- Total grants
- Total funders
- Total recipients
- Earliest award date
- 10 Apr 2001
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
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.
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.
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.
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.
The relationship between innate immune cell function and bacterial infections in severe acute malnutrition 22 Feb 2017
Severe acute malnutrition (SAM) underlies one million deaths in children under 5 years old annually. Immunodeficiency is implicated in SAM mortality because deaths are predominantly due to infections and infectious mortality persists after nutritional rehabilitation; however, we know very little about how malnutrition affects immune cell function. This fellowship will characterise the relationship between bacterial infections and the anti-bacterial functions of monocytes and dendritic cells (DC) using blood samples collected from children admitted to hospital with SAM (n=200) and track this relationship during hospitalisation and over 48 weeks of community-based nutritional rehabilitation (n=100). I will evaluate both the capacity of monocytes and DC to bind and respond to bacteria in vitro, and how pro-inflammatory mediators in plasma, which are elevated in SAM, affect healthy monocyte and DC. These assays will generate a detailed profile of monocyte and DC function in each child which I will use to determine whether innate immune function is: 1) compromised relative to adequately-nourished controls (n=200); 2) associated with bacterial morbidity and mortality; and, 3) restored by treatment. Understanding the relationship between innate immune cell dysfunction and bacterial mortality in children with SAM could identify new immunotherapeutic targets to improve clinical outcomes in this high-risk population.
Severe acute malnutrition (SAM) affects 13 million children worldwide. SAM presents as two distinct clinical phenotypes: oedematous-SAM and non-oedematous-SAM. Oedematous-SAM has more complex morbidities including steatosis and diarrhoea, however treatment protocols fail to distinguish between the two forms of the disease. SAM is also defined by a disturbed gut microbiota and metabolic phenotype. However, little research has examined the gut microbiota in oedematous-SAM versus non-oedematous-SAM and how it may contribute to differing clinical outcomes. An observational study will be performed in children hospitalized with oedematous-SAM, non-oedematous-SAM and healthy controls. Whole metagenome shotgun sequencing on fecal samples and metabolic phenotyping on urine and plasma samples will be performed at hospitalisation, discharge, and 12, 24 and 48 weeks post-discharge. The key goals include: Characterise the gut microbiota and metabolic phenotype of children with oedematous and non-oedematous-SAM to examine whether a disrupted microbiota impairs: (i) tryptophan metabolism; (ii) oxidative stress and inflammation; (iii) choline and bile acid metabolism; 2. Map long-term changes in the microbiome and metabolome after treatment. 3. Evaluate associations between microbial/metabolic variation and clinical outcomes. This project has the potential to identify novel microbial and metabolic targets for intervention to improve clinical outcomes of oedematous-SAM.
Vacation Scholarships 2017- Queen Mary University London
This secondment project seeks to improve the organisation, accessibility, and public knowledge of the objects and papers held by the Science Museum relating to the work of William Grey Walter and his colleagues at the Burden Neurological Institute (BNI). Documenting pioneering work that has left a profound mark on clinical research and practice, the BNI collection constitutes one of the richest archival and material resources in Britain for understanding the development of twentieth-century neuroscience. This project aims to raise the profile of this unique resource in three ways. Firstly, the project will digitise and expand the existing catalogues of the BNI collection, empowering researchers to locate and use materials in new and innovative ways. Secondly, the project will provide fully researched biographies of key personnel for the 'creators' records on the Science Museum's Collections online website. These will provide comprehensive yet accessible introductions to the careers and personalities that shaped the BNI's work. Finally, the project will produce an online visual resource open to both researchers and the public. Using the recorded brain waves of the electroencephalograph (EEG) as a model, this resource will help users to visualise how the documents, objects, and personalities of the BNI interacted.
