- 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
The project will look at the different ways in which the body has been used to mobilise public support for humanitarian campaigns in the post-war period. Drawing on the recently catalogued Oxfam collections at the Bodleian Library and the records of the British Leprosy Relief Association (LEPRA) at the Wellcome Library, the project will show how donor and recipient bodies have functioned as sites of learning and feeling. It focuses on two types of activity: the use of medical discourses to describe the suffering bodies of recipients of aid; and donors’ use of self-denial and physical hardship to increase bodily empathy with recipients. By uncovering the different kinds of body knowledge that were developed in this period, the goal is introduce a medical humanities perspective to the history of post-war humanitarian sentiment. In the short term, I will write a journal article on my case studies in the post-war period. In the long term I will use the research as a foundation from which to develop an interdisciplinary collaborative project on embodied empathy, and as the starting point for a monograph on changing attitudes towards body knowledge in humanitarian work in the nineteenth and twentieth centuries.
Ras proteins are molecular switches that regulate signalling pathways involved in cell proliferation and survival. These form transient nanoclusters on the plasma membrane, whereby Ras effectors are recruited. The spatiotemporal organisation of lipids within the Ras nanoclusters determine Ras function in signal transduction. Incorporation of dietary fats such as omega 3 polyunsaturated fatty acids (n3-PUFA) into the membrane phospholipid bilayer alters their biophysical properties. In addition, n3-PUFA has been associated with cancer prevention and attenuation of Ras signalling. We propose that n3-PUFA modulation of Ras nanoclustering is responsible for the attenuated signalling response. Different Ras isoforms occupy distinct nanoclusters. In addition, both isoform and oncogenic mutation-specific Ras signalling differ. It is unclear whether the role of n3-PUFA is highly context specific or if they are pan-Ras modulators. Therefore, to test our hypothesis and determine the specificity of n3-PUFA effects, we will profile the proteome microenvironment of different Ras isoforms and mutation variants treated +/- n3-PUFA. In parallel, studies measuring the nanoclustering responses of the same Ras variants to n3-PUFA will also be performed. These results will be correlated with studies profiling the signalling network response. Together, these studies will define the extent to which n3-PUFA modulates oncogenic Ras signalling.
KIFC1 (HSET) is a minus-end-directed kinesin whose depletion promotes multipolar mitosis in cancer cells carrying additional centrosomes. Centrosome amplification often occurs in breast and ovarian cancers where KIFC1 is also frequently overexpressed. While cancer cells usually overcome the presence of additional centrosomes by clustering them into two groups to form pseudo-bipolar spindles, they lose this ability in the absence of KIFC1. As multipolar mitosis is usually lethal, targeting KIFC1 may selectively kill cancer cells without affecting non-transformed cells. This exciting hypothesis currently lacks systematic validation. Here, the KIFC1 requirement for normal mitosis and survival will be addressed in a panel of cancer and non-transformed cell lines. Stability of proteins in cells may be regulated by a family of ~90 deubiquitylase (DUB) enzymes, which recently aroused interest as potential drug targets. Targeting a DUB that stabilizes KIFC1 would be predicted to promote KIFC1 degradation and multipolar mitosis. In this project we will identify DUBs that maintain cellular levels of KIFC1, then characterize the effect of their depletion and their mechanistic interaction with KIFC1. Lastly, we will assess the clinical relevance of our findings, by evaluating expression of KIFC1 and its regulatory DUBs in breast cancer patient tissues and performing clinicopathological correlations.
Characterisation of extracellular vesicles derived from human mesenchymal stromal cells and exploration of their immunomodulatory effects 30 Sep 2018
Kidney disease is a worldwide public health issue and also a major socio-economic burden. Nowadays, effective treatments for slowing or preventing kidney disease progression are limited, making kidney transplantation or dialysis a necessity for patients with kidney failure. As a consequence, the development of alternative treatments are urgently needed. Mesenchymal stromal cells (MSCs) are adult cells able to improve the health of the kidneys in many kidney injury models in rodents, but the mechanisms by which they act are not fully elucidated. These cells do not migrate to the injured kidney when administered in animal models, and there is increasing evidence that they promote tissue regeneration through the release of particles that are enriched with bioactive molecules. These so-called extracellular vesicles (EVs) are derived from MSCs and are regarded as a potential mechanism of cargo transportation and intercellular communication of the MSCs. Therefore, the aim of this study will be the elucidation of the content of EVs derived from human MSCs and their role in improving renal health. A particular focus will be to investigate if the beneficial effects of the EVs are mediated through the cells of the immune system.
