- Total grants
- Total funders
- Total recipients
- Earliest award date
- 31 Dec 2005
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
An attentional bias (AB) towards emotional, and particularly threatening stimuli has been robustly demonstrated in anxious observers, with smaller biases in typical populations (Bar-Haim et al, 2007). Moreover, threat-related biases are suggested to occur even when observers are unaware of the threatening stimuli. A key paradigm used to measure AB is the visual probe (VP) paradigm, in both standard (aware), and backward masked presentations. Recent work (with typical populations) has highlighted the importance of controlling for low-level stimulus properties (e.g. luminance contrast), and using stringent measures of awareness (Hedger et al, 2016; Hedger, Adams & Garner, 2015a, 2015b) in order to properly interpret VP data. The current project aims to evaulate AB in anxious and typical observers in three variants of the VP task: a standard VP, and two VP methods that allow us to present threatening stimuli are outside of awareness: backward masking and continuous flash suppresion. Importantly, we will use careful stimulus controls to model the effects of low-level stimulus properties and stimulus awareness. The study will allow us to understand whether typical or anxious observers preferentially attend to threat stimuli during conscious and unconscious presentations. This has important applications for treatment development, such as attention bias modification.
Macrophages represent the most abundant antigen presenting cells in inflammatory infiltrates and tumors. An important immunoregulatory function of macrophages is to present antigen to cognate T cells. Antibody (IgG)-antigen complexes are internalized into macrophages through potential interactions with multiple different Fc receptors and are subsequently delivered to subcellular compartments where peptides derived from the proteolyzed antigen can be loaded onto MHC molecules. However, the multitude of possible Fc receptor interactions with the antibody-antigen complexes influences the spatial and temporal behavior of antigen and consequent peptide-MHC repertoire through a complex, and poorly understood, network of subcellular trafficking pathways. We have developed advanced microscopy tools to enable the analysis of three-dimensional, dynamic cellular processes at unprecedented levels of spatiotemporal resolution. We will combine these approaches with antibody engineering and analyses in mouse models of cancer and autoimmunity to elucidate how the combination of antigen delivery vehicle, microenvironmental factors and macrophage phenotype interplay to result in specific antigen presentation outcomes. The two long term goals of these studies are: one, to develop novel mechanistic insights into the fundamental cell biological processes determining the repertoire of presented antigens; two, to define how to deliver antigen to macrophages to orchestrate a predictable immune response.
Autophagy is an intracellular catabolic pathway that is required to maintain cell homeostasis during times of stress and starvation, as well as selectively degrade damaged organelles, protein aggregates, and intracellular pathogens. In order to develop future therapies that target this pathway to treat diseases such as cancer and neurodegeneration, further research is required to understand the mechanism of cargo selection, its mode of regulation, and its role in facilitating phenotypic alterations. Autophagy requires the integration of multiple signals, proteins, and lipids in order to identify the appropriate substrate, form the autophagosome, and fuse with the lysosome to degrade its cargo. This proposal will aim to elucidate the role of one such protein adaptor implicated in the autophagy pathway, Toll-interacting partner (TOLLIP), which has a crucial role in regulating both endocytic and autophagic cargo and their trafficking to the appropriate subcellular compartment. This project will utilise CRISPR-Cas9 gene knockout approaches and reconstitution experiments in an established human cell line to evaluate TOLLIP’s mechanistic role during autophagy.
