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Funders:
The Wellcome Trust
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Results

Investigation of pro-regenerative mesenchymal subpopulations during liver regeneration using a single cell RNA sequencing approach 30 Sep 2018

Chronic liver disease (CLD) is a major cause of morbidity and mortality worldwide. The liver has a remarkable ability to regenerate following injury, however in many cases of CLD this regenerative capacity is overwhelmed. Currently the only effective treatment is liver transplantation but demand for donor organs greatly outstrips supply. New therapies are urgently required. Liver regeneration involves a complex interplay between multiple cell types, including a family of cells called mesenchymal cells. Whilst traditionally, the role of mesenchymal cells was more often studied in the context of liver fibrosis (scarring), recent studies have shown that these cells are also important during liver regeneration. Initial experiments in the Henderson lab, using a cutting-edge technology called single cell RNA sequencing (which allows the sequencing of genes in single cells), has shown that mesenchymal cells, rather than being one family of cells with similar function, are actually very varied in terms of their function, performing many different, important roles within the liver. I will use this powerful technique to identify the pro-regenerative mesenchymal cell subpopulations responsible for driving liver regeneration. Using this information, we hope to design new treatments to harness specific cellular subsets to drive liver regeneration in patients with CLD.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Ethical Considerations of Alternative Clinical Trial Methods and Designs: Challenges and Opportunities 19 Feb 2018

During the Global Forum on Research Bioethics (GFBR) a critical and rigorous evaluation was carried out with respect to alternative designs and methods for conducting clinical trials. GFBR answered several questions related to the ethical implications of these alternative designs and methods, improved the understanding of their elaboration, and allowed attendees to consider the types of situations and research questions in which it may be more efficient and perhaps necessary to employ alternative clinical trial designs. However, GFBR also showed that alternative clinical trial methods and designs are well-known in high-income countries, but that there is little knowledge or literature in low- and middle-income countries. The Network of Committees for Ethics in Research (RECEIH) in Cali, with the support and expertise from several Latin American participants from GFBR, proposes the implementation of such a workshop in Colombia. This workshop will strengthen the roles and analytical skills of researchers, regulatory institutions, and CIE (Institutional Ethics Committee) members to make reasoned, rigorous, and critical reviews of clinical trials that use alternative designs and methods, in addition to ensuring their implementation according to the highest ethical standards.

Assessment of placental function in complicated pregnancy using advanced MRI 04 Dec 2017

Placental insufficiency underlies the major obstetric syndromes of fetal growth restriction (FGR) and pre-eclampsia and accounts for one third of stillbirths in high-income countries. There is an unmet clinical need for a method to properly characterise placental perfusion and determine if and when a placenta is likely to fail. The objective of this work is to develop an imaging method to assess placental function in complicated pregnancy. This work will help us to better understand placenta function in FGR. This project will compare placenta properties from appropriately developing and early-onset growth-restricted pregnancies to understand the differences in the appearance of the placenta in FGR. The key goals of this work are to assess a novel Magnetic Resonance (MR) Imaging method to measure fetal and maternal placental perfusion. This technique describes an MR signal that models the blood flow properties as they change between the maternal and fetal sides of the placenta. to link this to relevant clinical information including clinical ultrasound markers and fetal MRI. to use these results to establish a comprehensive imaging project for the placenta by providing an in vivo measurement of placenta function to complement information from ultrasound imaging and ex utero microCT.

Amount: £99,804
Funder: The Wellcome Trust
Recipient: University College London

Specialised Ribosomes – Does KSHV modulate ribosome composition 30 Sep 2018

Historically, ribosomes have been viewed as unchanged homogeneous units with no intrinsic regulatory capacity for mRNA translation. Recent research is shifting this paradigm of ribosome function to one where ribosomes may exert a regulatory function or specificity in translational control. Emerging evidence has identified heterogeneity of ribosome composition in specific cell populations, leading to the concept of specialised ribosomes. Specialised ribosomes may therefore exhibit control and regulation over the translation of specific mRNAs, resulting in a substantial impact on how the genomic template is translated into functional proteins. Due to the emerging concept that cells can control the composition of ribosomes to regulate protein expression, it would seem highly likely that viruses could also manipulate host cell ribosome compositions to enhance the production of viral proteins. We have quantitative proteomic and ribosomal profiling data suggesting Kaposi's sarcoma-associated herpesvirus (KSHV) manipulates ribosomal biogenesis. Firstly, we will investigate changes in composition and stoichiometry of proteins within the ribosome, driven by KSHV. We will isolate ribosomal complexes by tandem affinity purification, during KSHV infection and analyse changes by LC-MS/MS and cryo-EM. We will elucidate how these changes exert ribosome-mediated specificity to promote KSHV lytic infection using a number of cellular and molecular techniques.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Leeds

