- Total grants
- Total funders
- Total recipients
- Earliest award date
- 13 Dec 2005
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Metagenomic approaches are generating a long list of health and disease states associated with the microbiome (the microbes inhabiting our digestive tract) but without mechanistic understanding. The challenges arise from the enormous complexity of the microbiome, including genetic, environmental and dietary variations, microbe-microbe interactions, and the cost associated with studying the microbiome using murine models. If the field is to move beyond association, simple, well-controlled and cost-effective models allowing unbiased high-throughput studies are needed. The nematode C. elegans is a genetically tractable model, ideally suited for mechanistic and causative studies of host-microbiome and microbe-microbe interactions shaping host physiology and metabolism. Aims: 1) Establish an experimental microbiome in C. elegans based on strains from the human microbiome associated with health, disease and ageing 2) Generate fluorescent labelled bacterial strains and perform real-time imaging of gut colonisation 3) Characterise the effects of the experimental microbiome on the microbiome-gut-brain axis during ageing The experimental microbiome in C. elegans will be an important contribution to the field, complementing existing models. It will allow me to establish important collaborations, form a basis for my future research and address one of the most important questions of modern biology: the effects of the microbiome on host physiology.
Antimicrobials remain the main means to treat and control bacterial infections, but their efficacy is now compromised due to overuse in humans, animals, agriculture, with bacteria developing resistance that renders certain antibiotics ineffective. Infections due multi-drug resistant (MDR) bacteria have emerged as one of the most significant global threats to human and animal health in the 21st century. Thus, the development of new antibiotics, or better ways to deliver existing antibiotics more effectively, is an urgent priority. Polymyxins are "old" antibiotics that have re-emerged as the last resort for treating infections caused by MDR Gram-negative bacteria. There are two polymyxins in clinical use, polymyxin B and polymyxin E (colistin), but their low stability, unpredictable pharmacokinetics and nephrotoxicity still raise significant concerns. We hypothesize that nano-engineered carriers will be able to restore and/or enhance the efficacy of polymyxins against MDR Gram-negative bacteria by improving their pharmacokinetic profiles, compared to standard mono and dual antimicrobial formulations, whilst minimizing the risks of adverse systemic effects. We will develop and optimize novel self-assembled nanocarriers for the controlled delivery of polymyxins and assess their potential to treat more effectively bacterial-related infections. This data will make the basis for future grant applications under the AMR initiatives.
Domestic animals as a model to understand the relationship between deleterious mutations, demography and disease 04 Dec 2017
Most mutations have mildly to strongly harmful effects. In extreme cases, where populations experience acute demographic and selection processes, deleterious mutations implicated in both infectious and genetic disease can accumulate in the genome to impose a significant burden (a measure known as mutational load). Domestic animals provide such an extreme case because of their complex evolutionary history, marked by bottlenecks, population expansions and relaxed selection. They are thus an ideal model to investigate how different mechanisms contribute to mutational load. Recent relaxed selection (e.g. via antibiotics and vaccination) and dramatic population expansion likely increased disease transmission and the frequency of deleterious genetic variations throughout the genome, including in immune genes. Investigating these processes in domestic animals is therefore critical for human health because these species are a major source of zoonotic diseases (e.g. bird/swine flu). Using simulations, ancient and modern genomes, and transfection experiments, this project will: 1) develop computational methods to disentangle contributions from different mechanisms, such as population bottlenecks and positive or relaxed selection, towards increases in mutational load; 2) generate preliminary data and establish laboratory techniques to test the hypothesis that recent relaxed selection has had an impact on the immune capabilities of domestic animals.
East London Genes & Health: human knockouts in a population genomic medicine cohort of British-South Asians 10 Apr 2018
East London Genes & Health is a long term programme for population genomic medicine research in British-South Asian adults. Unique features include high rates of health deprivation, especially diabetes, cardiovascular disease and mental health; high rates of consanguinity (including human knockouts, rare predicted loss of function variants occurring as homozygotes); local excellence in e-health record access/analysis; and recall for further research by genotype/phenotype. In this proposal we wish to continue and expand successful East London Genes & Health recruitment and commence a new site Bradford Genes & Health - to reach 100,000 volunteers; add value to the Genes & Health resource through SNP array genotyping all samples; and by sequencing and analysing consanguineous individuals. This will then enable us as a collaborative team to ask detailed research questions about adult-human knockouts. Specifically we will perform population based analyses of naturally occurring adult-human knockouts to better understand their population genetics, and (with Deciphering Developmental Disorders) recessive disease; contribute to and establish The Human Knockout Project, a worldwide database of population-based studies of human knockouts; perform blood -omics to study major perturbations of biological systems including downstream networks; and deeply study individuals with knockouts and other variants in reported Mendelian disease genes.