The effect of systemic bacterial infection on the onset and progression of disease in an animal model of Alzheimers's disease. 01 Apr 2016
Tg2576 mice will be used as a model of human Alzheimer’s disease (AD). These transgenic mice are genetically modified to overexpress a mutant form of the amyloid precursor protein (APP). APP develops into beta amyloid protein which is a major component of plaques that form in the brain of AD patients. Brain tissue has already been collected at 12, 16 or 20 months. At each stage of the disease mice have been treated with saline or an attenuated strain of Salmonella typhimurium to investigate the hypothesis that systemic bacterial infections modifies plaque formation through promoting neuroinflammation. The ability of microglia and macrophages to phagocytose and proliferate will be investigated. This will help establish if the innate immune response to the infection is causing the increasing amyloid plaque deposition and neuronal loss that causes the onset and/or progression of AD. Antibodies will be used to stain microglial cells (via binding to MHCII, FcRI and CD11b).The antibodies iNOS and Ki67 will be used to analyse the microglia’s ability to perform phagocytosis and proliferating respectively. As well as this, antibodies SMI-32 and NeuN will be used to establish whether damage or swelling has occurred to neurons as a result of the pathogen.
tRNA Methylation as an Antibacterial Target 01 Apr 2016
In response to the continued evolution of bacterial resistance to antibiotics, the discovery and exploitation of novel bacterial target mechanisms, such as essential enzymes, is increasingly important to feed novel candidates into the antibiotic discovery pipeline. tRNA m(1)G37 methyltransferase (TrmD), catalyses the post-transcriptional methylation of guanine 37 in specific bacterial tRNAs, which is an essential step. Deletion mutants for this enzyme in both gram negative and gram positive bacteria causes an increase in translational errors, decelerated growth and cell death. Substantial structural differences have been identified between TrmD and the human equivalent (Trm5), strongly suggesting the development of highly selective inhibitors for TrmD should be possible, thus reducing the probability of off-target toxicity. Current TrmD inhibitors show promising in vitro potency (micromolar range), but their low activity against cultured bacteria is proposed to arise from poor bacterial uptake of the compounds (inefficient crossing of the bacterial cell wall). Our objective is to design, prepare and biologically evaluate a small library of novel TrmD inhibitors. These compounds will feature a range of modifications selected to enhance bacterial cell uptake. The activity of these compounds will be measured by comparing in vitro potency with activity in bacterial cultures.
Internal daily timekeeping systems known as circadian clocks are used by all types of organisms to regulate their metabolism. For example, the clock-controlled scheduling of food intake and use affects health and longevity in both mammals and insects. Time-restricted or nutrient-restricted feeding improves the health of both mice and fruit flies (Panda, Science 2016). The period gene, which plays a key role in the circadian clocks of animals, provides a link between daily timekeeping and metabolic health. Flies lacking the period gene store less glycogen and triglycerides in spite of ingesting more food and are, therefore, more sensitive to starvation. I propose to test where and how the period gene provides this metabolic function. In particular, I will ask whether its role in starvation resistance is due to its control of sleep/wake rhythms or its function in periperhal clocks of metabolic tissues such as the fat body. Moreover, Dr Wijnen's laboratory recently showed that the period gene is induced at colder temperatures (Goda et al., Proc Biosci 2014) and I will test whether period-mediated starvation resistance is found preferentially at colder temperatures.
The Indian and UK investigators represented in this proposal have worked together for 20 years to study connections between growth in early life and adult health. We have collected evidence that unbalanced nutrition and metabolic disorders, in pregnant mothers, programme the lifelong health of the next generation, causing impaired growth and cognitive function, and chronic non-communicable disease. Our future programme includes interventional, observational, and genetic studies, with common outc omes: body composition, cardio-metabolic measures and cognitive function. In two randomised controlled trials, we will test whether improving the overall micronutrient intake, and/or the vitamin B12 content of the mother's diet, pre-conceptionally and during pregnancy, improves outcomes in the children. Observational and genetic work will use a linked series of Indian birth cohorts, which have detailed data on mothers and children, to identify nutritional and metabolic 'messages' that cross from one generation to another to influence health. An over-arching objective is to build capacity for research into developmental origins of health and disease by strengthening networking between research groups in India and other low- and middle-income countries (LMICs), PhD studentships, and expansion of expertise in the study of epigenetic mechanisms that link maternal nutrition to health in the next generation.
