- Total grants
- Total funders
- Total recipients
- Earliest award date
- 25 Oct 2005
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Toxic DNA: a model for all domains of life 17 Jul 2018
The instructions for life are encoded by DNA. As such, it is counter intuitive that certain DNA sequences can be intrinsically toxic to the cell. The problem is acute for DNA where the frequency of adenine and thymine exceeds what is normal for a given organism. Toxic effects of such AT-rich DNA have been reported for species as diverse as E. coli and humans. Working with bacteria, I have shown that misdirection of transcription is closely linked to the toxicity of AT-rich DNA. This happens because promoters, the DNA sequences that instigate transcription, are also AT-rich. Since promoters from all cell types have a high AT-content, I argue this may be a universal phenomenon. If true, the implications are far reaching; AT-rich DNA impacts processes as diverse as antibiotic resistance in bacteria and cancer in humans. My application probes the mechanistic details underlying the toxicity of AT-rich DNA for both prokaryotic and eukaryotic cell types. Hypothesis: The toxicity of AT-rich DNA is a consequence of spurious transcription Aim 1. Understand molecular basis Aim 2. Understand toxic mechanisms Aim 3. Understand evolutionary prevalence
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.
Identification of essential Klebsiella pneumoniae genes required for survival within urine and adherence to urinary catheters 30 Sep 2018
Urinary tract infections (UTIs) are considered to be the most common bacterial infection, affecting 150 million people annually worldwide1. UTIs are becoming increasingly difficult to treat due to the widespread emergence of bacterial antibiotic resistance mechanisms. The bacterium Klebsiella pneumoniae is the second most common causative agent of hospital-acquired UTIs and is particularly prevalent within patients fitted with a urinary catheter. To successfully cause UTIs, bacteria must be able to survive and replicate within urine. The genetic factors which regulate urine metabolism by bacterial pathogens are largely unknown. Specific genes encoded by K. pneumoniae are essential for replication in urine and adherence to urinary catheters. Due to technological advancements in genome sequencing, several techniques have been developed to assay the essentiality of every gene within a microorganism. Essential genes represent favourable targets for therapeutic treatments of bacterial infections because the absence of these genes render the bacteria non-viable. Utilising one of these techniques, termed Transposon Directed Insertion Site Sequencing (TraDIS), we aim to identify essential genes encoded by K. pneumoniae for replication within urine and adherence to catheters. The identification of conditionally essential K. pneumoniae genes offers a strategy for elucidating novel antibacterial drug targets for therapeutic treatment.
Dissecting Androgen excess and metabolic dysfunction – an Integrated SYstems approach to PolyCystic Ovary Syndrome (DAISY-PCOS) 28 Nov 2017
Polycystic ovary syndrome (PCOS) affects 5-10% of all women; androgen excess is one of its major diagnostic features. While often perceived as a reproductive disorder, PCOS is now emerging as a lifelong, complex metabolic disorder, with increased risk of type 2 diabetes, hypertension, cardiovascular disease, and, as recently documented, non-alcoholic fatty liver disease (NAFLD). However, there has been no recent breakthrough regarding risk stratification or therapeutic intervention in PCOS. Our work has provided evidence for a key role of androgens in the development of PCOS-related metabolic complications. We will combine cutting edge in vivo physiology techniques, state-of-the-art metabolomics and machine learning-based computational approaches to address our overarching hypothesis that androgens are major drivers of metabolic risk in PCOS. We will use an integrated set of in vitro, ex vivo and in vivo experimental medicine studies to test this hypothesis and answer our specific questions: Does the control of androgen excess improve metabolic function? What is the role of different androgen pathways in conveying metabolic risk? Can we integrate phenome and metabolome data by machine learning to predict metabolic risk in PCOS? Our overall aim is the identification of novel personalized approaches and therapeutic targets for patients with PCOS.