Vacation Scholarships 2018 - Queen Mary University of London
The project aims to create opportunities to include different points of view in the dominant narratives in IVF practice, focusing on changes related to the introduction of more advanced visual technologies and the debate on evidence. We aim to actively engage IVF professionals and patients and other relevant institutional stakeholders in a series of themed discussion events to foster public debate and further understanding of the topic. We also plan to re-elaborate our findings from research with professionals and patients into visual narratives in the form of short video animations. These animations will be realised with the support of a creative company, shown at dedicated events and finally made available on the project blog. Building on these activities, we aim to encourage new opportunities for conversations among professionals and patients. The aim of these would be twofold. Firstly, to contribute to public understanding of the emerging technology through dedicated activities targeted at IVF patients and other relevant stakeholders, increasing non-expert awareness of what evidence means in the context of changing IVF treatment options. Secondly, to create a space of discussion for IVF professionals and patients and other relevant stakeholders to foster a deeper mutual understanding among people with differing perspectives, concerns and experience.
Ribosomes under attack: smFRET analyses of bacterial ribosomes in context of impaired rRNA stability and antimicrobial treatment 06 Sep 2018
Antimicrobial resistance is a major burden on public health and the economy. Current estimates put associated annual costs at EUR 1.5 billion and annual deaths at ~25,000 in the EU and ~700,000 worldwide. Research into resistance mechanisms is urgently needed to tackle this significant threat to society. A major antimicrobial target is the bacterial ribosome, which translates genetic information into polypeptides in a process involving large-scale movements of ribosomal subunits and tRNAs that is inherently asynchronous and heterogeneous. Single-molecule Förster-resonance-energy-transfer (smFRET) enabling analyses of translation-dynamics with single-codon resolution, sub-nanometer accuracy at physiological concentrations in real-time was instrumental in gaining novel insights into antimicrobial interference with ribosome-function. We will implement smFRET to reveal for the first time how the conserved yet previously unrecognised rRNA repair-system RtcAB that increases tolerance to ribosome-targeting antimicrobials affects ribosome-function. Specifically, smFRET will allow us to ask the following questions: Does RtcAB affect the i) conformation and population-dynamics of key states of the translation-apparatus? ii) translation-efficiency and ribosome subunit-rotation? iii) tRNA-selection? iv) ribosome-translocation? and v) ribosome-recycling? The answers to these questions will help us understand how RtcAB contributes to antimicrobial resistance and provide a platform for future studies of the interplay between rRNA repair and ribosome-targeting antimicrobials.
Apoptosis is a highly conserved and controlled process, with the Bcl-2 family of proteins playing an important role as key regulators. The family consists of both pro- and anti-apoptotic proteins and there is a careful balance within a cell controlling its fate. High levels of the anti-apoptotic proteins are often observed in cancer and not only contribute to the development of the tumour but also confer resistance to current therapies including chemotherapy and radiation treatment. In particular over-expression of myeloid cell leukemia-1 (Mcl-1) is one of the most common forms of genetic abnormality in cancer. In addition Mcl-1 has been shown to be essential for some tumours survival, resulting in a genetic vulnerability of the cancer cells which can be exploited by the design of Mcl-1 specific inhibitors. As a single agent, an inhibitor would target tumours that rely on Mcl-1 for survival and in combination with other therapies it is expected to overcome Mcl-1 mediated resistance. We have recently identified a small molecule capable of modulating the interaction between Mcl-1/Noxa. In this proposal we now seek to improve the binding affinity and selectivity of the compound through synthesising a small library of analogues.
Bacterial symbiosis has decisively contributed to the evolution of life on Earth, but also underpins prevalent human disorders related to the digestive system, like obesity and diabetes. However, our understanding of how symbiotic bacteria influence host biology is limited. Siboglinid worms exhibit a remarkable case of symbiosis, where bacteria taken from the environment induce the loss of the gut as the worms harvest the bacteria inside their bodies for nutrients. Therefore, these gutless worms are a unique system to investigate the impact of bacterial symbiosis on gut development and the evolution of extreme dependency on symbiotic microbes. The key goals are: Identify common and lineage-specific genomic adaptations to bacterial symbiosis in siboglinid worms. Identify transcriptome-wide gene regulatory changes associated with symbiosis in the worm Siboglinum fiordicum. I will sequence, assemble, and annotate the genomes of Riftia pachyptila, Osedax rubiplumus and S. fiordicum and perform differential gene expression analyses of asymbiotic gut-containing larvae and symbiotic gutless adults of S. fiordicum. These outcomes will provide the first genomic and transcriptomic insights on bacterial symbiosis on these worms and set the foundations to establish S. fiordicum as a model to dissect the genomic, developmental, and physiological effects of bacterial symbiosis in animal guts.
