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Results

Regulation of SUMO in DNA double-strand break repair. 05 Apr 2017

Proper repair of DNA double-strand breaks (DSBs) is vital to immunological health, cancer protection and healthy ageing. The cellular response to this form of damage is highly co-ordinated by a series of diverse post-translational modifications. Recently we, and others, demonstrated a vital role for the small-ubiquitin like modifiers (SUMOs) in the DSB response. Despite an emerging picture of the mammalian SUMO-proteome our understanding of the regulation of SUMOylation following DNA damage is superficial and our current knowledge points to a largely passive process. Contrary to the current prevailing view of SUMOylation we hypothesise that the regulation of this modification in the DSB response is highly coordinated. We suggest this regulation is fundamental to correct DNA repair. Our aims are to identify mechanisms of SUMO enzyme cascade initiation, to establish how SUMO proteases perform the vital role of maintaining the balance of SUMO conjugates during DNA damage signalling, and to describe the features of a novel subclass of SUMO target modification site critical to the cellular response to DSBs. In achieving these aims we anticipate this programme will underpin future developments relevant to cancer treatment and healthy ageing by identifying new areas of regulation and cross-talk in the DNA repair process.

Amount: £1,503,277
Funder: The Wellcome Trust
Recipient: University of Birmingham

Vacation Scholarships 2017 - University of Birmingham 16 Jun 2017

Vacation Scholarships 2017 - University of Birmingham

Amount: £23,500
Funder: The Wellcome Trust
Recipient: University of Birmingham

The Role of MYBL2 in DNA damage response to etoposide in mouse embryonic stem cells (ESCs) 27 Apr 2017

Embryonic Stem cells (ESC) share common characteristics with cancer cells such as immortality and the ability to bypass the normal cell cycle checkpoints somatic cells have to pass through. This allows both cells to continuously proliferate without changing their cellular features. These similarities shared between both ESCs and cancer cells may relate to common patterns and mechanisms of regulating gene expression. In fact, as demonstrated by Yamanaka fully differentiated fibroblast could reverse their state of differentiation and be induced towards an embryonic stem cell-like state (induced-pluripotent stem cells (iPSCs)) by introducing four transcription factors expressed in a pluripotency state. These observations highlighted the importance of transcriptional factors in determining cell fate and their possible role in the induction of cancer. In this project, I will be working with mouse ESCs and will be looking at the role of MYBL2, a transcription factor highly expressed in ESC and iPSC, which is involved in cell proliferation and maturation, and try to better understand its role in the maintenance of genome integrity. I will be exploring how low levels of this gene affect the cell response to topoisomerase II inhibitor etoposide, a therapy currently used in to treat cancer.

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

The ability of platelet extracellular vesicles to promote adhesion of monocytes cells to endothelium 27 Apr 2017

There is an increasing realisation that haemostatic and inflammatory responses to tissue damage are linked by common mediators. Adhesive and signaling interactions between platelets and leukocytes have been well-described. Recently it has been realised that some of these interactions are actually mediated through extracellular vesicles (PEV) released by the platelets. Indeed, we find that PEV can bind to leukocytes and to endothelial cells, transducing signals and transferring adhesion receptors, and thus potentially amplifying inflammatory leukocyte recruitment. Here we aim to further expand our investigations by evaluating the specific ability of PEV once bound to endothelial cells, to support adhesion of monocytes. Building on our own previous observations where PEV were able to bind to endothelial cells and support adhesion of neutrophils, we will test the concentration and time dependence of PEV binding to the endothelial cells and how this modifies monocyte and lymphocyte adhesion. Based on their high avidity for PEV in suspension, we hypothesise that monocytes are particularly sensitive to interactions with PEV deposited on endothelial cells. This study will test whether this is correct, and supply further evidence as to whether PEV are potent players in the thrombo-inflammatory response, for example, linked with pathogenesis of atherosclerosis.

