Contribution: 27,200 GBP

    India is home to more than half the global population at risk of cholera. While cholera is significantly under-reported, there is recognition that sanitation and water interventions alone are insufficient to control disease in highly endemic areas, with significant environmental reservoirs and, during disasters and population displacements. Affordable killed oral cholera vaccines are available, but in limited quantities. A novel single strain whole cell killed oral cholera vaccine (Hillchol) has been developed by Hilleman Laboratories and evaluated for immunogenicity in a phase I/II clinical study. The further testing of this vaccine for efficacy is likely to be challenging for several reasons, including the need for large field trials, and the complexity of regulatory processes when a licensed cholera vaccine is available in India. A cholera human infection model, would permit evaluation of efficacy in adults in endemic areas, and would follow a pathway to licensure that has already resulted in one cholera vaccine (Vaxchora) being approved by the US FDA. The Christian Medical College, Vellore is already putting in place the infrastructure and processes for a human infection model of typhoid and will transfer the cholera model from Centre for Vaccine Development, Maryland, which was responsible for the Vaxchora study.

    more_vert
  • Funder: WT Project Code: 220025

    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.

    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
    Powered by Usage counts
    more_vert
  • Funder: WT Project Code: 219880

    The world around us is complex, but at the same time full of meaningful regularities. We can detect, learn and exploit these regularities automatically in an unsupervised manner, i.e. without any direct instruction or explicit reward. For example, we effortlessly estimate the average tallness of people in a room, or the boundaries between words in a language. These regularities, once learned, can affect the way we acquire and interpret new information to build and update our internal model of the world for future decision-making processes. Despite the ubiquity of passively learning from the structured information in the environment, the mechanisms that support learning from real-world experience are largely unknown. By combining sophisticated cognitive tasks in human and rats, neuronal measurements and perturbations in rat and network modelling, we aim to build a multi-level description of how sensory history is utilised in inferring regularities in temporally extended tasks. The ability to use sensory statistics to update the internal models may be impaired in individuals with dyslexia or with neurodevelopmental disorders, such as autism, or psychosis, such as schizophrenia. Our findings can have immediate application in better understanding and designing more accurate treatments for these disorders.

    more_vert
  • Funder: WT Project Code: 216293
    Funder Contribution: 6,898.79 GBP

    Introduction: The Ugandan National Biorepository was set up in September 2016 out of a need to store human biological specimens to promote low-cost public health and academic research. The National Biorepository is owned by the Government of Uganda under the custodianship of Central Public Health Laboratories (CPHL). For the last two years, National Biorepository has sought informed consent for long term storage and use of remnant clinical samples mainly from the centralized reference HIV early infant diagnosis (EID), viral load and isolates of antimicrobial drug resistance surveillance and disease outbreak investigations. Objectives: To evaluate the knowledge, attitudes, and perceptions of broad consent for bio-specimen and associated data in Uganda Methods: A cross-sectional study design will be carried out. This study will be performed in 14 Regional referral Hospitals. A multiple-choice questionnaire will be used for data collection. One thousand patients seeking health care at selected Health facilities will be enrolled in this project. A multiple-choice questionnaire will be used(1) (2). The questionnaire comprises 23 items, including 11 Likert scale items, 3 statement items, 2 open items, and 6 demographic questions. The information brochure and Broad consent form will be read and understood[DW1] by the participant before the questionnaire is administered.

    more_vert
  • Funder: WT Project Code: 215553
    Funder Contribution: 2,215,270 GBP

    Bacterial secretion systems release effectors into the extra-cellular milieu or directly into foreign cells. They represent fundamental mechanisms by which bacteria modulate their environment and induce human infection. Here we study two related and complementary secretion systems, the bacterial type II secretion system (T2SS) and the Tad secretion system (TdSS). The T2SS secretes effectors and toxins involved in cell adherence, biofilm formation and host cell death. The TdSS drives cell adherence and colonization through extra-cellular pilus formation. Both secretion systems constitute multi-component complexes with many shared components that span the cell envelope of Gram-Negative bacteria. The overall goal is to determine the molecular mechanism underlying T2SS and TdSS operation. Key aims for the T2SS include showing how substrate is recruited, how inner membrane components are organised, and how pseudo-pilus assembly is coordinated. The repertoire of K. pneumoniae T2SS virulence factors will also be expanded. For the TdSS, key aims include structure-function studies on the outer membrane secretin with its associated pilotin and pilus. Comparison of T2SS and TdSS structures will reveal common mechanistic and evolutionary principles. By understanding how the T2SS and TdSS function and promote pathogenesis, this research has the potential to facilitate drug development and combat anti-microbial resistance. Some bacteria cause infections in humans that kill millions of people annually. To trigger the infection, the bacteria contain nanomachines within their cell surface that act like miniature pumps. These are secretion systems. One role of secretion systems is to deliver harmful proteins from inside the bacteria to outside environments like your cells. These harmful proteins act as molecular weaponry in many ways. They can form grappling hooks to help the bacteria attach to environments like your intestine or as molecular malware that maliciously reprogram your cells. We use a powerful technique called cryo-electron microscopy, which allows us to visualize the precise position of the atoms within the secretion systems. In this way we can learn the 3D structure and chemistry of the secretion systems. By understanding how the secretion systems work we have a much greater chance of developing medicines that stop the secretion systems from causing human illness.

    more_vert
  • Funder: WT Project Code: 218247
    Funder Contribution: 616,706 GBP

    We request funds to purchase an Illumina NovaSeq 6000 DNA Sequencing System. This will enable the University of Exeter to sequence DNA from humans and other species relevant to human health with the best possible efficiency, throughput, speed, and flexibility. Our current Illumina HiSeq 2500 system is approaching the end of its useful lifespan. Replacing it with the NovaSeq 6000 will reduce running costs by ~75%. Local accessibility to the most up-to-date DNA sequencing technology is critical to many researchers, especially those translating research into the NHS, and underpins several “flagship” Exeter research programmes. The current equipment is routinely used by groups in the Medical School and Biosciences, and existing demand exceeds capacity. Local access to DNA sequencing has enabled Exeter researchers to drive world leading studies identifying the genetic basis of diseases including diabetes, obesity, dementia and schizophrenia, and enabled us to establish internationally-renowned projects in epigenomics and transcriptomics. The sequencer will be managed and operated as a Research Facility within the University, by an experienced sequencing team established more than 10 years ago, to provide a key resource for the biomedical research community in Exeter and beyond that is critical to our continued innovation and leadership in genomics. The last decade has seen tremendous advances in our understanding about the role of genetic variation in health and disease, driven by developments in technology for sequencing the genome. Genes involved in a spectrum of debilitating disorders and health-related traits have been identified, including many by researchers at the University of Exeter. We are requesting funds to purchase the most high-throughput and economical genetic sequencer currently available. Local access to the most up-to-date DNA sequencing technology is critical to many researchers, especially those translating research into the NHS, and underpins several “flagship” Exeter research programmes. For example, it will enable Exeter researchers to continue to drive world leading studies identifying the genetic basis of diseases including diabetes, obesity, dementia and schizophrenia. Given the considerable matched funding from the University, the funds requested here represent outstanding value for money, enabling Exeter to further drive innovation and excellence in UK genomics research.

    more_vert