Protein arginine methylation in the control of neural stem cell “stemness” and differentiation 08 Apr 2016
During development cortical neuroepithelial stem cells (NSCs) generate all the neurons and glia of the central nervous system in a precise spatiotemporal manner. Aberrations of this process are linked to neurological diseases, e.g., autism, schizophrenia, mental retardation. The molecular mechanisms controlling NSCs’ transition from "stemness" to differentiation remain elusive. We recently identified a novel regulatory complex, comprised of PRDM4 protein and the protein arginine methyltransferase 5 (PRMT5), whose activity maintains NSC "stemness" in vitro. We hypothesise that PRDM4/PRMT5-mediated protein arginine methylation (R-Me) is necessary to maintain NSC "stemness". To explore this hypothesis, we generated mice with the cortical NSC-specific deletion of PRDM4 (PRDM4fl/fl;Emx1-Cre) and analysed proteome-wide changes in R-Me of these mice. We propose to test our hypothesis by investigating the biological outcomes of the observed reduction in R-Me and validating the strongest candidate of the proteomic screen, KSRP protein, biochemically. We will: 1) characterise differentiation profiles of NSCs from the mutant mice, 2) biochemically characterise PRDM4:PRMT5-mediated KSRP-R-Me in vivo, using PRDM4fl/fl:Emx1-Cre and control tissue, and in vitro. Achieving these goals will validate a novel mechanism of NSC "stemness" control, mediated by protein R-Me, providing the basis for further investigations into its role in NSC reprogramming and neurological diseases.
This project has three goals: 1) To construct a limited genealogy of the idea of 'the social' in late-twentieth-century Britain (e.g. in social psychiatry or concepts of social control) showing it to be an historically specific way of thinking. 2) To show how different behaviours under the same umbrella term (Munchausen) illuminate shifts in how this realm is envisioned. 3) To root these changes in historically specific practical arrangements and intellectual assumptions. It has thre e sections: 1) Munchausen syndrome: drawing upon the history of factitious disorders (Kanaan & Wessely, 2010) and self-harm (Millard, forthcoming), I shall show how sociological sick role concepts become central to the pathological social needs at the core of this behaviour. 2) Munchausen syndrome by proxy (MSBP) emerges at the interface of peadiatric medicine and social work, drawing upon 1970s concerns about child abuse. The social still includes (parental) aspirations for the sick role, but is transformed by social workers' surveillance and regulation of the family. 3) Munchausen by internet refocuses attention on an increasingly important aspect of the social, the virtual social network of the internet.
We aim to study the previously unrecognised contribution to haematopoiesis made by the atypical chemokine receptor 1 (ACKR1; also known as Duffy Antigen Receptor for Chemokines or DARC). Our initial data show that DARC is expressed by nucleated erythroid cells and that mice, which lack DARC selectively on erythroid cells, have profoundly altered bone marrow (BM) parameters as compared to wild type mice. Over the next five years, we will discover the mechanisms by which DARC expression on erythroid cells affects: i) steady-state haematopoiesis and the molecular make-up and functional profiles of BM stem-, progenitor- and lineage restricted cells; and ii) diseases that rely for their pathogeneses on haematopoietic cell outputs, notably glomerulonephritis, prostate and breast cancer and anti-microbial host defence. We will correlate our findings in experimental mouse models with molecular and cellular parameters of haematopoiesis in individuals of West African origin who carry the common FyB(ES) polymorphism and thus selectively lack DARC in the erythroid lineage. FyB(ES) is the most predictive ancestry-informative marker of African origin and individuals with FyB(ES) are recognised to have altered incidences and outcomes of several debilitating diseases compared to other DARC polymorphisms. Our research seeks to provide a causative explanation for these findings.
