- 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
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.
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.
Sense and respond: Investigating molecular mechanisms regulating Cryptococcus neoformans Titan cell formation in response to bacterial triggers 06 Jun 2018
This fellowship investigates fungal-bacterial interaction in a major human fungal pathogen to test the hypothesis that conserved mechanisms of non-self surveillance trigger morphogenesis driving pathogenesis. During lung infection with the fungus Cryptococcus neoformans, small haploid yeast switch to large, highly polyploid Titan cells, markers of pathogenicity. I recently demonstrated that Titanisation is a regulated transition triggered by bacterial peptidoglycan. Peptidoglycan sensing by mammals and plants is well described, however mechanisms of peptidoglycan sensing in fungi remain unknown. My data contribute to growing evidence that peptidoglycan, a ubiquitous bacterial ligand, influences morphogenic transitions in fungi. In the environment, C. neoformans associates with bacteria that modulate fungal virulence. In patients, Titanisation occurs in the lung. Contrary to dogma that the lung is sterile, healthy lungs are colonized by gram-negative and gram-positive bacteria. My preliminary data suggest peptidoglycan subunits regulate two aspects of Titanisation: cell cycle (endo-reduplication leading to polyploidy) and cell size (switch from budding to isotropic growth). Here, I will dissect mechanisms underlying peptidoglycan-induced Titanisation, and suggest peptidoglycan acts via dual signaling pathways. This work will improve our understanding of cross-kingdom signaling modulating pathogenesis in a major human fungal pathogen.
The project will use a combination of empirical and philosophical methods to explore experiences of moral distress and its meaning in context. The primary aim of the project is to build a better understanding of what moral distress means in the UK nursing context, and the secondary aim is to consider how it might be both prevented and managed. These aims will be met by meeting a series of objectives: 1) To formulate a plausible conceptual definition of moral distress through critical review of the literature. 2) To explore nurses experiences of moral distress by carrying out semi-structured face-to-face interviews with UK nurses. 3) To conduct conceptual normative analysis of the meaning of, and appropriate response to moral distress, informed by the findings from objectives 1 and 2. 4) Develop recommendations for nursing practice based on enabling nurses to recognise and respond to moral distress. The overarching methodology will be drawn from 'reflexive balancing', in which the ethical analysis of how we ought to conceptualise and respond to moral distress is guided and supported by interdisciplinary engagement with empirical findings.
Identifying novel biologically relevant interactions between lymph node stroma and innate immune cells. 11 Sep 2015
Fibroblastic reticular cells (FRCs) reside in secondary lymphoid organs, where they strongly shape adaptive immunity. However, interactions with immunologically important macrophage and neutrophil populations are completely undescribed. I recently found the first evidence that FRCs directly induce monocyte differentiation, and that they attract macrophages then arrest their migration. Excitingly, I also found that FRCs express a gene signature highly relevant to macrophage and neutrophil influx and function, and that expression of key chemokines increases immediately (1h) after LPS exposure. As robust proof-of-principle, FRC depletion reduces macrophage numbers by 95% in lymph nodes. I therefore hypothesise that FRCs fundamentally regulate macrophages and neutrophils in secondary lymphoid organs. Robust demonstration that FRCs support the innate immune response will, I believe, be high impact if this project is developed. Goals: 1. To test FRC interactions with macrophages and neutrophils through co-culture and live cell imaging, developing relevant data that allows me to prove my abilities with innate immune cells. 2. To inhibit key factors produced by stroma, examining effects on macrophage and neutrophil migration, phenotype and function. 3. To use a targeted in vivo model of FRC depletion (FAP-DTR) to dissect FRC-mediated control of macrophages and neutrophil function.
Elucidating the role of early granuloma formation in dissemination during fungal infections in vivo. . 24 Apr 2015
Currently, over one billion fungal infections occur each year worldwide of which over two million develop into life-threatening invasive mycoses. At the same time, our current anti-fungal therapies are ineffective, expensive and show substantial side effects. As a result, up to 95% of patients with invasive fungal infections die. Several major fungal pathogens are known to induce the formation of granuloma tissue (e.g. Aspergillus, Cryptococcus, Histoplasma etc.). However, the function of th ese granulomas during fungal infections has not been studied to date. I propose to initiate a new line of research investigating the role of early granuloma formation during fungal infections using an in vivo zebrafish model. In particular, I propose to utilise this model in order to determine whether granuloma formation during fungal infection is protective (in trapping fungi) or damaging (in allowing persistence) to the host. This approach will provide information on the spatio-temporal pa tterns of granuloma formation and immune activation and how these correlate with disease dissemination. The data will be applied to explain the striking individual variability in susceptibility to and outcome of fungal infections.