PLVAP plays a critical role in mediating liver endothelial barrier function in the setting of chronic liver disease 31 May 2018
Chronic liver disease (CLD), irrespective of aetiology, follows a common pathway of persistent tissue injury leading to infiltration of immune cells into liver tissue which drives organ fibrosis. There are no medical therapies for end-stage fibrosis, and understanding novel regulatory pathways could lead to urgently needed therapeutic targets for CLD. One such regulatory pathway could be mediated by the interaction between lymphocytes and plasmalemma vesicle associated proteins (PLVAP) found on liver sinusoidal endothelial cells (LSEC). Our pilot data confirms that PLVAP is markedly upregulated within the sinusoids as well as sites of fibrosis during CLD. We hypothesise that PLVAP alters permeability of LSEC and mediates lymphocyte recruitment from the systemic circulation in CLD. Key goals will be to study the expression and regulation of PLVAP in human liver tissue and primary human LSEC. Flow adhesion assays and permeability studies will be utilised to elucidate the function of PLVAP in LSEC. These studies may identify PLVAP as potential therapeutic target for CLD.
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.
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.
The role of inflammation in the formation of multi-drug resistant lineages of Escherichia coli 30 Sep 2018
Multi-drug resistant (MDR) Escherichia coli and Klebsiella pneumoniae are the new superbugs of the 21st century. Strains of these bacteria are now commonly being isolated which are resistant to all front line clinical antibiotics, as well as last line compounds such as colistin. In the absence of new effective antibiotics we must find new ways of combatting such infections. Data generated by our lab suggests that the main genetic difference between MDR E. coli and normal harmless E. coli is the presence of signatures of natural evolutionary selection in genes involved in anaerobic metabolism, which are utilised by E. coli in an inflamed environment. We will test the hypothesis that the ability to better live in inflamed intestinal environments led to the formation of MDR strains of E. coli, which can outcompete other bacteria and set up long term infections. We will further test if this can be countered using simple anti-inflammatory measures.
The proposed research aims to examine the phosphorylation status of APC/C subunits in mitosis and G1 phase of the cell cycle through the use of retinal pigment epithelial (RPE-1) cells which have a diploid chromosome content and are a good model system for investigating APC/C function. Cells will be synchronised in mitosis through the use of spindle inhibitors, or synchronised in G1, following removal of spindle inhibitors. Cell cycle status will be validated by flow cytometry. Immunoprecipitation with APC/C subunit antibodies will then be performed to isolate the APC/C. APC/C phosphorylation status will be assessed by mass spectrometry. The primary aim of this project is to determine the phosphorylation status of APC7 in G1 and mitosis, as this has not been investigated in great detail before. Once we have identified APC7 phosphorylation sites, we will, through genetic manipulation, generate APC7 mutants that inhibit or mimic phosphorylation and investigate the effects of APC7 phosphorylation on cell cycle progression.
Periodontitis, inflammation of the gums and supporting structures of the teeth, is the most common chronic inflammatory disease of humans and has been linked to the development of diabetes and cardiovascular disease through co-morbid systemic inflammatory processes. The tissue damage surrounding the teeth is initiated by a microbial imbalance within the dental plaque biofilm, however is propagated by a dysfunctional host immune-inflammatory response to the bacterial biofilm. Peripheral blood neutrophils which dominate the immune response are both hyperactive and hyper-reactive with respect to Reactive Oxygen Species (ROS) release, with periodontal tissues showing extensive damage through oxidative stress due to this immune response. Metal-based compounds have been previously shown to modulate the level of ROS within cancer cells and are currently being developed and utilised as potent anticancer treatments. This project concerns the synthesis of novel metal-based compounds to reduce the level of oxidative stress within periodontal cells, treating and reducing the inflammation. This will be achieved through the synthesis of novel metal-based compounds as well as novel bidentate ligands incorporating elements of known anti-inflammatory treatments.