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

The Role of Epstein-Barr Virus in Mycosis Fungoides 27 Apr 2017

Mycosis fungoides (MF) is the most common type of cutaneous T cell lymphoma, a group of T cell cancers that generally affect the skin. Lesions/plaques arise in MF patients due to clonal expansion of epidermis-homing memory CD4+ T cell populations and the inflammation that accompanies this expansion. While the underlying cause of MF remains unknown, there is a strong association in a subset of MF with the common herpesvirus Epstein-Barr virus (EBV). The aim of this project is to investigate the impact of EBV on the phenotype and function of transformed CD4+ T cells isolated from skin lesions of MF patients. EBV positivity will be confirmed by qPCR of MF lesions. In cases which are EBV-positive, immune cells will be recovered from skin biopsies by mechanical and/or enzymatic digestion. Fluorescence in situ hybridisation (FISH) will be used to detect EBV-encoded small RNAs (EBERs) inside CD4+ T cells. This, in combination with staining for markers that identify CD4+ T cell subsets (naïve vs memory, cytotoxic, Treg, amongst others) will reveal the phenotype of the transformed cells. Finally, we will test the susceptibility of the isolated tumour cells to novel chemotherapeutic drugs and small molecule inhibitors.

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

The Politics of Fertility Treatment in 20th-century Britain 06 Nov 2017

Through Family Planning Association and associated archives held at the Wellcome, I will map historical medical provision for infertility at the local level and explore what the provision (or lack thereof) of infertility treatment reveals about the changing relationship between individuals, family, and the state in modern Britain. I will explore to what extent the state viewed infertility as a problem affecting the body politic versus a personal problem affecting individuals in the private family sphere, and how this has changed over time; what arguments about the availability and entitlement to infertility treatment as part of a nationally-subsidized or state-run health system can tell us about conceptions of individual rights and notions of "worthiness"; how debates over the state-provision of infertility treatments have been gendered, racialized, or approached from the perspective of class or eugenics; and what this can tell us about British political culture and society more broadly. This pilot research will be written up in academic journals and act as a springboard to an Investigator Award into the political history of fertility treatment, the results of which will both improve our understanding of the historical evolution of contemporary debates and help to shape current and future health policy.

Amount: £6,800
Funder: The Wellcome Trust
Recipient: University of Birmingham

Improving the engagement of pregnant/early postnatal women in research 16 Jan 2018

It is challenging to engage pregnant/early postnatal women with local maternity research, as pregnancy is a normal physiological process which is relatively short-term, and after which women find regular engagement challenging. As such, two different engagement approaches will be piloted by University-based researchers and Patient and Public Involvement advisers to engage local pregnant/early postnatal women in research development, recruitment and dissemination on a continuing and regular basis. Both approaches will involve local researchers coming to speak to women about the latest maternity research and opportunities for involvement. One approach will attach this activity to an existing class at a children’s centre, whilst the other will be attached to a new yoga and midwifery advice session developed as part of this project. Information provided during these sessions may be useful to women during their pregnancy or after they have had their babies, and the insights of women will help to ensure the research is relevant and has the best chance of success. Women will help researchers translate research findings into a format suitable for a range of audiences. The groups will be evaluated and, if successful, plans will be made to make the group self-sustaining.

Amount: £16,000
Funder: The Wellcome Trust
Recipient: University of Birmingham

HWB-NMR: a national resource for biomolecular research 06 Jul 2017

We are committed to ensuring that the UK remains world-leading in the field of biomolecular NMR spectroscopy and request support to continue offering the UK's only cryoprobe-equipped 900MHz NMR spectrometer and a 600MHz TXO cryoprobe as an open access resource to the UK biomolecular NMR community. HWB-NMR has continued to maintain and support an established national user base of ~50 groups, whose research has been published in high profile publications including Nature Chem Biol, Nature Commun, JACS, Angew Chem, Science, Cell Reports. The funding will allow us to dedicate 70% of available spectrometer time to external UK-based academic users, and to provide training to the next generation of researchers through hands-on spectrometer use and courses, as well as valuable networking opportunities at annual user meetings. We also request support to upgrade our 12-year old Agilent 800MHz instrument that we would like to equip with an ultra-sensitive low-volume cryoprobe and an autosampler to become a UK resource targeted towards innovative NMR applications for metabolism-related projects, while remaining accessible for structural biology and structure-based drug discovery. An instrument optimised for mass-limited samples at physiologically-relevant salt levels would increase our capability in fields of significant demand and scientific impact.

