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857 Projects

  • Wellcome Trust
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  • 2022

10
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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.

    more_vert
  • Funder: WT Project Code: 220029

    The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are the causative agents of neglected tropical diseases. They rely on surface glycans, chains of sugar units attached to proteins and lipids, for their survival and infectivity. These surface glycans are synthesized by enzymes called glycosyltransferases located in the secretory pathway. However, contrary to this canonical model of glycan synthesis and surface expression, our group has recently described the presence of an essential glycosyltransferase, a fucosyltransferase, in the mitochondrion of T. brucei. A similar putative fucosyltransferase gene, called TcFUT1, has been found in the genome of T. cruzi, the causative agent of Chagas’ disease, endemic in the Americas. We aim to obtain recombinant, active TcFUT1 protein in order to analyse its enzymatic activity, define its preferred substrate(s) in vitro, design assays for compound screening and to raise antibodies against it for immuno-localisation. In parallel, we also aim to define its essentiality and characterise its endogenous substrates. This work will provide an opportunity to uncover the function(s) of this novel mitochondrial fucosyltransferase and provide a much-needed drug target for Chagas’ disease.

    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: 208470

    “The Global Health Innovative Technology Fund (GHIT Fund) is an international non-profit organization headquartered in Japan that invests in the discovery and development of new health technologies such as drugs, vaccines, and diagnostics for infectious diseases in developing nations . Wellcome Innovations Division contributes to the Fund alongside the Japanese Government, the Bill and Melinda Gates Foundation and six Japanese pharmaceutical companies.”

    more_vert
  • Funder: WT Project Code: 215205

    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.

    more_vert
  • Funder: WT Project Code: 202800
    Funder Contribution: 2,027,840 GBP

    Efforts to eliminate malaria are threatened by the spread of resistance to the drugs and insecticides needed to control the disease. Through a massive, multi-country genome-wide association study conducted in the last few years, we now have unequivocal evidence for high-level protection against severe falciparum malaria by a number of new human genetic polymorphisms. Most relate to the red blood cell (RBC), the primary target of the malaria lifecycle in humans. The challenge now is to turn this knowledge into new drugs and vaccines. Through this fellowship, I will use the unique opportunities available to me in Kilifi, Kenya, to discover the protective mechanisms afforded by four key polymorphisms - mutations in GYP, ATP2B4 and the ABO and Knops blood group antigens - and to document their wider consequences. I will take a comprehensive and multi-disciplinary collaborative approach that will include studying the effect of these genes on: (i) malaria- and non-malaria-specific disease epidemiology; (ii) RBC structure and function; (iii) P. falciparum invasion both in vitro and in vivo through experimental human challenge; and (iv) in vitro correlates of malaria severity. These studies will be essential in determining the translational potential of these associations and informing future work. Almost half of the world’s population lives under the threat of malaria, and the disease killed >400,000 in 2015. Efforts to develop a vaccine have been disappointing and new approaches to control and treatment are badly needed. The existence of human genetic variants that provide natural protection against malaria has been recognized for >60 years. By studying such genes we stand to learn more about malaria, and potentially to discover new ways of treating it. Through this fellowship, I will focus on four genes for which we have strong evidence of natural protection. All affect the red blood cell - the natural target of human infections. I will (i) document their impact on both malaria and other diseases through population studies conducted in Kenya; (ii) observe their effects on rates of disease progression in adults volunteers who will be inoculated experimentally with live malaria parasites ; (iii) study their effects on red cell function and (iv) investigate parasite invasion in the laboratory. If we are able to pinpoint the precise mechanisms for malaria resistance afforded by these genes we may be able to use them as a basis for drug and vaccine development.

    visibility140
    visibilityviews140
    downloaddownloads548
    Powered by Usage counts
    more_vert
  • Funder: WT Project Code: 220991
    Funder Contribution: 1,217,830 GBP

    Background; It is unknown how prior exposure to commonly circulating human coronaviruses (HCoV) impacts immunity against highly-pathogenic species (SARS, SARS-CoV-2 & MERS). There are limited data, across Europe, Asia and Africa, on the prevalence of infection and seroconversion against widely circulating and mildly symptomatic HCoVs (229E, NL63, OC43, and HKU1). There is a current supposition that antibody-dependent-enhancement (ADE) may play a role in the pathophysiology of COVID-19. ADE occurs when non-neutralizing antiviral proteins facilitate virus entry into host cells, leading to increased infectivity in the cells. In such cases, higher viremia has been measured and the clinical course of disease can be more severe. In preclinical animal models, immunopathology was observed after challenge following vaccination with some SARS vaccines. Therefore, concerns have been raised regarding the impact of immunopathology and ADE on prophylactic vaccination against SARS and possibly SARS-CoV-2. Goals: to perform detailed systems serology of pre-existing immunity, in children and adults, from the UK and Africa, towards novel and commonly circulating coronaviruses. Impact: These studies highlight the limited knowledge in the field and a need for a systematic approach to investigate cross-reactive humoral immunity against HCoV to inform the immunopathology and pathophysiology of COVID-19.