Role of STAT3 in bovine protozoan infection 31 May 2018
Signal transducer and activator of transcription 3 (STAT3) is a pleiotropic transcription factor and signalling molecule. Whole animal knock-out mice are embryonic lethal, while cell-specific KO present with differing phenotypes including exacerbated and reduced inflammatory responses dependent on the cell type altered. Using a bovine model of protozoan challenge, we have noted an age-related difference in monocyte responses. Differential gene expression analysis indicates that the STAT3 network is more robustly activated in neonates and this corresponds with enhanced parasite clearance[CJ1] . We now propose to test the actions of STAT3 in two systems to determine if age-dependent resistance to infection is dependent on STAT3. Firstly, bovine neonatal and adult monocytes will be challenged with the abortifacient Neospora caninum; the cytokine response and parasitemia will be measured against a background of STAT3 chemical inhibition. Secondly, using a novel bovine intestinal organoid model, the role of STAT3 in N. caninum infection of the small intestinal epithelium will be tested. Differentiated organoids will be challenged under conditions in which STAT3 has been acutely inhibited, and the cytokine response and parasitemia measured. This work will determine if the differential age-related response to infection extends beyond the monocyte and is STAT3 driven.
Investigating the role of deubiquitylases on the stability of programmed death-ligand 1 and epidermal growth factor receptor in non-small cell lung cancer 30 Sep 2018
This project will examine the relationship between two proteins: epidermal growth factor receptor (EGFR) and programmed death-ligand 1 (PD-L1) relevant to non-small cell lung cancer (NSCLC). Mutations in the EGFR drive tumour growth and survival, whilst the presence of PD-L1 at the cell surface limits the effectiveness of an immune response. We will study the relationship between EGFR activity and PD-L1 expression in a model cell system, with the specific aim of identifying intermediary proteins. We will also study each protein individually with the aim of understanding the processes which set the high levels of protein displayed at the cell surface. Both proteins are validated clinical targets, but patients may acquire resistance to the existing drug therapies. Like any population, the amount of any given protein is governed by the rate of its creation versus destruction. A family of proteins called deubiquitylases (DUBs) is known to regulate the fate of specific proteins leading to either an increased or a decreased population size. We aim to identify particular DUBs that influence PD-L1 and EGFR and understand the mechanism by which they do so. By inhibiting these enzymes we will open up a new therapeutic strategy to reduce EGFR and/or PD-L1 levels.
Role of interleukin 22 receptor expression in Human Respiratory Syncytial Virus infection. Positive or negative? 31 May 2018
Respiratory Syncytial Virus (RSV) is the commonest cause of severe respiratory tract infection in infants with a global RSV disease burden of around 30 million cases each year. The cytokine IL-22 is known to be expressed at sites of infection, to enhance cell growth, tissue repair and aid protection from secondary infection by increasing secretion of antibacterial molecules including beta defensin. A previous student led project has shown RSV infection of cultured airway epithelial cells results in increased expression of the receptor IL-22R1 polypeptide. Potentially increasing the sensitivity of these cells to stimulation by IL-22. Here we wish to establish if IL-22 treatment of cultured airway epithelia cells has a positive effect through increasing beta defensin expression and or a negative effect increasing infected cell viability and RSV replication. This will be achieved by infecting beas-2B airway epithelial cells in vitro and studying IL-22R1 expression, viral replication and beta- defensin expression. This will work will provide a further understanding of IL-22 role during viral infection and potentially define if IL-22R or IL-22 are possible therapeutic targets.
Symptom networks in childhood: a new approach for understanding the structure and development of psychiatric disorders 15 Aug 2016
Psychiatric disorders have been traditionally considered as latent dimensions or factors that are represented by a set of indicators or symptoms. However, the adequacy of this approach is being questioned because it does not account for the inter-relationships between symptoms and their dynamic causal nature. In response to this limitation researchers have recently started visualising disorders as networks of symptoms, using analytic methods akin to mapping networks of people, leading to interesting insights for classification of psychiatric disorder in adults. Given that precursors for psychiatric disorder are evident in childhood and can play an aetiological role in their emergence, we propose to investigate the network of symptoms, beginning in early childhood and observe their evolution in childhood and adolescence. We will investigate (1) symptom networks within disorder domains (e.g. depression, hyperactivity), (2) symptom networks across all domains to identify comorbidities, and (3) differences in the network based on gender, exposure to maternal depression in early childhood and between non-clinical and clinical samples. By doing so we will establish the suitability, feasibility and utility of applying such methodology to child symptom data and thereby determine if the method offers new insights into the aetiology and development of psychiatric disorder.