Amount: £1,487,450
Funder: The Wellcome Trust
Recipient: University of Birmingham

Putting genomic surveillance at the heart of viral epidemic response. 05 Apr 2017

This proposal is to develop an end-to-end system for processing samples from viral outbreaks to generate real-time epidemiological information that is interpretable and actionable by public health bodies. Fast evolving RNA viruses (such as Ebola, MERS, SARS, influenza etc) continually accumulate changes in their genomes that can be used to reconstruct the epidemiological processes that drive the epidemic. Based around a recently developed, single-molecule portable sequencing instrument, the MinION, we will create a 'lab-in-a-suitcase' that will be deployed to remote and resource-limited locations. These will be used to sequence viral genomes from infected patients which will then be uploaded to a central database for rapid analysis. We will develop methods for a wide-range of emerging viral diseases. Novel molecular biology methods will allow us to sequence individual viruses within a patient. Bioinformatics tools will be developed simple enough for non-bioinformaticians to use, without reliance on Internet connectivity. We will develop software to integrate these data and associated epidemiological knowledge to reveal the processes of transmission, virus evolution and epidemiological linkage. Finally we will develop a web-based visualization platform where the outputs of the statistical analyses can be interrogated for epidemiological insights within days of samples being taken from patients.

Amount: £800,435
Funder: The Wellcome Trust
Recipient: University of Birmingham

Phase coding in the visual system: neuronal processing coordinated by brain oscillations 11 Jul 2017

The visual system receives a wealth of information of which only little is processed. My aim is to uncover the mechanisms involved in prioritizing information processing of visual scenes. To this end, I will test a novel hypothesis that explicitly predicts how brain oscillations serve to prioritize the flow of sensory information. The core idea is that neuronal oscillations serve to coordinate computations by organizing a temporal code. The theoretical framework predicts that alpha (8–13 Hz) oscillations support a ‘phase coding scheme’ in which a set of neuronal representations will activate sequentially within an alpha cycle. This mechanism serves to convert a complex visual scene into a temporal code: a ‘to-do list’ that can be processed sequentially by downstream regions. Spatial attention and saliency will determine the order in the list by differentially biasing the excitability of the individual representations. I will test this framework using intracranial recordings and magnetoencephalography (MEG) in combination with a new approach: ‘rapid frequency tagging’. Using a novel approach for visual entrainment of the alpha rhythm, I will test the model causally. The mechanism may generalize to brain networks beyond the visual system, thereby providing a general principle for neuronal coding and inter-regional communication.

Amount: £1,033,750
Funder: The Wellcome Trust
Recipient: University of Birmingham

Global regulators of antibiotic resistance in E. coli and Salmonella: understanding cross-talk and downstream resistance mechanisms 30 Sep 2018

Antimicrobial resistance is increasing with alarming speed. As a consequence, even simple surgeries may become impossible due to the risk of infection. As such, this represents a major health crisis. Antibiotic resistance arises because bacteria rapidly adapt to antibiotics in their environment. Adaptation can involve modifying gene expression patterns or acquisition of useful mutations. However, we do not have a complete picture of these pathways to resistance. In this project, we will study four transcriptional regulators that control the so called "multiple antibiotic resistance" response in E. coli and Salmonella. This response allows cells to combat antibiotics and is implicated in clinical levels of resistance. We will identify the key regulatory targets that provide resistance to antibiotics. In doing so, we will shed light on the underlying mechanisms of resistance. We will also determine how widely conserved these resistance mechanisms are and build a complete picture of regulation by understanding cross-talk between the regulators. Ultimately, by identifying new pathways to antibiotic resistance, this work will underpin the development of new treatments for bacterial infections.

