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Recipients:
University College London
Currency:
GBP
Award Year:
2018

Results

The Future of Maternity Care: challenges and opportunities to achieve person-centred care in the NHS 18 Jun 2018

I propose to review up-to-date research and evidence regarding new developments in technology and health education that aim to improve maternity care in the UK, particularly through improving women’s access to information, services, and their own medical records. Parliamentarians will require a balanced and concise summary of the evidence behind these new technologies and a sense of how they will be received by the public and health professionals. Key goals: Assess the work that has come out of the National Maternity Review, particularly advances in e-health and mobile technology such as the Digital Maternity Toolset being developed by NHS Digital Look more generally at the opportunities for health education in maternal health Explore the possibility of learning from policy innovations in other health systems Engage with a range of stakeholders over the course of the project to assess how policy recommendations will be received and identify potential areas for improvement

Amount: £6,514
Funder: The Wellcome Trust
Recipient: University College London

Residues and remains: Anthropology of practices around pregnancy endings 23 Jul 2018

My research explores the practices around pregnancy endings and their remains, including acts of forgetting and remembering, and asks what do these reveal about the status of foetuses, women and mothers in contemporary England? Pregnancy endings provide opportunities to interrogate anthropological assumptions about the contemporary family, motherhood, personhood and kinship. To analyse this, I will focus on the practices in the aftermath of a pregnancy ending to understand what they reveal about the values afforded to the remains in different contexts (clinic, home, burial site, crematorium, grave site etc) and by different stakeholders. My research will explore how reactions to and practices around pregnancy endings and remains reflect wider cultural trends in the UK, particularly around motherhood as highly moralized and notions of foetal personhood. I ask how does grief (or the absence of it) intersect with the relationship of the materiality of the remains and the woman’s body. I will conduct in-depth, embedded and analytic ethnography at the Rose Hill Clinic, East Oxford and other sites. Key outputs include a monograph, 3-4 journal articles, and materials aimed at women/ couples (i.e. newspaper articles, information video, radio/ television), health professionals and relevant others (i.e funeral providers, support groups).

Amount: £388,698
Funder: The Wellcome Trust
Recipient: University College London

A Hotbed for Liver Cancer: Biomedicine, Exposure and Uncertainty in West Africa 23 Jan 2018

Incidence rates of primary liver cancer vary strikingly across the globe. West Africans are more likely than most populations to develop and die from it. Focusing on Senegal and The Gambia, my project investigates how this association between place and intensity of susceptibility to liver cancer has been understood, and how it has been maintained by gaps in protection from risky exposures and fatal illness. Its key goals are to: 1) Situate biomedical models of liver cancer aetiology and prevention in West Africa, by tracing the emergence of current biomedical knowledge and uncovering past and alternative explanations. 2) Delineate the past and emerging contours of partial, public prevention of exposure to major risks factors: chronic infection with Hepatitis B Virus and food contaminated by aflatoxin (toxic metabolites of fungi that colonize crops, notably groundnuts). 3) Observe the embodiment, materialization and enactment of liver cancer in local moral economies and infrastructures of care, and identify the dilemmas that arise. Combining historical and ethnographic methods, this project aims to elucidate how endemic exposures and intrinsic limits of care have been mutually shaped, in West Africa, by contingent political, economic and scientific histories of partial protection.

Amount: £301,612
Funder: The Wellcome Trust
Recipient: University College London

Technologies of Health c. 1450-1750 23 Jan 2018

This project investigates the production, use and impact of everyday health technologies in Britain and the global world c. 1450-1750. It explores a wide range of objects from Issac Newton's drawing of an ear trumpet to birthing chairs to patient records. Using a series of detailed case studies, it seeks to understand how technologies crucially influenced past sickness experiences, medical encounters and healthcare provisions and contemporary attitudes towards materials, skills and tools. The focus on the quotidian and, particularly, on how users adopted and modified technologies, will offer a view of medicine from the ground up, highlighting the dynamic relationship between patient and practitioner, user and maker and expert and lay. In doing so, it will revise existing narratives of early modern medical practice, answering calls to foster closer connections between histories of science, medicine and technology. Recognising the importance of colonial and commercial forces, it will also interrogate the relationship between expanding empires and ‘local’ ideas about health and the body. It will produce two main outputs - a monograph titled 'Technologies of Health in Early Modern Britain' and an edited volume of essays accompanied by a project website with a blog and a virtual exhibition of 'object studies'.