This research engages the history and practice of cinema as an unexplored framework through which autism can be contextualized as an evolving discourse of body language, and repositioned as a condition with benefits. Autism is widely known as a disorder in which communicative practices and embodiment are experienced in an idiosyncratic way, with the effect of isolating the autistic person from communal social interaction. Proponents of the neurodiversity movement have critiqued the framing of autism as an impairment deviating from the standard practice of verbal modes of expression underpinned by bodily communication. This contested binary of an a-typical and a-social embodied practice, versus a socially fluid communicative capacity, is a less assured division when viewed through the prism of cinema. The goals of the project are: To use film practice to elucidate the potential of autism to expand understandings of bodily communication. To examine autism as gesture and trace its changing modalities on film during the twentieth century. To compare autism as it appears in medical and commercial film during the twentieth century to identify binaries of legible/illegible body language. To work with autistic individuals to develop an alternative film language inclusive of the neurodiverse population.
The proposed project uses genetic counselling as a focused vantage point for understanding how genetics has been communicated, experienced and given meaning. Genetic counsellors are medical professionals who, today, help parents and patients interpret the results of genetic tests and make decisions about treatment and reproduction. Counselling encounters involve highly technical information about risk, are potentially highly emotional, and can powerfully impact intimate practices of family life, medical treatment and lifestyle. Genetic counselling has a seven-decade history in the UK and Ireland—countries that are especially important for their exceptional politics of healthcare, and the range of international collaborations forged by genetic practitioners. In tracing this history, the project has five aims: to chart the making of genetic counselling within the NHS; to produce a sustained history of the genetic counselling encounter; to examine how the profession accommodated and shaped practitioner and patient identities; to trace how efforts to contest genetic medicine changed ethical standards; to explore how genomics is refashioning counselling roles and practices. This will be the first sustained study of emotion in the history of genetic medicine, the first in-depth social history of genetic medicine in the postwar UK and Ireland.
‘Library as Laboratory’: Moral Treatment, Patient Libraries and Reading in Nineteenth-Century British Asylums 08 May 2018
This project will explore the ways in which reading was viewed as simultaneously psychologically disruptive and restorative within nineteenth-century asylums, and examine how reading was utilised through medical directives as part of the therapeutic regime. How did patients experience print culture within asylums during a period of increasing medicalisation of mental health treatment? I will gather a variety of perspectives on the psychological benefits and dangers of reading from nineteenth-century sources, both from asylum professionals and from cultural commentators, to contrast professional and lay attitudes towards reading as treatment. I will collect a large quantity of data from archival material from a representative sample of asylums across Britain. This dataset will allow me to make a comparison of the ways in which material was collected and made accessible to patients, and to identify the relationship between ‘ideal’ material and that consumed by patients. Finally, I will use asylum records and first-person writing by patients to assess actual patient experience of reading versus the ostensible provision, and evaluate the impact of location, gender and class on levels of access to reading. This project will challenge notions of the ‘failure’ of the moral treatment regime and examine an earlier history of reading-as-therapy.
Pathologies of Solitude, 18th - 21st century 25 Jul 2017
Loneliness today is a serious health concern. This is generally regarded as a recent development but in fact solitariness has long been perceived as a medical risk, especially a psychological risk. Our present-day concern about social isolation and loneliness is framed by this largely neglected history. This project aims to remedy this neglect by undertaking the first health-related history of western solitude. Its leading premise is that the development of modern society has involved changes in perceptions of solitude whose overall tendency has been to pathologise and medicalise it. By documenting and analysing this process, the project will yield unprecedented insights into one of humankind’s most fundamental experiences, and one of contemporary society’s most complex health challenges. The primary research focus is on Britain; its chronological starting point is the long 18th century when modern medical perceptions of solitude first took shape, with developments in this period compared to those in succeeding centuries. An interdisciplinary research network has been assembled that will bring these historical findings into dialogue with scientific research about contemporary experiences of solitude. The project will also engage with campaigns devoted to alleviating loneliness, while an ambitious outreach programme will take its findings to the general public.
The principal goal of this proposal is to develop novel platforms to study neurodevelopmental and mechanistic causes of severe obesity. Established very early in human development, body weight regulation is brain-governed by the hypothalamus. Consequently, genetic variants acting by disrupting hypothalamic function lead to severe obesity. However, the manner in which these variants contribute to obesity via exerting neurodevelopmental and molecular changes has been difficult to study since human brain tissue is inaccessible. Historically, rodent models have extensively contributed to our understanding of energy homeostasis, but they carry inherent limitations due to inter-species differences in brain structure and physiology, as well as gene sequences. Therefore, development of human study systems for disease modelling is an important complementary approach to animal and patient studies aimed at investigating human obesity. We propose to use several novel methodologies: precise genome engineering with CRISPR/Cas9 in stem cells, 2D hypothalamic cultures, as well as 3D brain organoids, to: (1) generate physiologically relevant cellular and tissue models of human genetic obesity; (2) investigate neurodevelopmental aspects of the disease; (3) utilise the models to study molecular mechanisms leading to obesity.