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

Exploring the role of Gamma Delta T cell subsets in chronic liver and bowel inflammation 30 Sep 2018

Chronic inflammation in the liver/bowel accounts for a large proportion of inflammatory diseases and causes significant morbidity and mortality. Whilst chronic inflammation is thought to stem from immune hyperactivation and failure of immunosuppressive pathways, much of this research is based on conventional lymphocytes such as alphabeta T cells and B cells. Unconventional T cell subsets such as gammadelta T cells are thought to also have a role in effector responses and immune regulation. They are enriched in liver and bowel tissue and can be potent producers of inflammatory cytokines. We aim to explore the dysregulation of gammadelta T cell function in chronic inflammatory conditions and how it aligns with conventional adaptive responses and other unconventional T cells such as Mucosal Associated Invariant T cells (MAITs) and invariant Natural Killer T cells (iNKTS). Using in vitro functional assays and molecular immunophenotyping techniques we will determine the phenotype of unconventional T cells in normal and inflamed human liver/bowel samples. We will also use mouse inflammation models to study the response of these cells to inflammatory stimuli. These studies will unravel the role of unconventional T cells in chronic inflammatory responses and may identify potential therapeutic avenues for suppression of unconventional inflammatory responses.

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

Determining The Intrathymic Mechanisms That Instruct Regulatory T-cell Production For Control Of Organ Specific Autoimmunity 30 Sep 2018

T-cells recognise and mount an immune response against pathogens however responses against self-tissue can occur, causing tissue damage and disease. In the thymus (a unique organ of T-cell development and education) autoreactive T-cells are removed but this isn’t 100% efficient, meaning a sub-population of T-cells termed regulatory T-cells (Tregs) is required to prevent self-reactivity. Our understanding of Treg development is incomplete and has been further challenged by findings of high heterogeneity in the thymic Treg population i.e. a large population of mature vs de novo Tregs. Furthermore possible Treg development outside the thymus by the most recent thymic emigrants (RTEs) remains unexplored. To accurately assess Treg development we use a novel mouse model with fluorescent markers that identify both a) Treg vs. non-Treg, and b) age. Distinguishing a cells identity along with its age allows us to investigate new and old Tregs in the thymus as well as Treg RTEs in the periphery using techniques such as flow cytometry, microscopy and qPCR to characterise thymic and extrathymic developmental stages. This work will provide new insight into how Tregs which regulate discreet tissue sites are generated, offering valuable new information on an essential regulator of self-reactivity and disease.

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

Birmingham-Wellcome Translational Partnership 30 Sep 2018

The Birmingham-Wei/come 'Translational Insights Platform' will drive a tangible, measurable change in our innovation culture by enabling researchers with limited experience or capacity for translational activities to engage competitively in this area, while at the same time providing more opportunities to up-skill and support those who have already begun to engage with translation. The Platform will foster and utilise healthcare challenge insights from a broad range of stakeholders and experts - including clinicians and patients - and develop an integrated portfolio of complementary interventions to develop these further and deliver sustainable benefit on a broad scale. It will form a clear, valuable support point between basic research and credible investment cases for translational development, creating a critical stepping stone of skills and support to access and accelerate the translational escalator within Birmingham

Amount: £600,000
Funder: The Wellcome Trust
Recipient: University of Birmingham

Investigating phosphatidylinositol phosphates in antigen presentation 08 Nov 2017

Presentation of exogenously acquired antigens to CD4+ T-cells by macrophages and dendritic cells is critical for generation of a robust adaptive immune response. These exogenous antigens are displayed on major histocompatibility complex class II (MHCII) molecules, providing molecular identification of captured pathogens. Antigens destined for presentation can be captured from the extracellular environment, or generated by degradation of phagocytosed pathogens. Phosphatidylinositol phosphates (PIPs) and their effector proteins are important for coordinating phagosome maturation and are a key virulence target of many intracellular pathogens. Despite their importance, the mechanisms by which PIPs and their effectors recruit the MHCII complex and initiate trafficking of the MHCII-peptide complex to the plasma membrane remain poorly understood. Using live fluorescence microscopy and manipulating dynamics and localisation of PIPs and their effectors, I aim to investigate the mechanisms of MHCII trafficking and how this can be subverted by pathogens. The main questions I will answer in this proposal are: What are the dynamics of MHCII recruitment to the phagosome and does this depend on specific PIPs and their effector proteins? Are PIP-mediated phagolysosomal tubules required for MHCII-peptide complex delivery to the plasma membrane? Is MHCII trafficking manipulated by pathogens to increase pathogen survival?