Southampton NMR Centre. 04 Feb 2010
The University of Southampton, as part of the development of the Institute for Life Sciences, is currently building a dedicated nuclear magnetic resonance (NMR) centre. Based on existing collaborations; the centre will bring together four groups from the Schools of Biological Sciences and Chemistry with expertise in NMR method and instrument development with those experienced in their application to biological systems. The centre s key objectives are: 1) To establish a state of the art experim ental NMR facility for the seamless integration of liquid and solid-state NMR for the acquisition of data on systems including soluble macromolecules, protein assemblies, biological membranes and fibrillar proteins. 2) To support a multidisciplinary research portfolio in the life sciences including the fields of amyloidogenic diseases, infectious disease, cancer science, membrane biology and drug development. 3) To facilitate the development of new NMR methods and technologies geared towards solving timely and fundamental problems in molecular cell biology 4) To promote an academic environment that fosters the exchange of ideas and sharing of expertise between different disciplines. 5) To provide a modern platform on which to train the next generation of researchers in the development and application of NMR to biological systems.
"Medicine, health and body" to be held between February 2010 and January 2011 at Southampton University. 18 Jan 2010
Our primary aim is to organize a seminars series that would promote and raise the profile of medical history/humanities at Southampton. It will also constitute a focal point for the interests of current researchers. There is an increasing awareness of the link between humanities and medicine. Many of our colleagues in the course of their work find the body at the centre of their research subjects, such as religion, magic, migration, ethnic conflicts, and wars. The second and ultimate aim of the seminar series is to exploit this potential by pulling together individual researches under an overarching research program. This would eventually allow us to build up a research group working on this subject and to develop a teaching and research program on medical history/humanities at the Schools of Humanities and Social Sciences.
Me my health and my children's health. 01 Oct 2008
This project aims to provide secondary school students in Southampton with a deeper understanding of how they can improve their own health and the health of their future children under a framework of 'Me, my health and my children's health'. The project tests a new method of student and teacher participation in order to tackle some of the biggest contemporary health issues facing young people. This approach involves giving the students first-hand experience of modern biomedical practices carried out in their local hospital. To stimulate interest and excitement, and encourage new ways of thinking about biomedical science, these will be practical activities based at the university using authentic hospital equipment, clear links will be made to the school curriculum in partnership with Southampton City Council, and a scheme of work will be written for future use by other schools. The programme will enable students and teachers to explore the latest scientific techniques that cannot be taught in schools, and will include professional development for the teachers. There will be a half-day event at which students will present their work and engage in informed debate about these important socio-scientific issues in front of parents/guardians and invited members of the community. The project will also include professional training for science teachers to enhance formal and informal learning about the issues and maximise the impact on the students. The project will be rigorously evaluated throughout, and findings will be disseminated by means of a half-day conference for science teachers, educators and researchers.
The impact of systemic bacterial and viral infections on innate immune responses in the brain. 07 Oct 2010
It is well known that systemic inflammation communicates with the brain but most of this research has been carried out using bacterial and viral mimetics. We will use real, transient bacterial and viral infections, in young and old mice, to model common infections of humans. We will study how these infections influence the phenotype of the innate immune cells in the brain, the macrophages and microglia, and also the endothelium. We will characterise the phenotypic changes and establish how long the changes last and whether different infectious agents produce similar or different phenotypes. We propose that the microglia become primed by a systemic infection such that they give an exaggerated response to a secondary stimulus. We will investigate the primed response by stimulating toll-like receptors and immunoregulatory receptors and studying the signalling pathways in microglia isolated from the brains of animals after a systemic infection. We will then confirm that the primed pheno type is present in vivo using inflammatory and neurotoxic stimuli. We propose that the microglia in the aged mouse brain will show an exaggerated priming response and that a secondary challenge will lead to heightened production of potentially neurotoxic molecules when compared to microglia from young animals.