    visibility100
    visibilityviews100
    downloaddownloads336
    Powered by Usage counts
    more_vert
  • Funder: WT Project Code: 218585
    Funder Contribution: 499,992 GBP

    Tp identify the top-4 molecules by the end of the grant. From those, a preclinical candidate mAb that can be used as a single prophylactic agent to prevent liver stage P. falciparum malaria infection, with significant improvement upon the existing parental AB317, will be selected. These melecules will be mAb's that will fulfil requirements in terms of developability and manufacturability, including critical quality attributes, appropriate safety profile, demonstrated anti-malarial efficacy and extended plasma half-life with acceptable COGs. The starting points will include AB317 and other Ab’s that have been identified from MAL0719. GSK has unpublished data indicating that antibody Fc effector function is also important for protection. Therefore, early studies for this project will also seek to define and validate the benefit that specific Fc effector functions can have in the efficacy of neutralizing antibodies for malaria. In the longer term, one of these four molecules, the selected candidate molecule, will be further progressed to PhI clinical trials, including efficacy endpoints using CHMI, with the ultimate goal of delivering a molecule that could prevent malaria infection. This is in alignment with the significant interest that WT has in the use of human challenge models led by Dr Charlie Weller. Chemoprevention efforts for malaria (IPTp, SMC) have had a major impact decreasing malaria cases but have downsides (adherence to treatments, parasite resistance). GSK and PATH identified IgG´s in GSK’s candidate malaria vaccine RTS,S/AS01B vaccinees (MAL071 study)9 that prevent malaria infection in animal models. PATH is developing one of them, AB317, that will enter a PhI clinical study using controlled human malaria infection (CHMI). AB317 is a tool molecule to demonstrate proof of mechanism (PoM) for a mAb in malaria prevention. In this project, AB317 and other MAL071 mAb´s will be evaluated and optimized for potency, pharmacokinetic properties, optimal manufacturing stability and yields to have the required profile of a prophylactic mAb able to prevent P. falciparum liver infection, with the ultimate goal of prevention of blood stage infection. The molecules should have 3-4 months half-life and acceptable cost of goods (COGs), to overcome drawbacks of the current prophylactic therapies.

    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
Advanced search in
Projects
arrow_drop_down
Searching FieldsTerms
Any field
arrow_drop_down
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857 Projects
  • 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: 220029

    The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are the causative agents of neglected tropical diseases. They rely on surface glycans, chains of sugar units attached to proteins and lipids, for their survival and infectivity. These surface glycans are synthesized by enzymes called glycosyltransferases located in the secretory pathway. However, contrary to this canonical model of glycan synthesis and surface expression, our group has recently described the presence of an essential glycosyltransferase, a fucosyltransferase, in the mitochondrion of T. brucei. A similar putative fucosyltransferase gene, called TcFUT1, has been found in the genome of T. cruzi, the causative agent of Chagas’ disease, endemic in the Americas. We aim to obtain recombinant, active TcFUT1 protein in order to analyse its enzymatic activity, define its preferred substrate(s) in vitro, design assays for compound screening and to raise antibodies against it for immuno-localisation. In parallel, we also aim to define its essentiality and characterise its endogenous substrates. This work will provide an opportunity to uncover the function(s) of this novel mitochondrial fucosyltransferase and provide a much-needed drug target for Chagas’ disease.

    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: 208470

    “The Global Health Innovative Technology Fund (GHIT Fund) is an international non-profit organization headquartered in Japan that invests in the discovery and development of new health technologies such as drugs, vaccines, and diagnostics for infectious diseases in developing nations . Wellcome Innovations Division contributes to the Fund alongside the Japanese Government, the Bill and Melinda Gates Foundation and six Japanese pharmaceutical companies.”

    more_vert
  • Funder: WT Project Code: 215205

    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.

    more_vert
  • Funder: WT Project Code: 202800
    Funder Contribution: 2,027,840 GBP