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Birmingham

Visualising human health and medicine throughout history using transformational make-up techniques. 26 Apr 2006

VISUALISING HUMAN HEALTH AND MEDICINE THROUGHOUT HISTORY USING TRANSFORMATIONAL MAKE-UP TECHNIQUES 1. The Centre for the History of Medicine is currently expanding its outreach work with a new project. The main aim is to bring the history of medicine to life through the medium of 'special effects' make-up. In this way audiences can explore and assume the physical and emotional characteristics associated with trauma and disease. This particular approach very literally animates and demonstrates the characteristics surrounding disease and health while providing participants with the chance to interpret and visualise the effects of a particular ailment using a combination of both artistic and scientific skills using a three-dimensional approach. In this way injuries, for example war wounds, and diseases such as smallpox and scarlet fever, will be realistically represented and each subject grounded in its appropriate medical-historical context. 2. The above method will be delivered in a series of practical demonstration sessions in schools, FE and sixth form colleges, museums and galleries, with supporting exercises and worksheets written on agreed topics. The project hopes to bring to teachers, pupils, parents and the wider community a better understanding of medical history for those with little or no knowledge of the subject. 3. By using this technique as the means of communicating health, disease and society, a variety of processes are used in the craft of special effects make-up, including knowledge of a number of affiliated subjects, including anatomy, chemistry, sculpture and history of art. 4. The principal applicant is trained to the standards of the International Health and Beauty Council of Great Britain, holds a BA in the History of Art and Design and is currently studying for an MPhil degree undertaking research into the toxicology of cosmetics and body ornamentation in the ancient world for which the applicant holds a Centre Bursary.

Amount: £7,005
Funder: The Wellcome Trust
Recipient: University of Birmingham

Left anterior negativities (LANs) as electro-encephalographic responses to the processing of morphologically complex words: rules or storage? 04 Jul 2006

This project investigates the nature of a language-related EEG effect, i.e. the left anterior negativity (LAN), focussing on its elicitation by misapplications of morphological rules during the visual processing of words. Previous studies have demonstrated a differential LAN for violations of morphological properties of irregular but not regular word forms. LANs have also been shown to be sensitive to violations of syntactic rules in sentences. In both cases, it has been argued that the LAN refl ects violations of rule-based procedures in language processing. A recent study, though, suggests that LANs elicited by morphological violations might be caused by a mismatch of the presented word with its stored representation in the mental lexicon instead of a misapplication of rules. The proposed project compares the effect of morphological, formal, and syntactic mismatches on the occurrence of LANs in German and English. Its primary aim is to provide a unified account of findings across a ra nge of languages and a clearer understanding of the functional source of LANs and possible sub-types. The results will clarify whether LANs provide diagnostic evidence for so-called rule and knowledge-based processes.

Amount: £156,070
Funder: The Wellcome Trust
Recipient: University of Birmingham

Mechanisms by which fibroblasts from different origins modify the transendothelial recruitment of T-cells and their retention in inflammed tissue. 07 Nov 2005