Gene Therapeutic Strategy for Autosomal Recessive Spastic Paraplegia Arising From Mutations in SPG47 31 May 2018

Hereditary spastic paraplegias (HSPs) are a family of progressive lower-limb spasticity disorders characterized pathologically by degeneration in the corticospinal and spinocerebellar tracts. Spastic paraplegia type 47 (SPG47) is a subtype of HSP, caused by recessive mutations in the AP4B1 gene, leading to a significant reduction in the transcript protein levels. The gene codes for a subunit of Adaptor protein complex 4 (AP4), an essential intracellular trafficking protein in neurones. A loss-of-function hypothesis for SPG47 is backed by substantial emerging evidence, as mutations in all the other subunits of the AP4 complex disrupt the protein's normal and cause a very similar clinical presentation to that of SPG47. Gene therapy aimed at restoring AP4B1 protein expression therefore represents a rational therapeutic approach to ameliorate the disease phenotype. This project aims to design therapeutic vectors (AAV9 and AAV-PHP.B.) to express human AP4B1 gene under Chicken Beta Actin promoter. It also aims to evaluate their in vitro efficacy in cortical neurons isolated from AP4 ß-/- knockout mouse model and AP4B1 KO HeLa cell lines. If successful, the vectors can be tested in the future in animal models and eventually in clinical trials, aiming to treat SGP47 and improving patients’ quality of life.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Sheffield

Quantifying the influence of wind on mosquito flight and consequences for malaria transmission in southern Malawi 21 May 2018

Spatially targeting malaria control interventions in areas of high disease burden will become a more cost-effective and sustainable approach for national programmes in the era of elimination. To achieve this the geographical scale in which to implement control and identify the most likely sources and routes of infection are critical. Wind-assisted mosquito dispersal is an important, yet currently undervalued, source of information to track the spread of malaria and predict outbreaks. We will develop and apply a model, previously and successfully used to track the wind-borne spread of Bluetongue virus by midges, to predict the spread of malaria in a rural region of southern Malawi. The ‘spatial-temporal wind-outbreak trajectory simulation’ (SWOTS) model will use wind data, household infection status and insect flight parameters to determine the most likely source and route of infection during the rainy season. We will empirically validate the output from SWOTS using a simple mark-recapture field experiment to determine the influence of wind direction and speed on vector movement. This pilot project will determine the applicability of SWOTS as a risk assessment and disease preparedness tool for malaria in rural Africa and lay the foundations to extend to other transmission settings and vector-borne disease systems.

Amount: £94,334
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Elucidating allosteric processes in immunoglobulin E 31 May 2018

Immunoglobulin E (IgE) is thought to be the first line of defence against parasitic pathogens, mediating immune reactions by binding to either of its two receptors, either the high-affinity FcepsilonRI receptor or the low-affinity CD23 receptors. While the IgE molecule was previously thought to exist in a primarily acutely bent conformation in solution, Drinkwater et al. (2014) found that IgE was able to exist in a fully extended conformation while Davies et al (2017) showed that omalizumab (XolairTM by Novartis) trapped IgE in a partially bent state to block its action on its FcepsilonRI receptors. The McDonnell Laboratory has derived a series of anti-IgE antibody Fab fragments, selected for their ability to affect IgE’s overall structure and dynamics and consequently to allosterically affect the binding to IgE’s receptors. In this proposed study, we will investigate how observed ligand-mediated changes in conformational dynamics manifest themselves as entropically-driven allosteric modulation. As a complement to NMR studies of ligand-mediated changes in protein dynamics, currently ongoing in the McDonnell Laboratory, direct measurements of the thermodynamic parameters of ligand binding will be performed using isothermal titration calorimetry.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London

Depression, anxiety and quality of life in a palliative population: a comparative study across different settings – home, hospice and hospital 31 May 2018

Palliative medicine deal with a fragile population- both in terms of the patient themselves and their families. Psychological health is often an extremely delicate topic to approach. By conducting a comparative study across different settings – home, hospice and hospital I intend to begin bridging that gap between physical and psychological care. I will conduct a cohort study to gather qualitative data on the mental wellbeing of palliative care patients, specifically measures of depression, anxiety and quality of life. Examining the relationship between symptoms depression, anxiety and adjustment disorder in a palliative population will allow terminally ill patients the opportunity to be heard. Publishing my data and statical findings introduces the possibility that end-of-life patients could improve their peers treatment and quality of life. Furthermore, by uncovering an intricate connection between a palliative patient's environment and their overall wellbeing, my research could help to produce local and national guidelines for a more tailored healthcare plan.