Understanding the functional heterogeneity between memory B cells expressing different immunoglobulin subclasses 05 Sep 2017
The quality of the antibody response to different antigens in distinct microenvironments is determined by the functional properties of specific B cells. Evidence suggests that B cells expressing different antibody subclasses display functional heterogeneity that could influence their ability to expand, migrate and differentiate following activation. This study will test the hypothesis that human memory B cells expressing different antibody subclasses are functionally distinct. Rates of clonal diversification (expansion, class-switching, somatic hypermutation and differentiation) by B cells expressing different antibody subclasses will be compared following antibody repertoire sequencing of human tonsil B cell subsets. In addition, the functional diversity of human class-switched B cells will be assessed by single-cell RNA sequencing. B cell subtypes will be classified using gene-expression-based clustering and the distribution of B cells expressing different antibody subclasses across different clusters will be calculated. Identification of genes and gene-related pathways that define functionally distinct B cell subtypes would lead to more precise understanding of how B cell memory is generated. This would inform approaches that aim to promote or suppress specific antibody responses and would provide a basis for examining mechanisms that drive dysregulation of B cell memory in human disease. Keywords: B cells, antibody, immunology, immune memory
Investigating a novel approach to gene-environment interaction in depression and anxiety 05 Sep 2017
Psychosocial adversity increases the risk of depression and anxiety. However, only a minority of those exposed develop mental illnesses. It has been hypothesised that genetic factors make individuals more or less sensitive to environmental influences. The identification of these genes has a clear potential for impact on health by providing insight into the biological mechanisms of risk and resilience and allowing preventions and interventions to be targeted at the most vulnerable. Nevertheless, capturing environmental sensitivity genes remains a significant challenge. We recently successfully piloted a novel approach to this problem using identical twins. We aim to build on this work by establishing the Genetics of Sensitivity to the Environment Consortium bringing together the world’s twins with genetic data. This will allow us to: Replicate and refine our findings from the pilot study Investigate environmental sensitivity genes across disorders and ages Estimate the heritability of sensitivity to environmental influences This project will lead to a larger programme of research focusing on the mechanisms underlying genetic sensitivity to the environment in the development and treatment of mental illness. In addition, we will develop our consortium to establish a new resource for researchers combining twin designs with genetic data.
Adenine methylation (6mA) is the main DNA modification in unicellular eukaryotes and despite being identified for some time, the biological functions of this modification are still poorly understood. As with many systems, computational modelling can provide important insights into molecular processes but efficacy is often restricted by the complex nature of multicellular organisms. In this project, we propose to investigate the role of 6mA during growth in the single-cell eukaryote Tetrahymena thermophila. We will produce the first genome-wide maps of 6mA in a single-cell model eukaryote, determine the relationship between 6mA and transcription and investigate whether 6mA is dynamic during growth. These studies will lay the foundation for Tetrahymena thermophila to be used as an effective computational model organism, exploiting its complexity, unicellularity and physiological responses, to further explore the biological functions of 6mA. Strikingly, organisms which have high levels of 6mA have low levels of 5-methylcytosine (5mC) while those with high levels of 5mC have low levels of 6mA. This suggests that there may be a common biological function for 6mA and 5mC and that understanding the biological function of 6mA may prove useful in understanding the biology of 5mC.
Virulence strategies for Mycobacterial persistence: Investigating the role of the Mammalian Cell entry proteins. 12 May 2017
The global burden of mycobacterial infections especially tuberculosis is inconceivable with at least one new case of infection arising every second, every third person being latently infected and around 2 million people dying annually. Persistence of mycobacteria arises from long durations of dormancy within host macrophages evading host defense mechanisms and utilising unusual nutrients. Mycobacterial Mce (Mammalian cell entry) transport systems play an important role in facilitating cell entry and import of nutrients like cholesterol or lipid. This proposal concentrates on characterizing the Mce4 proteins and their assembly in the Mce4 transport system. One of the key goals is to isolate a minimal hetero-complex of the Mce proteins forming the transport channel for structural and functional studies. Two possible models for organisation are proposed: i) a heterohexamer of six Mce proteins or ii) a stack of six homo-hexamers of individual Mce proteins. Biochemical characterisation of individual Mce proteins and interaction studies between different Mce proteins will help establish the organisation model of Mce4 proteins. Structural studies using X-ray crystallography or other techniques, and functional characterisation for cholesterol binding and cell invasion will shed light on the structure-function relationship of Mce4 proteins within the transport assembly.