Our key goal is to show how the recruitment of T-lymphocytes through vascularendothelium and subsequent retention in tissue might be modifed by stromal cells, particularly synovial fibroblasts from patients with rheumatoid arthritis. We suggest that there is a variable stromal 'postcode' whereby fibroblasts in different regions influence the development of inflammation by virtue of their patterns of gene expression, e.g., for chemokines and growth factors. This leads to the hypothesis that fibroblasts fulfill an important regulatory function which becomes modified in chronic inflammatory disorders, causing lack of control of the deposition of T-cells in tissue. We will use endothelial-fibroblast co-culture systems developed in Birmingham, to examine time courses of adhesion and migration of T-cell subsets on endothelial monolayers, and movement through sub-endothelial layers of fibroblasts. These models will incorporate delivery of T-cells from flow and stimulation with cytokines where appropriate. Fibroblasts from different sources will be compared. Based on variations in recruitment and retention ofT-cells, we will disect gene expression and production of cytokines and chemokines, to identify mediators of differential responses. We will test theroles of candidate mediators using blocking strategies. Thus, we aim to identify critical factors affecting 'resolution' of normal and disrupted inflammatory processes.

Amount: £199,177
Funder: The Wellcome Trust
Recipient: University of Birmingham

Meeting entitled "Written in Bone: The Use of History and Anthropology for Investigating Medicine, Disease and Biology in Past Societies. Session to be held at 8th annual BABAO meeting. 14 Dec 2005

Written in Bone: The Use of History and Anthropology for Investigating Medicine, Disease and Biology in Past Societies. Session to be held at 8th annual BABAO meeting. Combining data from anthropology and history may provide new insights into medical treatment, health, disease and the biology of past societies. When used in combination these two disciplines have the potential both to complement each other's strengths and compensate for each other's limitations. However, very anthropologists undertaking studies of human skeletal remains have made a conscious effort to integrate their results with evidence derived from written sources. Whilst the increased numbers of post medieval skeletons analysed in recent years has prompted some British anthropologists to consider the information that can be obtained from historical sources, these developments could be criticised for lacking focus and failing to have a common goal. Two speakers will be invited: Dr Piers Mitchell of Imperial College and Dr Ann Herring of McMaster University, Canada (both have agreed to speak in this session). Dr Mitchell is the most prominent British academic who has published widely on both medical and anthropological aspects of the history of medicine, and Dr Herring is a leading international scholar in these fields. The participation of both these speakers would attract significant interest in this session. Both speakers will be asked to present work on how anthropological and historical data have been combined to further research relating to the history of medicine. Abstracts for the other podium presentation and the linked poster session will be accepted on any topic within the broader remit outlined above, but preference will be given to papers dealing with aspects of the history of medicine, especially for podium presentations.

Amount: £1,035
Funder: The Wellcome Trust
Recipient: University of Birmingham

Vascular Adhesion protein-1 (VAP-1) and the development of inflammation in non-alcoholic steatohepatitis (NASH). 06 Dec 2007

Non-alcoholic steatohepatitis (NASH), a manifestation of the metabolic syndrome, is a leading cause of liver cirrhosis in the developed world. The adhesion molecule vascular adhesion protein-1 (VAP-1), which promotes lymphocyte recruitment to liver, is a semicarbazide sensitive amine oxidase (SSAO). ). VAP-1/SSAO deaminates primary amines resulting in the generation of aldehyde, ammonia and H2O2 which activate NFkB-dependent chemokine and adhesion molecule expression. Blockade of SSAO signific antly reduces lymphocyte trans-endothelial migration. A soluble form of VAP-1 is shed from liver endothelium and circulating levels are elevated in patients with alcoholic liver disease and diabetics with vascular disease and hyperlipidaemia. Thus VAP-1/SSAO might be implicated in hepatocyte steatosis and in amplifying NFkB-driven inflammation and leucocyte recruitment during the development of steatohepatitis. I propose that VAP-1 blockade will reduce oxidative stress, NFkB-driven inflammat ion and leucocyte recruitment in steatohepatitis. I will determine whether patients with NASH have increased serum VAP-1 and SSAO activity and if so whether this is associated with increased binding of leucocytes to liver endothelium in vitro. I will then use mouse models to investigate the role of VAP-1/SSAO in vivo. These studies may suggest novel therapeutic strategies for the treatment of NAFLD.

Amount: £229,729
Funder: The Wellcome Trust
Recipient: University of Birmingham