Neutrophil extracellular traps (NETs) are nuclear chromatin structures covered in anti-microbial proteins that catch and kill pathogens. They are released from neutrophils in response to infection and represent an important and novel defense mechanism. The exposure of proteins and DNA within NETs can also trigger auto-immune responses, e.g. in systemic lupus erythematosis (SLE), where auto-antibodies to double-stranded DNA and cytoplasmic proteins contribute to disease pathology. Emerging evidence in rheumatoid arthritis (RA) suggests that NETs expose citrullinated neoepitopes (e.g. histones), and this may cause a loss of immune tolerance and development of antibodies to citrullinated proteins (ACPA), a hallmark of severe RA. This pilot study will test my novel hypothesis that NETs exposed by neutrophils from SLE and RA patients contain different proteins, thereby exposing different auto-antigens to the immune system. A series of proof-of-principle experiments will carry out comprehensive, quantitative analysis of the proteins decorating SLE and RA NETs, using immunofluorescence and quantitative proteomics. These experiments will provide the first insights into molecular properties of NET material in SLE and RA, and will allow me to generate a new hypothesis on the contribution of NETs to the development of auto-antibodies in these two diseases for an independent fellowship application.
Wellcome Trust Clinical PhD Programme, University of Liverpool 'Health Priorities in the Developing World' 14 Jul 2014
Tuberculosis is responsible for the death of nearly 1,500,000 people annually. TB treatment takes a minimum of 6 months, and even with excellent adherence, is complicated by the risk of treatment failure and acquired drug resistance. Outcomes are worse in those with HIV-TB co-infection, with higher mortality and greater risk of TB relapse or re-infection after completion of treatment. We hypothesise that the intrapulmonary and intracellular site of Mycobacterium tuberculosis infection represents a sanctuary from drug- and immune-mediated eradication, and is an obstacle to effective and shorter therapy. In the context of a longitudinal cohort study, I will conduct an intrapulmonary study to explore the compartmental pharmacology of anti-TB drugs, and local immunology in the infected lungs, of patients receiving treatment for pulmonary TB. Bronchoalveolar lavage will be performed to collect samples for pharmacokinetic analysis and functional immunologic assays. I will develop population pharmacokinetic models of TB drug exposure in plasma, epithelial lining fluid, and alveolar macrophages, and assess alveolar macrophage function in the presence or absence of HIV early and late in treatment. The relationship between these predictor variables and the endpoints of sputum culture conversion, bacillary elimination rates, and clinical outcomes will be explored in mathematical models.
Effect of exposure to rotavirus vaccine on household rotavirus transmission in a semi-urban Malawian Population. 29 Aug 2014
Rotavirus is responsible for the deaths of almost 500 000 children under 5 years old annually. Whilst rotavirus vaccination is expected to substantially reduce the burden of severe rotavirus disease worldwide, vaccine efficacy is much lower in resource poor settings. Understanding additional (indirect) benefits of vaccination is therefore extremely important from public health and health economic perspectives. This study will use a prospective cohort design to investigate the impact of rotavirus vaccination of infants on secondary transmission within families in the event of exposure to a symptomatic index rotavirus case. Children with rotavirus gastroenteritis (RVGE) will be recruited and their vaccination status determined. Household contacts of recruited children will be followed up to compare the rotavirus secondary attack rate (SAR) in households exposed to a vaccinated child to SAR in those households unexposed to a vaccinated child. I will i) quantify the difference in SAR for asymptomatic and symptomatic infection in households containing vaccinated versus unvaccinated index children ii) explore the relationship between severity of symptoms in the index child and SAR among household contacts iii) quantify the difference in total household shedding density in households containing vaccinated index children compared to those containing unvaccinated index children using a model of viral shedding derived from intensive sampling in a subset of households.