Amount: £258,969
Funder: The Wellcome Trust
Recipient: University College London

Politics, medical knowledge and development: from Israel to Ethiopia and Eritrea (and back) 07 Mar 2018

This project will critically study how the circulation of medical knowledge and practices of developing health programs between Israel, Ethiopia and Eritrea, shape regional politics, immigration dynamics and racialization processes in Africa and the Middle East. Specifically, how political instrumentalisation of medical knowledge affects three interrelated dynamics: Constructing health development schemes that facilitated an Israeli strategic foothold in Ethiopia. Establishing a strainer mechanism to sift through the Ethiopian Jews immigrating to Israel and legitimising the detention and potential incarceration of Eritrean asylum seekers upon their arrival to Israel's border with Egypt. The project's principal goals are: 1. Conducting exploratory research into the medical interactions between Israel, Ethiopia, and Eritrea. 2. Developing a research platform including an advisory board, research workshop, a panel in an international conference, and a digital archive. 3. Consolidating an academic network for an intellectual community of leading scholars and early career researchers examining the politics of medical development in the Middle East and Africa. 4. Constructing a platform and network as the first phase of research exploring the political legacies of medical development and health aid in the Global South.

Amount: £29,330
Funder: The Wellcome Trust
Recipient: University College London

Politics, Philosophy and Economics of Health 30 Jun 2018

This project will examine benefits sharing for the provision of genetic information in the creation of medical treatments for infectious diseases. Networks to enable the international sharing of genetic material are a cornerstone of pandemic preparedness initiatives. Countries with the highest disease burdens share their isolated virus strains, that are utilised by pharmaceutical companies to create patented therapies, typically inaccessible to the citizens of the country from which they originated. The inequity of such a system is clear. In response to Indonesia’s 2006 protest, the Pandemic Influenza Preparedness Framework (PIP) was developed to facilitate benefits sharing. Uniquely, this framework set a standard of practice for governments, academics, and the private sector, and enabled it to be enforced through the use of civil contractual legislation. However, recent scientific and technological advancements, such as gene sequencing data (GSD), may serve to diminish the framework’s capacity to promote global health justice. Through an evaluation of the effectiveness and equity of current policy, this research attempts to highlight areas of tensions that arise in light of recent innovation. If left unaddressed, these new gaps could impede the goal of fairness that these policies set out to achieve, directly impacting the health of individuals globally.

Amount: £27,140
Funder: The Wellcome Trust
Recipient: University College London

Does ROCK-dependant actomyosin activity kick-start nuclear descent during inter-kinetic nuclear migration in the mammalian neuroepithelium? 31 May 2018

In the posterior neuropore (PNP), actomyosin-driven apical constriction reduces the apical surface area of neuroepithelial cells, aiding neural fold apposition. This constriction is superimposed on changes in apical dimensions due to interkinetic nuclear migration (IKNM). Regional IKNM regulation is believed to alter PNP architecture, but the degree to which IKNM is linked to force generating apical constriction is unknown. The host lab recently showed that inhibiting the actomyosin-regulating Rho-associated protein kinase (ROCK) produces an atypical bimodal distribution of apical dimensions. This, alongside heterogeneous phospho-myosin light chain (pMLC)II staining, suggests only a subset of neuroepithelial cells are actively constricting at any one time. We hypothesise: ROCK-dependent active apical constriction at the end of mitosis initiates neuroepithelial nuclear descent in IKNM. To address this, I will use CD1 mouse embryos to: Compare apical dimensions and pMLCII immunofluorescent staining of neuroepithelial cells in M phase, G1, and intervening phases by confocal microscopy. Establish the time course of apical area changes and pMLCII staining following ROCK inhibitor treatment. Determine if apical area changes induced by ROCK inhibition is cell cycle phase dependent. Produce descriptive 3D in silico models of nuclear movements and apical dimensions for neuroepithelial cells with/without ROCK inhibition from confocal images.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Investigating notch signalling in patient-derived models of familial Alzheimer's Disease. 31 May 2018

Alzheimer's Disease (AD) is characterised pathologically by extracellular plaques composed of Abeta peptides, which are generated by the successive proteolytic processing of the amyloid precursor protein (APP) by multiple enzymes including the gamma-secretase complex. Human genetics supports a causative role for Abeta in AD: mutations and gene duplications in APP cause familial AD. Further, mutations in PSEN, which forms part of the gamma-secretase complex, are also causative of fAD. However, substantial clinical heterogeneity exists in fAD patients with PSEN1 mutations, the molecular basis of which is not well understood. Our hypothesis is that differential processing of non-APP substrates of gamma secretase may contribute to neurodegeneration in fAD. The aim of this project is to investigate the processing of non-APP substrates of gamma-secretase in fAD, using induced pluripotent stem cell-derived neurons from 7 fAD patients with mutations in APP and PSEN1 and age/sex matched controls. Specifically, we will use western blot to analyse the notch pathway in fAD and control lines and understand if this pathway is dysregulated in AD. This project will allow us to determine if the processing of non-APP substrates of gamma secretase is altered in fAD patient cell models, forming the basis for further mechanistic studies.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Evaluating the Co-Inheritance of Alpha-Thalassemia and Sickle Cell Anaemia and its Impact on Haematological Indices 31 May 2018