Towards a Single-Molecule Pharmacology of G-Protein-Coupled Receptors: Understanding Receptor Dynamics to Develop Innovative Drugs 17 Jul 2018
G-protein-coupled receptors (GPCRs) mediate the effects of several hormones and neurotransmitters and are major pharmacological targets. Despite recent advances, how GPCRs work in a cell to produce specific effects remains poorly understood. My group has developed an innovative single-molecule approach to investigate GPCRs in living cells with unprecedented spatiotemporal resolution. Using this approach, we recently succeeded for the first time in visualizing individual receptors and G-proteins as they interact and signal in living cells. We discovered that dynamic interactions among receptors, G-proteins and structural elements of the plasma membrane generate nanodomains where GPCRs produce highly localized signals ("hot spots"). We hypothesize that this organization is crucial for achieving efficient and specific signalling, its alterations might be implicated in diseases like heart failure, and might be exploited to modulate GPCR signalling beyond what is possible with current drugs. In this project, we will use beta-adrenergic receptors as a model and single-molecule microscopy to provide for the first time a detailed characterization of the key protein-protein and protein-lipid interaction involved in G-protein and beta-arrestin signalling, compare their nanoscale organization in cardiomyocytes under physiological and pathological conditions and, ultimately, exploit the new information to develop innovative therapeutic strategies for cardiovascular and metabolic diseases.
Dissecting the role of VAP-1 in innate immune cell responses in the establishment and progression of liver disease 30 Sep 2018
Liver disease is the third commonest cause of premature death in the UK and while recent advances in treatment of patients have shown promise, transplantation frequently remains the only treatment option for advanced disease (cirrhosis). This places a huge burden on health care systems worldwide, driven by the increasing frequency of liver injury due to alcohol or obesity. Our laboratories have shown that a molecule called Vascular Adhesion Protein-1 (VAP-1) contributes to the development of liver disease by reducing the function of the organ, and that the levels of VAP-1 in a blood sample can predict patient survival. Drugs that target VAP-1 have been developed and it is hoped that we can use therapies such as these to treat patients with not only liver disease, but also diseases in other organs and cancer. We propose to study how VAP-1 controls the migration of blood cells into and within the liver environment, using sophisticated models of liver disease and cutting-edge imaging and analysis techniques with donated human liver tissue. A better understanding of these processes will allow us to tailor drug treatment strategies for many patients and improve their chances of recovery from life-threatening illness.
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
Accelerated ageing as cause of disease pathogenesis, progression and multi-morbidity in Chronic Obstructive Pulmonary Disease 30 Sep 2018
Ageing is linked with defects in the immune system which contribute to many chronic inflammatory conditions. Chronic obstructive pulmonary disease (COPD) is a common, debilitating lung disease with limited treatment options and no known cure. It is the third leading cause of death globally, costing the UK £1B annually in disability. The causes of COPD are poorly understood, affecting smokers and non-smokers alike. Our data shows that immune cells (leukocytes) in patients with COPD make abnormal and injurious responses which damage the lung but also effect other organs in the body. As cells age they are removed and replaced with new functioning cells. Failure to remove these "senescent" cells is linked with age-related illnesses including diabetes and heart disease. Such conditions are common in patients with COPD. We hypothesize that damaging immune responses in COPD are caused by the accumulation of senescent leukocytes. We will examine the characteristics of blood leukocytes and test their ability to move into and within tissue. We will also determine the importance of specific regulatory pathways linked to leukocyte functions. Comparisons will be made between patients with COPD, cardiovascular disease or diabetes to test whether leukocyte senescence is a causative link for age-related inflammatory diseases.
The neurophysiology of the human cerebellum is almost unstudied because the main non-invasive recording methods (fMRI, fNIRS, EEG and MEG) are all unsuitable and there is no clinical therapy requiring sub-dural recordings. This technical gap has significantly limited our ability to understand its role in areas such as cognition (1). A timely opportunity has now arisen with the development of a new form of MEG sensor ("room temperature" optically pumped magnetometers, OPMs) that promises to overcome this barrier (2). The key goal of this seed award is to develop the use of OPMs to record electrophysiological signals from the human cerebellum, confirm the sources of these signals, and pilot methods to record during the learning of new motor and cognitive skills. The latter, in particular, will open up an entirely new research field, allowing us for the first time to study not only when the cerebellum engages in cognition but how it is trained and what training signals it responds to, and thus to also understand what it learns. This work will advance our understanding of cerebellar physiology, with impact on many cerebellar disorders (developmental and degeneration disorders; stroke, tumour resection, trauma, alcoholism etc.).