Risk factors for and spatio-temporal distribution of acute encephalitis syndrome in Nepal 15 Sep 2014
Acute Encephalitis Syndrome (AES) causes high rates of morbidity and mortality in Nepal, particularly in children. Despite the introduction of a vaccine against Japanese encephalitis virus (JEV) (a major cause of AES), numbers remain high, and there are many cases of AES where the cause is unknown. The majority of these are in the low-altitude, densely irrigated, southern Terai region and coincide with the wet season. This suggests that many cases may be due to vector-borne pathogens. The primary goal of the study is a) to identify the environmental, socio-demographic and behavioural risk factors associated with known and unknown causes of AES using a case-control study and b) to assess the extent to which these factors explain the observed spatio-temporal distribution of AES. This will improve knowledge of the epidemiology of AES, provide guidance towards the cause, and help disease control methods. Secondary goals are: 1. To estimate and map the residual, unexplained spatio-temporal variation of AES and to produce a model which aims to estimate the population-based risk of AES. 2. To analyse the contact patterns and daily activities of healthy participants living in districts of high AES incidence, and produce models of exposure to risk factors associated with vector-borne diseases. This will be an exploratory aim.
Understanding the Pharmacokinetics of Antiretroviral Drugs in Breastfeeding Mother-Infant Pairs. 18 Jun 2014
Despite evidence that perinatal use of antiretroviral therapy (ART) can reduce the rates of mother to child transmission (MTCT) of HIV to less than 1%, approximately 430 000 children are infected annually. Consequently, WHO recommends commencing pregnant HIV+ women on lifelong ART irrespective of CD4 count or clinical stage. Whilst benefits are likely, this strategy carries several potential risks; increasingly, infants will be exposed to ART in utero and through breastmilk (BM). Several recent studies highlight both toxicities and the risk of multi-class drug resistance should the PMTCT fail. My aim is to characterise ARV accumulation in BM, relative infant dosing and systemic absorption following feeding. Sparse pharmacokinetic sampling from postpartum women receiving ARVs in Kampala will evaluate covariates (eg gestational age, birth weight, nutritional status, pharmacogenetics, maternal CD4) of infant ARV exposure. Clinical outcome measures will include HIV viral load in mothe r, BM and infant, drug safety, and vertical transmission. A population pharmacokinetic (and pharmacodynamic) model will characterise ARV exposure and efficacy in mother-infant pairs, and simulate outcomes with alternative dosing regimens and combinations. I have developed novel dried blood and dried BM spot methodology for some first line ARVs in support of this Fellowship.
Fully integrated, real-time detection, diagnosis and control of community diarrhoeal disease clusters and outbreaks 02 Feb 2015
Seventeen million people suffer a diarrhoeal disease every year. These diseases often lead to outbreaks of infections, like norovirus - now among the costliest infectious burdens on the NHS.The sooner diseases are detected, the sooner they can be brought under control - limiting their health and financial impact. It is known from outbreaks of Escherichia coli O104 in Germany and O157 at Godstone Farm in Surrey that surveillance is key to detection; but with fewer people now consulting their GP over diarrhoea, outbreaks are increasingly difficult to detect using traditional methods. This hides the true burden of disease. Professor Sarah O’Brien at the University of Liverpool and her collaborators will use data from multiple sources to scout for infection in the community, take samples and analyse them, using modern technology to detect organisms. The researchers will analyse the DNA of microbes to discover which family of organisms they belong to and how they are evolving. Since many diarrhoeal diseases can pass between humans and animals the project team will develop and integrate veterinary and medical surveillance. The ultimate goal is an integrated real-time, surveillance/diagnosis/investigation system - centred on the patient - that detects community outbreaks sooner, enables Health Protection professionals and Environmental Health Officers to intervene quickly and thus lessen short- and long-term harm.
My key goals are to ascertain the main reasons behind fathers killing their children, the factors which contributed to a successful insanity plea, the extent to which the insanity plea was gendered with regards to infanticide, the extent to which the crime of infanticide itself was gendered, the role of the medical establishment in the court and attaining a successful insanity plea and the role of the media and public opinion in attaining a successful insanity plea. I intend to carry out my re search in London, Liverpool and Manchester using the same methods of research in each city. I will begin by looking at local assize court records for cases of child murder and infanticide committed by men and I will then look up these cases in local and national newspapers. I will explore medical treatises on both infanticide and insanity across the period to track the change in medical opinion concerning these issues to see if they are reflected in the outcome of the insanity pleas. I estimate that I would spend the majority of my first year at the archives I have named collecting primary material.