Sickle Cell Anaemia (SCA), the most severe and most common form of sickle cell disease, is a major public health problem in sub-Saharan Africa. Homozygosity for sickle haemoglobin (HbSS) causes SCA but the clinical phenotype is variable in severity. Alpha-thalassemia, caused by deletions in the alpha-globin genes, co-exists at very high frequencies in the same sub-Saharan African regions as the sickle cell trait (HbAS). Nigeria has the highest burden of SCA globally but there is limited information on the co-inheritance of SCA and alpha-thalassemia in Nigerians and reports from other sub-Saharan African countries have given differing results. Ethnic diversity in Nigeria necessitates ascertainment of information from different geographic regions. While personalised medicine is not realistic in sub-Saharan Africa at present, it is important to obtain information on variation, relevant for healthcare provision at the community level. This study aims to investigate the relationship between the alpha-globin gene deletions (3.7kb and 4.2kb) and haematological indices in SCA patients and controls from Abuja.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

The role of the Trem2 R47H mutation in the development of Alzheimer disease phenotypes in APP knock-in mice 31 May 2018

The field of research into Alzheimer’s disease is lacking a transgenic mouse model which shows progressive degeneration like in humans. Recently, there has been increased interest in the involvement of the immune system of the central nervous system, particularly microglia, which co-localise with amyloid-beta plaques, potentially limiting toxicity. TREM2 is a protein expressed by microglia and the R47H mutation is an identified risk-factor for Alzheimer’s disease. We propose that combining this microglial risk-factor with raising amyloid beta in APP knock-in mice may exacerbate the Alzheimer's phenotype, potentially leading to tau pathology. Initially I will be taught to perform whole-cell voltage-clamp in brain slices. I will then use a novel TREM2(R47H) knock-in mouse and examine variables previously reported as altered in transgenic APP/PSEN1 mice (and confirmed in APP knock-in mice, unpublished). In particular I will record spontaneous and miniature excitatory postsynaptic currents, the frequency of which is dependent on the probability of glutamate release and number of synapses; the amplitude dependant on the number of postsynaptic receptors. These experiments will help to elucidate the effects of microglia in early synaptic changes involved in AD and will provide initial characterisation of the TREM2 mice that will be crossed with APP knock-in mice.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Local cAMP regulation of the slow after-hyperpolarization 31 May 2018

The slow afterhyperpolarization (sAHP) occurs following trains of action potentials, and it plays a crucial role in regulating neuronal excitability. It determines the timing of action potential firing, thereby modulating neuronal processes including synaptic plasticity. The sAHP has important implications for disease, since elevated neuronal activity is associated with neurological disorders including epilepsy. Currently, little is know of how the sAHP is regulated at the molecular level. The aim of this research project is to investigate at the molecular level how the second messenger cyclic AMP suppresses the sAHP. This summer project will use a combination of molecular biology and electrophysiology to investigate sAHPs in hippocampal CA1 pyramidal neurons in rat brain slices. Two specific aims will be pursued. First, an anchoring disruptor peptide will be applied to determine whether anchoring of cAMP-dependent protein kinase (PKA) is required for sAHP suppression. Second, we will utilise novel tools for manipulating the phosphorylation state of PKA regulatory subunits to investigate the hypothesis that PKA regulatory subunit phosphorylation supports sAHP suppression by PKA. This approach has the potential to reveal important molecular features of an important physiological process with implications for neurological disorders.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Inhibitory Mechanisms Of Homeostatic Plasticity In Vivo 17 Jul 2018

Homeostatic plasticity is the compensatory mechanisms that regulate activity levels in the brain during ongoing changes, for example following learning or input loss. To date, homeostatic plasticity studies have largely focused on changes in excitatory neurons; however, inhibitory neurons also play an important role in regulating overall network activity. Given the known connectivity of excitatory and inhibitory neurons in mouse visual cortex, changing activity in different inhibitory subtypes would have drastically different effects on network activity, but the role of specific inhibitory subtypes in homeostatic plasticity is unclear. We will use in vivo two-photon imaging in behaving adult mice expressing genetically encoded calcium indicators to measure the activity levels of inhibitory subtypes during the homeostatic recovery of activity that follows the loss of sensory input to the visual cortex. We will then use optogenetic tools to change activity levels in these inhibitory subtypes, to determine: 1) their causal role in the maintenance of activity after homeostatic activity recovery, and 2) their interactions with homeostatic plasticity mechanisms that facilitate homeostatic recovery. These experiments will identify which inhibitory subtypes are critical for homeostatic plasticity.

