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Results

Investigating the Structure of FcγRIIa and its Interactions within the Membrane 30 Sep 2018

Human Fcgamma receptors (FcgammaRs) are proteins found on the surface of immune cells. They bind to antibodies, which are produced by the body, in response to infection. Some antibodies produced recognise their own tissues and are found in many diseases, including rheumatoid arthritis and lupus. It has been shown that genetic changes in the FcgammaRs are found more frequently in rheumatoid arthritis sufferers compared to healthy individuals. This project will focus on FcgammaRIIa, which is present on cells which are responsible for the destruction of many antibody-bound objects. Through a combination of cutting edge techniques, spanning physics, biology, immunology and medicine, we will uncover fundamental information within this field. This information would aim to inform the production of effective therapies to treat diseases such as arthritis, which put a huge strain on the NHS every year.

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

A structural investigation into the action of and resistance to ribosome-targeting antibiotics 30 Sep 2018

Antibiotics are crucial to modern medicine, allowing treatment of life-threatening bacterial infections and making many surgeries like transplantations possible. However, pathogenic bacteria are rapidly evolving to resist their effects. Protein synthesis is one of the main antibiotic targets in bacterial cells. I will use structural biology techniques, principally cryoEM and single particle image processing, to understand how both novel natural products and clinical antibiotics bind to the ribosome to bring about their inhibitory effects on protein synthesis. Furthermore, I will investigate the cause of toxicity of certain ribosome-binding antibiotics by examining how they bind to the mammalian mitochondrial ribosome. Finally, I will use a combination of cryoEM and protein X-ray crystallography to elucidate how certain ribosomal-protecting proteins form complexes with the ribosome in order to bring about antibiotic resistance. On an individual level, these studies will allow an assessment of the viability of novel natural products as suitable clinical antibiotics. More generally, they will contribute to our knowledge of how different classes of antibiotics target the ribosomes of pathogenic bacteria, and how these bacteria evolve resistance. This knowledge will help the development of methods to rationally design new ribosome-targeting antibiotics that are able to overcome or circumvent resistance.

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

Cellular Dynamics and Regulatory Networks Controlling Endometrial Remodelling during the Window of Implantation 17 Jul 2018

The endometrium undergoes iterative cycles of menstrual shedding, regeneration, rapid growth, and differentiation in response to ovarian hormones. During the mid-luteal phase, the endometrium becomes transiently receptive to implantation, heralding the start of a process of intense tissue remodelling, characterized by secretory transformation of glandular epithelium, angiogenesis, differentiation of stromal cells into secretory decidual cells, and activation of specialized immune cells. Several reproductive disorders, including recurrent pregnancy loss, are linked to defects in tissue remodelling at implantation. However, the cellular complexity and dynamic nature of the endometrium have so far precluded precise characterization of the underlying pathological mechanisms and drivers. We will employ high-throughput single-nucleus sequencing to map the dynamic changes in gene expression and chromatin accessibility (cis-regulatory regions) in all endometrial cell types across the luteal phase in defined patient groups. The data will be back-mapped to a future successful pregnancy or miscarriage. This analysis will yield unparalleled insight into the sequence of endometrial events (i.e. changes in cell populations, cellular states, gene expression and transcriptional regulation) leading to a successful or failed pregnancy. Further, 3D organoid cultures, consisting of glands and stroma, will be used to investigate putative drivers of endometrial dysfunction and to evaluate new treatment targets.

Amount: £1,281,629
Funder: The Wellcome Trust
Recipient: University of Warwick

PhD Grant Proposal 30 Sep 2018

Older people are often classed as either experiencing ‘normal’ cognitive ageing, or ‘pathological’ cognitive ageing as a result of diseases such as Alzheimer’s (AD). However, these classifications fail to reflect the spectrum of cognitive decline that is experienced as we age. Age-related cognitive decline is a hugely important health problem; it has a profound impact on quality of life, increases the risk of depression and may herald dementia. Because of this, it is important to investigate what influences how well we age cognitively. Age itself is the biggest risk factor for cognitive decline. The comprehensive causes and mechanisms of ageing are not fully understood but we do know that the process is closely integrated with inflammation – the body’s immune response to injury or irritants. Although recently receiving significant attention, the precise cause-and-effect relationship between inflammation and cognitive ageing has not yet been fully explored. Using different techniques, this project will investigate the role of inflammation in cognitive ageing, and whether the process can explain why some people are more resilient than others. Understanding the differences in individual’s cognitive decline is critical to developing interventions to prolong cognitive health and to gain insight into diseases of cognition such as AD.