ISSF Small Grants Fund The Life Sciences Institute (LSI) Small Grants Fund is an early stage fund designed to support pilot projects aimed at the identification and early support of promising ideas for the future development of larger proposals and initiatives. ISSF Proof of Concept Fund Sitting alongside QMUL’s established Proof of Concept Fund, this LSI Fund is aimed at supporting work that is intended to develop new life science ideas, technologies or processes from a pilot or early-stage exploration to the next stage of a more comprehensive commercial plan. Early Career Stage Researchers Bridging Fund Support for researchers early in their careers (ECRs) is essential to ensuring that they are able to take full advantage of opportunities to develop and succeed. Critical points typically occur in transition periods, when funding rounds for fellowships, major grants and permanent positions may not coincide with contract end-points. The LSI ECR Bridging Fund is aimed at addressing this need and will support periods of funding for up to four months for the salary costs of four leading ECRs working within the relevant research areas of the LSI. Some matching funding commitment is required from the home School or Institute of the ECR – equal to 30% of the ISSF funding. Funding: Implementation The ISSF/QMUL award supports three posts that are critical to the progress of the Life Sciences Initiative and the development of the proposed Life Sciences Institute: A Programme Director (who will focus primarily on external engagement work) A Programme Manager (who will mainly provide professional services management support for the Initiative) A 0.5 fte Programme Officer (who will provide administrative support for the Initiative). Funding: Public engagement Public engagement is a key element of our Life Sciences Initiative and is embedded across all aspects of it. Our Centre for Public Engagement (CPE) leads on this work and the ISSF award supports a dedicated community engagement post, support for training and collaborative projects, and a programme of outreach through the Centre of the Cell, focussed on life sciences work. The Community Engagement Officer will liaise regularly with local community groups, and engage sections of the community not accessed easily through existing links, with the aim of raising the voice of community partners within our planning for, and delivery of, research for the life sciences.
The effects of neo-adjuvant chemotherapy on myeloid cells in high-grade serous ovarian cancer metastases. 02 Mar 2016
Many tumours have abundant macrophage populations. Tumour-associated macrophages (TAMs) frequently have tumour promoting roles and high levels are associated with poor clinical outcome. In mouse cancer models chemotherapy appears to increase TAM density. Furthermore, macrophage depletion improves response to chemotherapy in breast cancer models. The host lab has studied the effects of neo-adjuvant chemotherapy (NACT) on T-cell responses in high-grade serous ovarian cancer (HGSOC) patients and shown potential enhancement of the host anti-tumour immune response following NACT. However, we do not know the effect of chemotherapy on TAMs in these patients. We hypothesise that targeting the recruitment, polarization and effector function of TAMs may improve HGSOC response to chemotherapy as well as having independent anti-cancer activity. We will characterise TAMs in HGSOC pre and post NACT using human samples and mouse models. Anticipating significant heterogeneity of TAM populations we will employ single-cell and whole myeloid population RNA-sequencing to define the major macrophage populations in HGSOC pre and post NACT. These results will be validated using flow cytometry and immunohistochemistry. We will test the effects of chemotherapy and macrophage-targeting agents on TAM populations and tumour response in mouse HGSOC models. Our aim is that these results will translate to clinical trial.
Mechanical stimulation is one of the key physiological stimuli. Abnormalities in mechanical load or in cellular mechano-sensitivity have been linked to diseases such as osteoporosis, osteoarthritis or polycystic kidney disease. No effective treatment exists for these conditions as our understanding of mechanotransduction is still incomplete. A unique membrane protrusion called primary cilium, and a number of membrane receptors sensitive to mechanical and chemical stimuli have been already implic ated in the mechanotransduction, however the signalling pathways remain uncertain. We hypothesize that the actual role of receptors involved in mechanosensing is affected by their precise location within the fine ultrastructure of the primary cilium. To investigate this hypothesis we propose the use of scanning nanopipette microscopy capable of functional assessment of membrane channel and receptor activity with nanoscale spatial resolution. We will establish recordings of channel activity in re sponse to mechanical stimulation at precisely defined locations on primary cilium and develop technique for mapping local sensitivity to chemical stimuli by means of highly localised dosing via the nanopipette. The established techniques will be subsequently used to gather preliminary data on the distribution of mechano-chemical receptors to support research proposal aimed at understanding the reorganisation of mechanotransduction in ciliated cells in disease.