Amount: £1,566,641
Funder: The Wellcome Trust
Recipient: University College London

NMR structural studies of protein folding during biosynthesis on the ribosome 30 Sep 2018

Proteins must fold into their tertiary structure in order to function. This complex process has been well studied over recent decades. However, most of these studies rely on small isolated proteins; protein folding inside of cells can be very different. In cells during translation, the ribosome synthesises proteins by adding amino acids to the growing polypeptide chain, this eventually extends out of the ribosome tunnel and can can begin to fold while still being synthesised; representing a major difference between historical folding studies and the real picture inside cells. In our lab we aim to characterise the process of protein folding on the ribosome. We are especially interested in how the ribosome may aid proteins to fold efficiently. To do this we use Nuclear Magnetic Resonance (NMR) spectroscopy to generate structural information of proteins attached to ribosomes alongside Cryo Electron Microscopy and Molecular dynamics computer simulations. This PhD project will aim to fully characterise the structure and dynamics of a nascent chain attached to the ribosome using a variety of NMR experiments. We will then analyse a variety of proteins to try and understand why they fold at different points during translation.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Dynamics of Inhibitory Golgi Interneurons in the Cerebellar Cortex 30 Sep 2018

Neural circuits in the brain underlie sensory perception and motor control, functions that are often impaired during neurological disorders. However, many aspects of circuit function remain unclear. These include how sensory and motor information is represented and transformed as it flows through neural circuits. In this project, I will study the properties of Golgi cells, a particular type of inhibitory neuron in the cerebellar cortex, a brain area that helps coordinate movements and predict thier sensory consequences. To do this I will use a new high speed 3-dimensional microscope technology that can measure signals as they rapidly flow through complex neural circuits deep within the brain of mice expressing fluorescence reporters of neural activity. By examining how the activity of populations of inhibitory neurons change during different behavioral tasks and during learning, I will determine how these neurons contribute to information processing in the cerebellum. By combining this imaging method with methods for manipulating neuronal activity and network models of circuit function I will identify the underlying mechanisms. This research will lead to fundamental new insights into cerebellar function and will provide a framework for understanding what goes wrong during neurological disorders.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Impact of catastrophic genomic events on immune responses in oesophageal cancer 31 May 2018

Genomic instability triggers catastrophic events that restructure parts of the genome and provide a proliferative advantage to the cancer cell (e.g. through oncogene amplification) in up to 30% of cancers. There is recent evidence that suggests these types of events may also impact immune responses, by affecting genes that are involved in the interaction between cancer cells and their microenvironment. This project aims to study the impact of two well defined catastrophic events, chromothripsis (massive chromosome-wide rearrangements) and kataegis (hypermutated regions), on genes involved in immune-related pathways in oesophageal adenocarcinoma. The student will work with whole-genome sequencing data from 120 samples of oesophageal tumours available from the International Cancer Genome Consortium and will employ bioinformatics approaches to address the following key goals: (1) identify chromothripsis and kataegis events using computational protocols previously established in the group; (2) identify the genes affected by these events via genomic overlap methods; (3) summarise the proportion of the genes affected that are involved in immune signalling pathways (as recorded in relevant pathway databases). This will enable us to assess the likely impact of such catastrophic events on immune system processes and further clarify their implication in immune evasion during cancer development.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Developing novel gene therapy technology for treatment of glycine encephalopathy 15 Sep 2018

"Glycine encephalopathy, also known as non-ketotic hyperglycinaemia (NKH), is a life limiting inherited neuro-metabolic disease which presents soon after birth and leads to severe neurological outcomes including epilepsy and profound developmental delay. Current treatments for NKH are neither effective long-term, nor curative. Glycine encephalopathy is characterized by accumulation of glycine and is known to result from mutation of genes that encode the glycine cleavage system so that glycine cannot be broken down. The majority of affected children carry mutations in GLDC, encoding glycine decarboxylase. In this project we aim to develop gene therapy for glycine encephalopathy to restore GLDC function in the liver using lentiviral vector to provide permanent delivery of the therapeutic sequence. In a glycine encephalopathy model we will test a novellentiviral vector that offers enhanced safety and performance. This will be a key step towards potential clinical implementation of this therapy