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

Functional characterization of a novel KMT2D-related developmental disorder 31 May 2018

The proposed research uses standard molecular biology, protein purification and biophysical structural analysis methods in a focused series of experiments that comprise a complete 6-week project. This builds on existing molecular genetics studies that have identified novel missense mutations in KMT2D (also known as MLL2) as the cause of a unique phenotype (renal tubular dysgenesis, choanal atresia and athelia). Previous studies have identified KMT2D mutations as a major cause of Kabuki syndrome, a comparatively common autosomal dominant congenital mental retardation syndrome. The missense mutations occur in a central region of the KMT2D protein (2841-3876) that does not have variants associated with Kabuki syndrome. This central region contains a series of coiled-coil domains that are likely to mediate protein-protein interactions. However, the effect of the missense mutations on KMT2D structure and interactions is completely unknown. This project will determine the structure-function relationships between KMT2D and a unique phenotype that are likely to be caused by altered protein-protein interactions, as well as describing the broader genotype-phenotype correlations in this important gene. The approach described in the proposal is the only tractable way to understand possible structure-function relationships, given the large size of the gene and encoded protein.

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

Developmental gene expression profiling for novel mediators of epithelial fusion in the chick embryo 31 May 2018

Title: Developmental gene expression profiling for novel mediators of epithelial fusion in the chick embryo. Hypothesis: Tissue fusion processes in vertebrates are essential for normal embryonic development. Novel factors recently identified in our lab using transcriptome profiling during epithelial fusion within the embryonic chick eye may have roles in fusion in additional embryonic contexts. We will perform whole mount in situ hybridization for the genes NTN1, FLRT3, CYP1B1 and RGMB using chicken embryos at key fusion stages in the developing neural tube, body wall and heart. These analyses will inform us whether the protein products of these genes are required for fusion in these tissues. Uniquely in the chicken embryo, the palatal shelves do not fuse. Therefore, identification of continual gene expression in the developing non-fusing palate will also help to identify which of these factors may act to prevent fusion. Data will be collected and analysed using brightfield microscopy and optical projection tomography (OPT). Key goals: (i) Establish spatial gene expression profiles for four genes between chick embryonic stages HH16-26; (ii) determine those genes with conserved roles in fusion for multiple tissues; (iii) categorize genes into likelihood of promotion or inhibition of tissue fusion.

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

Decoding adaptive immunity: high-throughput sequencing and characterisation of the immune repertoires produced during parasitic infections 30 Sep 2018

Despite extensive research, there remains no effective vaccine licensed for any human parasitic infections. This has been attributed to a lack of knowledge available regarding the development of naturally acquired immunity to such infections. Following pathogen exposure, clonal expansion of T and B-cells occurs, generating repertoires of lymphocytes that are a distinct response to the pathogen. High-throughput sequencing, in combination with proteomics, now provides the opportunity to study these immune responses in precise detail, delineating components of protective immunity and identifying their critical antigenic targets, providing unparalleled insights in to the mechanisms underlying immunity to a pathogen. By sequencing T and B-cell repertoires produced during parasitic infections, we aim to document conserved T cell and antibody responses that convey protection, and identify what antigens they are targeting, to inform vaccine design. Key goals are to provide proof of principle for this approach using a controlled animal-model of the malaria parasite Plasmodium chabaudi, before analysing human acquired immunity in Schistosomiasis. We aim to document TCR and antibody sequences that are elicited during immune responses to these parasitic infections, identify conserved ‘public’ antibody signatures generated and characterise their antigenic targets, thereby addressing the key knowledge gaps that have precluded effective vaccine design.

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

Structure and mechanism of a key bacterial cell division protein 06 Sep 2018

To divide and multiply, bacteria must remodel their cell envelope to facilitate physical separation of daughter cells. FtsEX is a key player in coordinating cell division events on either side of the bacterial inner membrane. FtsEX belongs to the same protein superfamily as the MacB efflux pump and the LolCDE lipoprotein trafficking complex, collectively termed Type VII ABC transporters. Current models for FtsEX activity suggest long range conformational changes in FtsEX regulate periplasmic enzymes responsible for peptidoglycan hydrolysis while maintaining cytoplasmic interaction with the septal Z-ring. Structural and functional data are essential to understand how FtsEX works and to assess viability of inhibition using chemical compounds. This project seeks to characterise the interaction of FtsEX with its binding partners, the role of ATP binding and hydrolysis, and to obtain structural data using X-ray crystallography. The project builds on published work on Type VII ABC transporters and is supported by preliminary data showing FtsEX has been crystallised. The Seed Award will presage future applications to the Wellcome Trust, MRC or Leverhulme Trust to further explore the structure and function of bacterial cell division proteins as targets for future antibiotic development.