Twentieth century disease ecologies: an intellectual history of emergence, 1920-1970 - Extension. 31 Mar 2015
Although the origins of the modern ecological understanding of infectious diseases has been examined by other scholars, for the most part these studies have focussed on specific groups of scientists and/or disciplinary settings. Moreover, preliminary studies of the subject are divided as to the extent to which these ecological perspectives were already present in medical micribiology as opposed to being importation from biology and molecular genetics. There is a need therefore for a comprehensiv e, monograph-length study that surveys the history of ecological perspectives across a range of disciplines from bacteriological epidemiology, to evolutionary biology, parasitology, animal ecology and immunology, and across a broader group of scientific researchers. In particular, this study will build on the preliminary surveys of this field by Anderson, King, Mendelsohn, and Tilley (see bibliography) by tracing the intellectual influences and professional associations between scientists at the forefront of research into epidemic diseases in the interwar and post-war periods. At the same time it will examine the connections between these scientists and key public health institutions, such as the Rockefeller Foundation and the Hooper Foundation, and the effect that post-war debates around the eradication of infectious diseases and environmental politics had on these nascent ecological perspectives
Harnessing the immune response in chronic HBV infection to optimise current treatment strategies. 26 Feb 2015
We have shown that Pegylated-Interferon-alpha (Peg-IFN-aplha) expands activated NK cells with restored antiviral effector potential. These innate effects are not seen with Nucleos(t)ide analogues (NUCs), but T-cell restoration has been demonstrated with NUCs. We hypothesise that complementary innate/adaptive immune boosting can be achieved in patients receiving sequential NUCs following Peg-IFN-aplha exposure. Although the antiviral function of NK cells is restored with Peg-IFN-aplha, we postula te the documented increase in expression of the death ligand TRAIL promotes deletion of HBV-specific T-cells expressing the TRAIL-R2 receptor. We will dissect the temporal dynamics of T and NK cell reconstitution and examine whether TRAIL blockade enhances the efficacy of Peg-IFN-alpha/sequential NUC therapy by protecting antiviral T-cell responses from deletion. We will use PBMC and fine needle liver aspirates from patients undergoing therapy to determine if innate boosting and restoration of T-cell responses are optimised on sequential NUC therapy. We will perform functional experiments in vitro, with TRAIL blocking antibodies and NK cell depletion to rescue Peg-IFN-alpha driven killing of T-cells. TRAIL pathway manipulation may boost adaptive immunity by interrupting NK cell-mediated deletion of T-cells in the face of innate boosting, with the goal of achieving sustained responses with a finite treatment duration.
Parental relatedness (e.g. cousin marriage) is common in certain UK ethnic groups including the health disadvantaged British-Bangladeshi and British-Pakistani communities. Recent studies indicate that outbred human genomes contain ~100 genuine complete loss of function (LoF) variants. Consanguineous (parental and/or historic) individuals carry genomic regions identical-by-descent (autozygous), thus rare frequency variants occur as homozygous genotypes. Our knowledge of human gene function an d genome annotation remains incomplete. Characterisation and deep-phenotyping of healthy adult individuals enriched for naturally occurring homozygous knockout alleles will provide invaluable knowledge of human biology. We propose a large-scale community based exome sequencing programme of consanguineous individuals (25,000) of whom a subset (3,000) with genotypes of interest will be later recalled. We will focus on East London populations whose recruitment and recall will be coordinated arou nd our Whitechapel site. We will recall sequenced individuals possessing autozygous variants of biomedical importance (predicted complete LoF, coding, and regulatory) for deep-phenotyping and experimental medicine studies. Our proposal complements existing rare disease sequencing programmes, national sequencing studies (UK10K, DDD), and other UK BioResources (Cambridge and NIHR BioResources, TwinsUK and UK BioBank). We will substantially engage East London communities and increase our existing p ublic engagement activities around genetics and genomics.