Amount: £365,837
Funder: The Wellcome Trust
Recipient: University College London

Mechanisms of progression to invasive lung cancer: a systems biology approach 30 Sep 2018

Lung cancer remains the leading cancer-related cause of death in the UK. Early detection and treatment are critical to improving outcomes. Our lab has collected a unique set of lung tissue samples from patients with pre-cancerous disease, some of whom have gone on to develop cancer. By studying the genetic and molecular profiles of these samples we aim to elucidate the mechanisms of progression from pre-cancerous disease to invasive cancer. By doing so we can identify future methods of treatment and prevention. My work focuses on analysis of vast quantities of data produced by this program. We have recently studied the genetics of these samples, including which genes are expressed, which are mutated, and how they are regulated. From these complex networks we identify key signals of instability in the genome, which we believe are driving progression to cancer. These data provide a snapshot of early cancer. The first aim of this project is to investigate the dynamics of this process using longitudinally collected samples, and new techniques which can probe these samples on a single-cell level. The second aim is to study the immunological mechanisms by which some pre-invasive lesions regress and do not become invasive cancer.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Principles of synapse-astrocyte networking in the brain 07 Jul 2018

Astrocytes are emerging as active contributors to the operation of synaptic circuits, in health and disease. Whilst important aspects of synapse-astroglia signalling are being revealed at a pace, the underlying principles are poorly understood. Whether this signal exchange system adapts to the changes associated with learning and memory remains an enigma. Building upon our recent findings and several methodological breakthroughs, the overall aim here is to establish the causality of cellular mechanisms engaging astroglia in brain circuit operation. We will focus on cortical circuitry, combining single-cell electrophysiology, two-photon excitation imaging and uncaging, time-resolved and super-resolution fluorescence microscopy, cell-targeted genetic optical sensors, in situ and in vivo, with high-end cell and network modelling. Firstly, we will establish rules that shape functional identities and co-operation among presynaptic sites carried by individual axonal circuits. Secondly, we will determine how these presynaptic identities are influenced by the astrocytes they trespass. Thirdly, we will find out how astroglial microenvironment contributes to use-dependent local circuit remodelling. Fourthly, we will unravel basic principles of functional micro-compartmentalisation and signal integration in astrocytes. Finally, we will explore models of astrocytes and neuron-astroglia networks, to reveal theoretical principles upon which astroglia can influence information handling by brain circuits.

Amount: £2,737,900
Funder: The Wellcome Trust
Recipient: University College London

Irritability, Reward Processing and Adolescent Depression 30 Sep 2018

Depression is a common mental health problem and a leading cause of disability. Rates of depression increase throughout adolescence, with most adult disorders beginning during this time. Despite this, we do not fully understand why depression increases during adolescence or why some people are more vulnerable than others. Depressed adults show changes in processing of reward related information, which potentially contribute to their risk of depression. Children who are more irritable (i.e. more prone to anger in response to frustration e.g. omission of an expected reward) are more likely to develop depression when older. Such children also show changes in processing of reward. Adolescence is a time of significant social, emotional and cognitive development both biologically and environmentally. I hypothesise that irritability in childhood is a consequence of differences in reward processing that lead to depression in adolescence in the context of the developmental and environmental changes. This study aims to investigate these relationships by looking at childhood irritability, reward processing and depressive symptoms. Depression has a complex multi-factorial aetiology; studying childhood risks for depression will improve our understanding of the mechanisms underlying depression, allowing development of more targeted interventions and preventive strategies.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Influence of language on emotion regulation in adolescence: links with mental health 31 May 2018

Evidence from a number of epidemiological and clinical research studies have demonstrated a robust link between child language and later social, emotional, and mental health (SEMH), which impacts children’s educational experience and increases the risk of poor mental health in adulthood. An effective intervention strategy requires an understanding of the mechanisms that underpin the link between child language and later SEMH, which remain unclear. The proposed research will investigate the hypothesis that the ability to regulate emotional responses mediates the link between language ability and later SEMH in late adolescence (ages 18-21). The proposal’s key goals are 1. To determine the influence of language ability on temporal distancing success, 2. To identify cross-sectional developmental differences in temporal distancing success, and 3. To evaluate the test-retest reliability of the temporal distancing experimental paradigm. Finding a significant association between language ability and emotion regulation success would identify emotion regulation behaviours as the more proximal target for intervention strategies for SEMH concerns in adolescence. The temporal distancing paradigm has yet to be evaluated in a test-retest comparison, and reliability estimates will advance understanding of the developmental relationships in emotion regulation. Keywords: mental health; language disorder; adolescence; emotion regulation; temporal distancing

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London