Amount: £98,945
Funder: The Wellcome Trust
Recipient: University of Warwick

1 year extension application 30 Sep 2018

This fellowship investigates the incompletely understood processes underlying worsened acute kidney injury (AKI) and impaired renal regeneration in the elderly. My collaborators have recently demonstrated that young recruited monocytes can restore successful repair in other aging organ systems. I hypothesise that altered monocyte/macrophage behaviour impairs regeneration after renal injury in the elderly I will: 1) Dissect the contibution of the aging immune system, the renal parenchyma, or the interplay of both in determining the regenerative potential of the aged injured kidney. 2) Define how these responses can be manipulated to enhance renal repair after injury. To address these issues, with my collaborators at Harvard University I will establish a model of AKI in parabiotic mouse pairings. This will permit incisive experiments examining the impact of old + young circulating cells recruiting to the same injured kidney, and the cross-talk between these cells and the old or young parenchyma. Goals: 1. Characterise the effects of aging macrophage phenotype on maximal severity of AKI 2. Investigate reparative macrophage phenotypes and parenchymal responses in the aged regenerating kidney 3: Dissect interactions of aged macrophages and apoptotic and viable parenchymal cells in vitro

Amount: £264,314
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Conserved Epitopes in Rosetting PfEMP1 Variants: Prevalence will Inform Potential as a Therapeutic Target in Severe Malaria 30 Sep 2018

Rosetting, where parasitised red blood cells bind to non-parasitised red blood cells, has consistently been associated with severe forms of Plasmodium falciparum malaria. There is therefore interest in the development of anti-rosetting therapies which aim to alleviate the microvascular obstruction caused by rosettes. However, the highly polymorphic nature of the parasite-derived antigen family, Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), responsible for rosetting has made this challenging. A recent report showed that polyclonal sera from rabbits immunised with the N-terminal domain of two rosette mediating PfEMP1 variants showed extensive recognition of heterologous rosetting parasite lines. These cross-reactive antibodies suggest that conserved epitopes exist on some rosette mediating PfEMP1 molecules. Here, we propose to develop a monoclonal antibody targeting one of these cross-reactive epitopes. This will allow us to characterise the epitope, and to estimate the percentage of severe malaria clinical isolates displaying this target. Fundamentally, the work proposed here aims to determine whether one of the cross-reactive epitopes recognised by the rabbit cross-reactive polyclonal sera has therapeutic potential, either as a target for a molecular therapy, or as the basis for a vaccine against rosette mediated disease.

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

Revealing how extracellular matrix glycans define chemokine gradients 31 May 2018

The diffusion of chemokines in the extracellular matrix is a requirement for the formation of chemokine gradients that guide immune cell migration to sites of inflammation, and controlled by matrix glycans of the glycosaminoglycan family. The focus of this research is to use well-defined models of the extracellular matrix to probe the interaction between the chemokine CXCL12 and the glycosaminoglycan heparan sulphate, and how this defines the mobility of CXCL12. The first key goal of the project is to design and produce a fluorescently-tagged CXCL12 mutant with modulated glycosaminoglycan binding which can be compared against the wild-type chemokine and other mutants already available. The second key goal is to use the biophysical method of fluorescence recovery after photobleaching to characterise the differential diffusion of mutant and wild-type CXCL12 in glycosaminoglycan-rich matrices. This project thus combines biochemistry and biophysics to gain a better understanding of the molecular mechanisms underpinning the formation of chemokine gradients in extracellular matrix.

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

Understanding resident macrophage autonomy during inflammation. 30 Sep 2018

Macrophages are one of the main immune cells in the peritoneal cavity, forming the first line of defence against germs that may enter from the gut or other abdominal organs. Our lab has recently shown that in the healthy cavity peritoneal macrophages are slowly replenished by circulating cells called monocytes. In response to infection or injury in the peritoneal cavity, the majority of the resident macrophages disappear and a large influx of monocytes takes place in a process called inflammation. These monocytes give rise to inflammatory macrophages that are different from their resident macrophage counterparts. However, during the process of inflammation resolution when the abdominal cavity returns to a normal healthy state, the few remaining resident macrophages proliferate to reconstitute the normal population, while the large population of inflammatory macrophages gradually die. Our aim is to determine why monocytes recruited to the cavity during inflammation appear unable to differentiate into resident macrophages during the resolution phase of inflammation and why instead, resident cells undergo repopulation solely by proliferation in this period. By investigating these processes we will reveal how self-renewal of resident macrophages contributes to the resolution of inflammation and whether pathological consequences occur if this mechanism is impaired.