    Efforts to eliminate malaria are threatened by the spread of resistance to the drugs and insecticides needed to control the disease. Through a massive, multi-country genome-wide association study conducted in the last few years, we now have unequivocal evidence for high-level protection against severe falciparum malaria by a number of new human genetic polymorphisms. Most relate to the red blood cell (RBC), the primary target of the malaria lifecycle in humans. The challenge now is to turn this knowledge into new drugs and vaccines. Through this fellowship, I will use the unique opportunities available to me in Kilifi, Kenya, to discover the protective mechanisms afforded by four key polymorphisms - mutations in GYP, ATP2B4 and the ABO and Knops blood group antigens - and to document their wider consequences. I will take a comprehensive and multi-disciplinary collaborative approach that will include studying the effect of these genes on: (i) malaria- and non-malaria-specific disease epidemiology; (ii) RBC structure and function; (iii) P. falciparum invasion both in vitro and in vivo through experimental human challenge; and (iv) in vitro correlates of malaria severity. These studies will be essential in determining the translational potential of these associations and informing future work. Almost half of the world’s population lives under the threat of malaria, and the disease killed >400,000 in 2015. Efforts to develop a vaccine have been disappointing and new approaches to control and treatment are badly needed. The existence of human genetic variants that provide natural protection against malaria has been recognized for >60 years. By studying such genes we stand to learn more about malaria, and potentially to discover new ways of treating it. Through this fellowship, I will focus on four genes for which we have strong evidence of natural protection. All affect the red blood cell - the natural target of human infections. I will (i) document their impact on both malaria and other diseases through population studies conducted in Kenya; (ii) observe their effects on rates of disease progression in adults volunteers who will be inoculated experimentally with live malaria parasites ; (iii) study their effects on red cell function and (iv) investigate parasite invasion in the laboratory. If we are able to pinpoint the precise mechanisms for malaria resistance afforded by these genes we may be able to use them as a basis for drug and vaccine development.

    visibility140
    visibilityviews140
    downloaddownloads548
    Powered by Usage counts
    more_vert
  • Funder: WT Project Code: 220991
    Funder Contribution: 1,217,830 GBP

    Background; It is unknown how prior exposure to commonly circulating human coronaviruses (HCoV) impacts immunity against highly-pathogenic species (SARS, SARS-CoV-2 & MERS). There are limited data, across Europe, Asia and Africa, on the prevalence of infection and seroconversion against widely circulating and mildly symptomatic HCoVs (229E, NL63, OC43, and HKU1). There is a current supposition that antibody-dependent-enhancement (ADE) may play a role in the pathophysiology of COVID-19. ADE occurs when non-neutralizing antiviral proteins facilitate virus entry into host cells, leading to increased infectivity in the cells. In such cases, higher viremia has been measured and the clinical course of disease can be more severe. In preclinical animal models, immunopathology was observed after challenge following vaccination with some SARS vaccines. Therefore, concerns have been raised regarding the impact of immunopathology and ADE on prophylactic vaccination against SARS and possibly SARS-CoV-2. Goals: to perform detailed systems serology of pre-existing immunity, in children and adults, from the UK and Africa, towards novel and commonly circulating coronaviruses. Impact: These studies highlight the limited knowledge in the field and a need for a systematic approach to investigate cross-reactive humoral immunity against HCoV to inform the immunopathology and pathophysiology of COVID-19.

    visibility100
    visibilityviews100
    downloaddownloads336
    Powered by Usage counts
    more_vert
  • Funder: WT Project Code: 218585
    Funder Contribution: 499,992 GBP

    Tp identify the top-4 molecules by the end of the grant. From those, a preclinical candidate mAb that can be used as a single prophylactic agent to prevent liver stage P. falciparum malaria infection, with significant improvement upon the existing parental AB317, will be selected. These melecules will be mAb's that will fulfil requirements in terms of developability and manufacturability, including critical quality attributes, appropriate safety profile, demonstrated anti-malarial efficacy and extended plasma half-life with acceptable COGs. The starting points will include AB317 and other Ab’s that have been identified from MAL0719. GSK has unpublished data indicating that antibody Fc effector function is also important for protection. Therefore, early studies for this project will also seek to define and validate the benefit that specific Fc effector functions can have in the efficacy of neutralizing antibodies for malaria. In the longer term, one of these four molecules, the selected candidate molecule, will be further progressed to PhI clinical trials, including efficacy endpoints using CHMI, with the ultimate goal of delivering a molecule that could prevent malaria infection. This is in alignment with the significant interest that WT has in the use of human challenge models led by Dr Charlie Weller. Chemoprevention efforts for malaria (IPTp, SMC) have had a major impact decreasing malaria cases but have downsides (adherence to treatments, parasite resistance). GSK and PATH identified IgG´s in GSK’s candidate malaria vaccine RTS,S/AS01B vaccinees (MAL071 study)9 that prevent malaria infection in animal models. PATH is developing one of them, AB317, that will enter a PhI clinical study using controlled human malaria infection (CHMI). AB317 is a tool molecule to demonstrate proof of mechanism (PoM) for a mAb in malaria prevention. In this project, AB317 and other MAL071 mAb´s will be evaluated and optimized for potency, pharmacokinetic properties, optimal manufacturing stability and yields to have the required profile of a prophylactic mAb able to prevent P. falciparum liver infection, with the ultimate goal of prevention of blood stage infection. The molecules should have 3-4 months half-life and acceptable cost of goods (COGs), to overcome drawbacks of the current prophylactic therapies.

    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