(Pilot) Development grant for a multicentre, randomised trial to reduce surgical site infection following emergency gastrointestinal surgery 16 Nov 2015
SPECIFIC DEVELOPMENT GRANT OBJECTIVES:1. To produce a working, finalised trial protocol based on selected interventions that will act as the framework for acompetitive application in 2017 (to either the Joint Global Health Trials Scheme or equivalent available programme).2. To select clear interventions with local stakeholder engagement that are important, relevant and deliverable in low andmiddle income countries (LMICs).3. To develop individualised plans for implementation and quality assurance of the selected interventions.4. To create individualised plans for 30-day follow-up at each site, by developing a predicted plan including outpatient,mobile telephone and home visit assessments.5. To confirm our sample size calculation.6. To train and develop local surgical research skills capacity, enabling surgeon principle investigators to develop their ownresearch 'hub and spoke' networks.LONGTERM NETWORK OBJECTIVES: The broader objective of the collaborative is to develop a network that cancontinue deliver large, pragmatic gastrointestinal surgical trials across LMICs in the future. We envisage harmonising eachsite's administration so that trials can be delivered with increasing speed in the future. These trials will hopefully be largerand of increasing complexity, spanning a range of perioperative care issues that will reduce morbidity and mortality. Wealso aim to disseminate our NHS based 'hub and spoke' surgical network models to LMIC settings, developing lastingcultures of research skills. We will support and train local lead surgeons to lead their own networks.
Primary biliary cholangitis (PBC) is an autoimmune disease that strikes 1/1000 women over the age of 40. Autoimmune diseases are caused by the immune system mistakenly attacking the individual's own tissues. In the case of multiple sclerosis, immune cells enter and attack the brain, in type I diabetes they ultimately destroy the pancreas whereas in PBC they enter the liver where they cause irreparable tissue damage often resulting in organ failure. Drugs against PBC can delay progression but simply don't work in about 1/3 of those affected. Our research has revealed a way to "switch off" the immune cells that cause autoimmune diseases. We have shown that this works in diseases such as multiple sclerosis and Graves' disease. By designing drugs that will switch off the immune cells causing PBC, we aim to provide a therapeutic strategy that will greatly improve treatment of this condition.
University of Nottingham and University of Birmingham - Antimicrobials and Antimicrobial Resistance 30 Sep 2016
University of Nottingham and University of Birmingham - Antimicrobials and Antimicrobial Resistance
Investigating the cross-talk between hypoxia and autophagy in the Hepatitis B virus lifecycle 19 Nov 2015
Hepatitis B virus (HBV) is a global health problem that leads to progressive liver disease including cirrhosis and hepatocellular carcinoma. Despite the development of a vaccine and anti-viral drugs, 240 million people are persistently infected with HBV for which no curative therapies exist, highlighting the need for new therapies. Autophagy is a conserved cellular process where cytoplasmic macromolecules and unwanted organelles are degraded to maintain cellular homeostasis. HBV encoded proteins increase autophagosome biogenesis and autophagy has been suggested to play a role in HBV replication and envelopment, providing a new avenue for therapies. Autophagy-modulating treatments are currently under investigation in diverse human diseases, including neurodegeneration and cancer, so it is timely to study their impact on viral replication. Hypoxia stimulates autophagy as a pro-survival stress response and since HBV infection stabilizes hypoxia inducible transcription factors (HIFs), I will investigate the role of HIF-activated autophagy in HBV infection of human embryonic stem cell differentiated hepatocytes and hepatocyte-derived cell lines. Using an image based fluorescent autophagy reporter I will screen a library of autophagy-modulating compounds to identify the most potent and liver-specific molecules for anti-viral studies. Our goal is to identify hepatocyte-specific autophagy modifiers with anti-viral activity for treating chronic hepatitis B