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

DNA repair and genetic stability: Elucidating the effects of cell physiology in Escherichia coli 05 Apr 2018

One of the biggest problems for data re-use in Open Research is the quality of data description (metadata), which often lacks sufficient detail. The problem is acute in quantitative microscopy, which is the central method for my project to measure DNA repair proteins in living bacteria. A carefully-tuned sequence of image and data analysis steps is critical for us to count or track individual protein molecules. However, the intermediate results tend to become dispersed during the process. Each stage of analysis must be recorded and described to make the research reproducible, in addition to sharing the voluminous image data. Preparing our recent publication showed that our current manual process is error-prone and cripplingly slow. Here, we will develop a software platform that solves this problem, by linking the research tools that we use daily with existing, public and institutional repositories. First, the platform will collect automatically the necessary metadata at each step. Second, the platform will assemble comprehensively-described datasets. Third, it will make them automatically available for open access, on the University’s DataShare service. By developing a fully automated platform we will make open data sharing far easier and more accurate. The comprehensive data packages will be more valuable for re-use. The platform builds on established data-sharing resources, which are sustainable and will also make our methods and results easier to find. Finally, we will use the platform to share data with our collaborators thus improving working practices in other groups.

Amount: £49,675
Funder: The Wellcome Trust
Recipient: University of Edinburgh

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

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

Development of a proteome-wide assay to measure phosphatase substrate dephosphorylation rates in human cells 31 May 2018

Temporal ordering of cellular events during mitosis is crucial for accurate cell division. Temporal control is dynamically regulated by reversible phosphorylation by the opposing activities of kinases and phosphatases. Recent work in yeast has suggested that intrinsic differences in substrate phosphorylation rates by kinases are important for imposing temporal order. Compared to kinases, much less is understood about the full repertoire of phosphatase substrates in human cells and how dephosphorylation rates vary among substrates. To address this gap in knowledge, I will develop a screen to measure substrate dephosphorylation rates in cells using purified phosphatases and fixed human cells. These methods on fixed, permeabilised cells provide an opportunity to measure biochemical properties of proteins in the context of a static, but intact macromolecular environment. The project will be a collaborative effort between the Welburn and Ly laboratories. I will first express and purify the mitotic phosphatases in the Welburn lab and then perform phosphatase reactions on fixed human cells in the Ly lab. I will focus on PP1gamma and PP6, phosphatases that have been previously shown to be important in regulating mitotic progression. The assay will then be used for large-scale characterization of substrate dephosphorylation kinetics by mass spectrometry-based phosphoproteomics.

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

The regulatory effects of apico-basal polarity on cell identity 30 Sep 2018

My research will investigate changes in cell orientation (i.e. the way cells are organised in 3D space) in cells of the early embryo that can become all the cell types of the body. Crucially, we would like to understand if changes in cell orientation influence the decision of what specialised cell type (muscle, heart, blood etc.) these cells would become. Changing cell orientation could affect this process by altering the way cells perceive the signals that control their identity. Additionally, I am interested in analogous events during the emergence of cancerous cells in the epidermis where cell orientation may influence the natural suppression of tumour cell formation, a process that has been likened to wound healing. We will manipulate cell orientation by interfering with growth scaffolds, introducing genetic mutations or using chemical means to disrupt the cell internal structural scaffold, monitoring resulting changes in shape, orientation and cell identity by fluorescence imaging and computational analysis. This will help us control differentiation, tumorogenesis, and tissue repair.

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

Understanding the role of retinoic acid in cyanobacteria 31 May 2018

We will be investigating the viability of using cyanobacteria as a model for our own by exploring the evolutionary links as well as the similarities between human cells and cyanobacteria cells in terms of the communication and cell differentiation. This will allow us to use the cyanobacteria as a model for human stem cells. There are 3 cases which will be investigated: metabolism of retinoic acid, nitrogen-fixing cells and prostaglandin cell signalling. In each case, we will be blocking the signal, modifying the bacteria and studying how this affects the bacteria. The production of proteins and the chemical signalling are amongst the several responses we will be monitoring. Using information gained from this we will be able to see if there is a viable link that can be used to monitor cyanobacteria that have human orthologues spliced into it.

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

Unravelling the regulatory mechanisms underlying expression of COL5A1 in human cornea in health and disease 30 Sep 2018

Keratoconus is the most common corneal dystrophy. Patients with keratoconus experience corneal thinning and bowing of the cornea causing problems with vision. The condition usually effects both eyes where moderate to severe cases require corneal transplant to improve vision. Unfortunately, diagnosis proves as challenging, where early disease is difficult to recognise. Mild to moderate disease can be treated with glasses or contact lenses to improve vision, although subjective vision gain is variable depending on level of astigmatism. The underlying process that leads to keratoconus and corneal thinning is unknown. Research suggests that there is a strong genetic component underlying the pathogenesis of corneal thinning and disease. Recent work from the Vitart lab has identified genetic regions that may be implicated in corneal thinning and keratoconus. Some of these regions are near a gene that codes for a type of collagen called COL5A1. We are interested to see if these regions have a role in regulating this gene, thereby implicating its importance in variation of central corneal thickness and keratoconus. This research will look at unlocking those complex genetic mechanisms by use of a cell line and a mouse model.

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