Predicting disease progression in cognitive impairment using a brain ageing biomarker 06 Sep 2018

Earlier detection of the neurodegeneration that precedes dementia is needed if we are to address the rising burden that dementia places on our ageing global population. While cognitive impairment is an important risk factor, alone it is insufficient to identify who will experience pathological deterioration and subsequent dementia. Here, I aim to harness the power of neuroimaging as an objective and sensitive index of brain structure, using an ‘ageing biomarker’ framework to measure so-called ‘brain-age’ in people with mild cognitive impairment (MCI) or subjective cognitive impairment (SCI). This project aims to 1) validate the utility of brain-age for predicting future health outcomes in people with MCI or SCI, and then 2) implement a software pipeline to convey these individualised predictions directly to clinical settings. I will meet these goals by taking advantage of the large existing MRI database of memory clinic patients and linked electronic health records available at King’s. Collaborations with memory services across King’s Health Partners NHS Trusts will enable trial clinical deployment of my software pipeline. Using brain-age in combination with clinical expertise in memory services will enable optimal and cost-effective allocation of resources, moving towards the application of precision medicine to detect dementia risk earlier.

Amount: £83,104
Funder: The Wellcome Trust
Recipient: King's College London

Investigate the role of SET1A in the activation of gene expression 30 Sep 2018

The regulation of gene expression is fundamental for cellular integrity and is partly achieved by the opposing action of repressive and activating histone modifications. One such histone modification is the tri-methylation of lysine 4 on histone H3 (H3K4me3), which is known to correlate with transcriptional activity. The SET1A complex is responsible for depositing the majority of H3K4me3 in mammalian cells and disrupting its function often leads to gene expression defects. However, the mechanisms by which SET1A regulates gene expression remain unknown. I will use the auxin-inducible degron system to rapidly deplete SET1A levels. A series of genomics technologies, including ChIP-seq and NET-seq will then be used to determine the effects of SET1A loss on chromatin architecture and transcriptional activity. Additionally, proteomics techniques will be used to identify the pathways perturbed upon SET1A loss, hence identifying the mechanisms by which SET1A supports active transcription and furthering our understanding of how gene transcription is regulated. This is essential for the development of novel therapies targeting genetic diseases in which the control of gene expression is perturbed.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Whipworm infection – defining and exploiting the niche biology of a parasitic intestinal nematode 10 Apr 2018

Little is known about the mechanisms underpinning chronic infection by intestinal dwelling nematode parasites. If we are to develop novel and effective ways to control these infections and exploit their immune evasion strategies, we require a much deeper understanding of the parasite itself, how it interfaces with its environment and how it survives immune attack during long-term infection. We will address this bottleneck using the Trichuris muris mouse model of human whipworm infection. We will: Define the biology of the major secreted protein produced by whipworm during chronic infection, which we have shown binds interleukin 13 and tethers to glycosaminoglycans and matrix. We will precisely map binding sites, define function in vitro and in vivo and the activity of the human parasite homologue (T. trichiura). Define the tripartite interaction between parasite, host and intestinal microbiota which we have demonstrated is critical to both establishment and survival of the parasite. We will re-colonise germ free mice with Bacteroides thetaiotamicron which effectively supports whipworm infection and plays a major role in scavenging intestinal glycosaminoglycans to identify the key genes of each partner that underpins chronic infection and will test them functionally in vivo to identify novel pathways for intervention.

Amount: £1,996,029
Funder: The Wellcome Trust
Recipient: University of Manchester

Localisation and inheritance of translation factor mRNA granules in yeast. 30 Sep 2018

During the process of producing proteins from DNA, the localisation of intermediate mRNA is an essential regulation. Misregulation of protein activity due to mislocalisation of mRNA can adversely affect both developing organisms and adult tissues. Studies on mRNA localisation in yeast have served as a paradigm for other systems. Recently the Ashe lab have identified several mRNAs that associate together as a granule, and this granule is preferentially inherited by the new daughter cell during cell division. Interestingly, these mRNAs encode for proteins that are important for the translation of other mRNAs into proteins. Therefore, the purpose this mRNA granule inheritance may be to allow rapid growth and development of the new daughter cell. The aim of this project is to investigate the purpose of RNA granule inheritance by comparing the physiology of daughter cells that inherit RNA granules and those that do not. Also, the mechanisms of mRNA localisation to these daughter cells will be studied using NIP1 mRNA, which localises to these RNA granules during cell division. This project therefore aims to study mRNA localisation to investigate mechanisms and consequences of translation factor mRNA granule inheritance, processes which may also be conserved in other organisms.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Manchester