There has been a surge of interest in long read sequencing, driven by recent advances in sequencing technology. Long reads have numerous advantages compared to traditional ‘NGS’ approaches because they are able to generate highly complete de novo genome assemblies. These are critical when creating an initial reference sequence for an organism. Long reads are also vital for resolving complex structural rearrangements within populations, as well as being critical in understanding the development and progression of cancer. However, whilst developments by long read sequencing platform vendors provide the underlying platform chemistry compatible with long read applications, there is a skills and knowledge gap for users wishing to use these methods on their own samples. We therefore propose to establish a technology development programme to serve a broad community of researchers interested in benefitting from these techniques. We will focus on three important areas: DNA extraction: evaluating DNA extraction methodologies for a diverse range of animal, plant and microbial samples for long read sequencing DNA library preparation: new methods and refined methods for generating sequencing libraries from high molecular weight DNA Automation of above steps: development of automation-friendly protocols for generation of ultra-long reads (up to and above 1 megabase)
Animals must quickly respond to changes in their environment and internal physiological states to increase their chances of survival. Neuropeptide pathways are essential for generating behavioural flexibility, and their dysregulation has been implicated in mental and psychiatric disorders, such as anxiety and depression. Despite their significance and widespread occurrence, little is known about how neuropeptides work in the brain to modulate adaptive behaviours. This project aims to investigate the role of neuropeptides in behavioural choices in the fruit fly Drosophila. Leukokinin (Lk) is a neuropeptide involved in feeding behaviour in Drosophila. My preliminary data suggests that Lk+ neurons play an important role in regulating fly reproductive behaviours, and might adjust behaviour according to feeding needs. Using powerful genetic tools available in Drosophila, we will dissect the Lk neural pathway involved in controlling fly courtship behaviours, and test whether Lk acts as a physiological gating point for promoting appropriate behavioural selection, i.e. foraging vs. mating. Taking advantage of a genetically tractable model system, this research offers a unique opportunity to uncover principles of action-selection that might be conserved among species. This knowledge will ultimately help us better understand the function of the brain in health and disease.
Behcet’s disease (BD) is a multisystem inflammatory disorder affecting the vasculature. Neutrophils are the most abundant leukocyte in the blood and is shown to directly influence that pathogenesis of BD. These cells circulate in the blood and infiltrate tissue at sites of inflammation as a result of chemotaxis gradients set up by the release of chemokines from the inflamed tissue. Neutrophils belong to the broad category of granulocytes and kill unwanted pathogens by the process of phagocytosis. Internalisation of the pathogen into a phagosome allows the neutrophil granules filled with toxic molecules to fuse with the phagosome killing the pathogen. Until recently it was identified there are different types of neutrophils. In this project I will be purifying low and normal density neutrophils taken from patients with BD, to be compared with results obtained from healthy, age and sex-matched individuals. Cells obtained will be used in migration studies to determine their response to the chemokine gradient. Moreover, receptors for the attracting molecules on the surface of the neutrophils will be analysed for expression levels. I hope to achieve results that can add to the understanding of neutrophils in BD and potentially in other conditions.
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.
Child health and welfare: enabling access to the Save the Children archive This two-year project focuses on cataloguing and preserving the extensive archive of Save the Children (1919-2002), held at the University of Birmingham. Health and welfare of children is the guiding principle of this charity, established by sisters Eglantyne Jebb and Dorothy Buxton. Its objects being to: preserve child life; relieve child distress; promote child welfare; improve the conditions of child life. Jebb’s ‘Children’s Charter’, drafted in 1922, would later evolve into the ‘Convention on the Rights of the Child’ as adopted by the UN General Assembly in 1989. The archive comprises 2,000 boxes including minutes, project reports and publications. Material documents the charity’s work in child health, nutrition and well-being both overseas and in the UK. The outcome of this project will be a fully searchable electronic catalogue. This will enable access and reveal the full research potential of this internationally significant collection. The project will establish an ongoing rolling programme to open up access to files once over 25 years old. Preservation activities are also included in this project, focusing on the repackaging of thousands of photographs and transparencies which provide visual support to the written record.
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.