Elucidating the mechanisms of host cell gene expression control by human papillomavirus (HPV) 31 May 2018
The Parish lab has demonstrated that the cellular protein CCCTC-binding factor (CTCF) associates with several sites within HPV genomes. The known cellular functions of CTCF include transcription insulation, epigenetic boundary formation and genetic imprinting, but why CTCF is specifically recruited to HPV genomes has not yet been established. The association of CTCF with its cellular target sequences changes upon cellular differentiation and this affects gene expression. ChIP-Seq experiments performed in the lab show that HPV infection results in a rapid and stable re-distribution of CTCF throughout the host cell genome. In addition, gene expression array analysis of HPV negative and HPV positive cells shows that expression of many genes is altered upon HPV infection. For example, CTCF recruitment to the cellular L3MBTL4 locus is significantly reduced following HPV infection, corresponding to a dramatic decrease in the expression of L3MBTL4 transcript encoding a methyltransferase thought to be important for the methylation of histones. The alteration of L3MBTL4 expression in this manner allows HPV to dramatically alter the cellular environment to support viral persistence. We hypothesise that HPV infection deregulates CTCF-dependent control of specific loci to facilitate efficient life cycle completion and maintain persistent infection.
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?
Memory and language in synchrony: The role of theta oscillations in binding multisensory speech in memory. 24 Apr 2018
How does the brain process auditory and visual streams at a time to form multisensory memories of conversations? In real-life, speech is often audiovisual and brain oscillations are entrained in the theta band by tracking the syllabic structure conveyed at ~4Hz in both modalities (i.e. utterance and corresponding lip movements). Additionally, theta activity has been shown to be the most dominant oscillatory activity in the hippocampus and to support episodic memory formation. This proposal addresses multisensory speech and memory processes, which have rarely been studied together within an oscillatory framework. I aim to investigate the causal role of theta synchronisation between dynamic auditory and visual inputs on multisensory episode formation in the hippocampus, as it conveys the fundamental unit for speech perception. In a series of experiments, I will test the behavioural consequences of manipulating the theta phase synchrony between modalities, with a new memory task using natural speech episodes. I will combine this task with state-of-the-art electrophysiological recording techniques, i.e. Magneto-Encephalography (MEG), and single unit recording in the human hippocampus (intracranial Electro-Encephalography in epileptic patients). Lastly, I will implement the results in a recent theta-based speech model to test the effect of sensory input asynchrony on hippocampal networks.
Explaining and exploiting the spectrum of isocitrate dehydrogenase driver mutations in different tumour types 10 Apr 2018
Recently, there has been great interest in mutational processes in cancer. This project looks at the other side of the coin, namely important genetic changes in cancer that cannot be explained by mutational processes and hence probably result from natural selection. The driver oncogenes IDH1 and IDH2 are frequently mutated in several cancer types, including some with a very poor prognosis. The mutations cause de novo production of the "oncometabolite" D2HG. Pathogenic IDH1 and IDH2 mutations occur at specific amino acids, but the mutation spectrum varies strikingly across cancer types, independent of underlying mutational processes. Preliminary evidence suggests that different IDH mutations vary in their ability to produce D2HG and the most frequent mutations may not make the most D2HG. This project tests the model that tissues vary quantitatively in their D2HG production and/or detoxification and/or activation of oncogenic pathways in response to D2HG. We hypothesise that the most common IDH mutations in each tumour type are selected to produce the level of D2HG that best promotes tumorigenesis. We shall test whether some mutations actually produce too much D2HG for efficient tumour growth, opening up exciting new therapeutic opportunities based not on targeting mutant IDH, but on raising D2HG levels.