Investigating stiffness alterations in spinal cord injury 30 Sep 2018

Spinal cord injury is a devastating condition that may lead to loss of limb movement, sensation and bladder control. Despite intense research, treatment is still very limited. Most research to date has focused on biochemical signalling. However, some more recent studies have hinted that mechanics might play an important role in spinal cord regeneration. Using atomic force microscopy (AFM), a cutting-edge technique which allows us to very precisely measure stiffness maps of biological tissues, we will investigate the stiffness of spinal cord tissue at various time points after injury and compare this to the stiffness of healthy spinal cord. We will test whether artificially modifying the stiffness of the damaged spinal cord or modifying mechanosensing in spinal cord cells improves regeneration of neurons after spinal cord injury. Our studies will be carried out in a cervical contusion model in rats which closely mimics the pathology seen in the human spinal cord after injury, even though the behavioural impairments the animals show are markedly less grave.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Dengue Controlled Human Infection Model - Development Grant 17 Nov 2017

Following a positive response to the preliminary submission for grant funding to establish a Dengue Controlled Human Infection Model (Dengue-CHIM ) in Ho Chi Minh City, Vietnam, I am submitting this request for a small grant to assist in refining and developing the main proposal prior to final submission in March 2018. During this pre-submission phase I plan to employ an experienced post-doctoral immunologist to carry out a) a scoping review of the current landscape of dengue vaccines in development, and b) a review exploring the current understanding of the immune response to/protection from DENV infection and disease, particularly focusing on immune correlates of protection. This will be the first application of a Dengue-CHIM approach in any dengue endemic setting, and raises a number of important bioethical concerns. Therefore I also plan to employ a Vietnamese social science research assistant for a period of 4 months to engage with key Vietnamese stakeholders to discuss the important issues surrounding endemic setting CHIMs, conduct preliminary informal interviews with these individuals, and help to develop the agenda for a 2 day workshop focused on Bioethics and Stakeholder Engagement related to endemic setting CHIMs that will take place in early March.

Amount: £23,690
Funder: The Wellcome Trust
Recipient: University of Oxford

The mammillary bodies and memory: from encoding to consolidation 17 Jul 2018

The mammillary bodies (MBs) are critical for memory but their specific functions have remained largely elusive. Historically, the MBs were associated with memory encoding, however, our recent findings suggest an as yet unexplored role in memory consolidation, both at the cellular and at the systems level. The proposed research will use multi-level, comparative approaches to investigate the contribution of the MBs to post-encoding processing, during wakefulness and sleep. The combined rodent/human methodologies will take advantage of the unique benefits provided by each line of research. The application of convergent techniques with rodents (inactivation, calcium-imaging, electrophysiology, behaviour) will interrogate the contributions of the MBs to different stages of memory processing, both in an intact system and when the system is disrupted. Complementary research with humans will address similar questions. fMRI will help to assess diencephalic contributions in the intact system. The impact of damage to the MB system on aspects of sleep-related consolidation will also be assessed. Together, this research will provide a comprehensive analysis of post-encoding memory processes and support the development of wide-reaching models of MB function.

Amount: £1,563,892
Funder: The Wellcome Trust
Recipient: Cardiff University

Grb2-mediated regulation of miRNA maturation in the basal state. 30 Sep 2018

Cancers develop as a result of many interacting factors. Two such factors are cell stress and microRNA (miRNA) expression. Cell stress causes fluctuations in protein levels, which can perturb the proper functioning of the cell. miRNAs silence specific genes, and therefore can induce changes within the cell which cause them to become cancerous. However, little is known about how miRNA expression is altered. I aim to investigate a novel mechanism of miRNA regulation, which may be perturbed by cell stress. I will determine how the levels and activity of key components in miRNA biogenesis are altered in cells expressing different proteins and which have been subject to different stress conditions, using a range of in vitro, cell-based and biophysical approaches. I will also perform several screens to identify key microRNAs regulated by this mechanism, and how their expression changes with cell stress. This work will reveal new avenues for cancer therapy and help us to target cancer with a fresh perspective.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Leeds

Molecular and antimicrobial characterisation of Propionibacterium acnes isolates from patients with severe recalcitrant papulopustular and nodular acne 31 May 2018