Genetic manipulation of Chlamydia trachomatis. 19 Oct 2006
The field of chlamydia research has been hampered by the inability to take a direct genetic approach to study the function and regulation of genes. The development of a system by which modified genes can be introduced will provide a significant boost to studies on this important human pathogen. Preliminary data generated in collaboration with Dr. Kahane and Prof Friedmann, presented in this application, provides 'proof of principle' that this much sought after technological goal has been reached. However, the protocol developed is time consuming, requires an experienced chlamydiologist and high level cell culture skills.Using this successful approach as a starting point we now plan to develop an efficient gene transfer system for Chlamydia trachomatis. Our key goal is to improve the protocol making it possible to establish this technology as a routine procedure for the study of chlamydial molecular biology. This will be achieved by improving the efficiency of the method, producing improved vectors for selection of transformants and using plasmid free chlamydial host strains for transformation studies.
Hydrocephalus is a condition in which abnormal accumulation of cerebrospinal fluid (CSF) in the brain causes increased intracranial pressure inside the skull. This is usually due to blockage of CSF outflow in the brain ventricles or in the subarachnoid space at the base of the brain. Chronic hydrocephalus (CH) is characterized by increased cerebrospinal fluid volume with or without increased intracranial pressure (ICP), and often associated with impaired cognition thought to be related to decrease cerebral blood flow and oxygen delivery. In hydrocephalus, increased ICP and vascular compression as the result of enlarged ventricles may be directly responsible. VEGF plays a critical role in angiogenesis, neuronal protection as it relates to ischemic/hypoxic events.
Asthma affects 150 300 million people worldwide, inflicting significant morbidity, mortality and financial cost. Disease heterogeneity is increasingly recognised, but the underlying mechanisms, especially in the severe neutrophilic asthma phenotype, remain unclear. Aberrant responses to viral infection play an acknowledged role in asthma exacerbations, but their immunological correlates are poorly understood. The recently described cytokine interleukin-17, whose expression characterises the nove l T helper-17 (TH17) lymphocyte subset, may play a critical role in both these areas. I hypothesise that a dysregulation of the balance between TH17 and regulatory T (TREG) cell subsets may underlie, and help define the severe neutrophilic asthma phenotype. I also hypothesise that in asthma an aberrance of the TH17: TREG response to respiratory pathogens, particularly viruses, contributes to the development of exacerbations. I propose to characterise TH17 cells in airway inflammation in three contexts: in a cross-sectional study of severe asthma, mild-to-moderate asthma and health; and in longitudinal studies during naturally occurring asthma exacerbations, and during in vivo challenge with human rhinovirus. The anticipated practical outputs of this work include a deepened understanding of the role of IL-17 in the pathogenesis of asthma, and potentially the identification of new biomarkers for asthmatic phenotypes and new therapeutic targets.
Colonial Medicine and Indigenous Health Practices in Southern and Eastern Princely States of India, c. 1880-1960. 14 Nov 2006
The project maps developments in public health (drinking water supply, cholera prevention), the emergence of specialised medical institutions (leper/lunatic asylums), and the influence of western medicine on indigenous medical communities (and their patients) and the interaction between them, in particular during the influenza epidemic of 1918. A comparatively large state (Mysore), considered 'progressive' and 'enlightened', and some of the 24 Orissa Princely States, seen as 'backward' and 'despotic', will be at the centre of investigation. Contentious issues currently debated in the existing scholarship on medicine in British India and other colonies will be explored (such as the 'indigenisation' of health services; the inter-relationship of colonial and indigenous paradigms of medical practice; the impact of specific political and administrative events and changes on health polices). Developments in public health and the emergence of medical institutions in Princely India will be traced from both Indian and European perspectives and British medical policies and the Indian reactions and initiatives they evoked in different Princely States with highly varied socio-economic, cultural and administrative set-ups examined.
For this research we wish to address the biology of the costimulatory ligand TL1A. Specifically the stability of TL1A mRNA in Dendritic cells (DC) and T cells and examine the biological significance of the membrane bound versus the soluble form of this cytokine.