The widespread use of antibiotics for the treatment of acne vulgaris has led to the selection of Propionibacterium acnes ‘super-bug’ strains that are now resistant to first line antibiotics. Consequently, a growing number of patients are emerging with forms of acne that are non-responsive to common antibiotic therapies. As alarming, many of these patients also have extremely severe and aggressive forms of the disease, as well as resistance to oral retinoids. Characterization of the P. acnes population associated with severe recalcitrant papulopustular and nodular acne is therefore vital so we can identify new, pathogenic, multi-drug resistant lineages that may be driving this pathology. Such a study will also enable us to investigate if novel super-bug lineages of this bacterium are disseminating within the population, as well as providing an invaluable platform for the generation of skin microbiome-based diagnostics. The aim of this project will therefore be to characterize antibiotic resistant isolates of P. acnes recovered from patients with severe recalcitrant papulopustular and nodular acne, and a key goal will be to determine if strains represent new genetic sequence types circulating within the population. Another key objective will be to examine minimum inhibitory concentrations (MICs) and biofilm formation by these strains.

Amount: £0
Funder: The Wellcome Trust
Recipient: Ulster University

Measuring frailty in older rural South African population - Construction and validation of a Frailty Index 31 May 2018

Data from the HAALSI cohort from rural South Africa will be used to achieve 3 aims: To derive a Rockwood deficit-accumulation Frailty Index (FI) in this population To test whether the FI predicts mortality in the HAALSI population To compare results from the Fried frailty score and the FI A review of existing literature will inform the selection of a minimum of 30 variables for inclusion in the Frailty Index. Examples include (but are not limited to): disease diagnoses (e.g. angina, HIV), functional impairments (e.g. low gait speed, low grip strength), or biochemical/haematological derangements (e.g. low haemoglobin). Absence of a deficit scores zero; presence of a deficit scores 1. Cox proportional hazards models will be used to examine the association between the FI and time to death in the HAALSI data; unadjusted models and models adjusted for age and sex will be developed. Finally, the ability of the FI to predict 1 year mortality will be compared with the ability of the Fried phenotypic score to predict 1 year mortality in the HAALSI population. Receiver-operator characteristic curves will be developed for each score, and the c-statistic for each score compared.

Amount: £0
Funder: The Wellcome Trust
Recipient: Newcastle University

Investigating the protein and mRNA content of mRNA granules in Saccharomyces cerevisiae 30 Sep 2018

The central dogma of biology is that DNA makes mRNA, which in turn is converted into proteins. Translation, the process of decoding mRNA into protein, and its attendant regulation, thus underpins all life, as proteins are principal effectors of biological function; they catalyse most biochemical reactions and play many structural and regulatory roles. Although translation is a generally well understood process common to all eukaryotes (animals, plants and fungi) it is becoming clear that the localisation of mRNA within the cell is also important and can affect mRNA degradation, storage and the translation process itself. This can occur within granules within the cell, termed ‘mRNA granules’, that possess various physical properties ranging from aggregates to ‘liquid droplets’. These granules are often linked to ‘stress’ conditions and can have different functions, as well as being linked to numerous neurodegenerative and musculo-degenerative diseases such as Fragile X mental retardation and Alzheimer’s. We hypothesise that there are a number of related granules with overlapping as well as specific mRNA/protein components that together endow these granules with unique functions. To address this we will comprehensively characterize these granules in yeast using a range of modern biochemical techniques, coupled with semi-quantitative proteomics and integrative bioinformatics.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Manchester

Investigate the role of forced expression of Programmed Death-Ligand1 on mesenchymal stem cells on immunomodulatory properties in vitro. 31 May 2018

Despite success in in-vitro and in pre-clinical models, the therapeutic efficacy of mesenchymal stem or stromal cells (MSCs) is somewhat limited. In this project, we will investigate two different strategies to enhance their therapeutic efficacy by forced expression of Programmed Death-Ligand1. PD-L1 expression has been shown to protect cells and tissues from T-Cell mediated cell death. Recent work carried out by Prof.Ritter’s lab showed that overexpression of PD-L1 on corneal tissue before transplantation significantly prolongs corneal allograft survival upon transplantation in allogeneic recipients. This indicates a pivotal role for PD-L1 in immunomodulation. Additionally and as of interest, preliminary data indicate that expression of PD-L1 is highly up-regulated on licensed MSCs or on MSC treated with tumor conditioned medium (TCM) indicating a role in immune evasion of tumors. We aim to understand if forced expression of PD-L1 enhances the immunoregulatory properties of these MSCs in vitro. We will attempt to achieve this using either lentiviral gene transfer of PD-L1 or licensing with tumor-conditioned medium. This research will contribute significant data to the development of novel treatment protocols for patients suffering from inflammatory conditions such as impaired wound healing in diabetes and ocular surface injuries.