Cookies disclaimer

I agree Our site saves small pieces of text information (cookies) on your device in order to deliver better content and for statistical purposes. You can disable the usage of cookies by changing the settings of your browser. By browsing our website without changing the browser settings you grant us permission to store that information on your device.

Current Filters

Funders:
Paul Hamlyn Foundation
The Wellcome Trust
Essex Community Foundation
Recipients:
University College London

Results

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

Crafting Qualitative Health Research for the Future 04 Dec 2017

Healthcare environments across the globe are encountering new challenges as they respond to changing populations, global austerity, rapid technological advances, personalised medicine, and demands for more patient involvement. We believe that qualitative health research (QHR) can contribute to our understanding and responses to these challenges, and we have developed a proposal which aims to expand and improve the work of this field. This proposed work will be conducted through our UCL Qualitative Health Research Network (QHRN) and will include the following activities: 1) a networking and brainstorming event to create a forum for the critical analysis and improvement of QHR; 2) the fourth QHRN symposium, a two-day event with 200 delegates, 20 oral presentations and 40 posters; and 3) our quarterly seminar series, which showcases presentations from leading scholars in QHR. The main outputs generated through these events and activities will include: A position paper detailing recommendations for the improvement of QHR, publication of our proceedings from the symposium in a peer-reviewed journal, workshops and other training opportunities at the QHRN Symposium, the continuation of communication channels for members of the network (website, email listserv, and Twitter account), and dissemination of findings of QHR to patient organisations, practitioners and policymakers.

Amount: £29,198
Funder: The Wellcome Trust
Recipient: University College London

Global Health 50/50: Towards accountability for gender equality in global health 04 Dec 2017

We propose to establish Global Health 50/50, a new initiative seeking to advance action and accountability for gender-equality in global health. Gender is a key driver of power to exercise the right to health, including exposure to risks of poor health, health seeking behaviours, and access to quality health care. Gender inequalities continue to define and drive career pathways and opportunities for people working in global health organizations. While some progress has been made, major gaps and challenges remain. We seek to raise awareness of persistent inequality and identify pathways to change. We will establish a network of experts in gender and global health, working with an advisory body drawn from the realms of politics, development, management, advocacy, human rights, social justice. Global Health 50/50 will publish an annual report on the state of gender-related policies and practices of 150 major organizations working in the field of global health.

Amount: £29,764
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

Lost&Found: engaging with narratives of ageing 30 Nov 2017

no abstract available.

Amount: £123,300
Funder: The Wellcome Trust
Recipient: University College London

Mechanisms and Regulation of RNAP transcription 11 Jul 2017

This grant focuses on four lines of scientific enquiry converging on RNAP function Characterisation of the molecular mechanisms underlying RNA polymerase and basal factors that facilitate transcription initiation, elongation and termination by using multidisciplinary approaches in vivo and in vitro. This includes using bespoke transcription assays, structure elucidation and a global characterization of the occupancy and transcriptomes. Identification of novel gene-specific factors and characterization of the proteomes of transcription preinitiation- and elongation complexes in vivo. Identification and characterization of RNAP-associated proteinaceous- and RNA regulators. Characterisation of the structure and function of archaeal chromatin formed by A3 and 1647 histone variants. A biophysical characterization of protein-DNA interactions and a whole-genome view of histone occupancy. Focus on the impact of chromatin on RNAP as it progresses through the transcription cycle, and the role of elongation factors to overcome the inhibitory effect of chromatin. Characterisation of factors that modulate RNAP during virus-host interactions. Virus (RIP)- and host (TFS4)-encoded RNAP-binding factors function as global inhibitors of transcription and their mechanism is reminiscent of antibiotics. Using two virus libraries of we want to screen for novel RNAP-binding regulators and use them as molecular probes to dissect RNAP function.

Amount: £2,029,869
Funder: The Wellcome Trust
Recipient: University College London

Integrative structural biology of protein folding during biosynthesis on the ribosome 05 Apr 2017

Central to the activity of all living systems is the need for polypeptide chains to acquire their biologically-active structures and avoid the competing events of misfolding. It is well established that the majority of proteins begin to acquire structure as highly-dynamic nascent chains during biosynthesis on the cell’s protein biosynthesis machinery, the ribosome. A detailed molecular understanding of how this native structure is acquired and how misfolding is avoided during biosynthesis is sparse. We will build on our capacity to derive structural and dynamic mechanistic information of the fundamental process of co-translational folding: we will produce a multi-scalar analysis extending from in vitro to in vivo to provide a comprehensive, high-resolution description of emerging nascent chains (NC) during biosynthesis. Our research will integrate NMR and cryo-EM to answer emerging questions regarding the observation that the ribosome itself can modulate folding processes, and also act as a hub for the recruitment and co-ordination of auxiliary proteins that can assist NC folding and modification processes. Structure-based design, incorporating protein engineering and ribosome modification will dissect NC folding mechanisms and understand how misfolding is avoided. This underpins aims to reshape co-translational folding, targeting the ribosome and NC at the earliest stages of protein-biosynthesis.

Amount: £2,034,461
Funder: The Wellcome Trust
Recipient: University College London

Force Generation during Collective Chemotaxis in vivo 31 Jan 2017

Collective cell migration (CCM) plays an essential role in many developmental and physiological processes. However, much remains unknown about the mechanisms driving this CCM with a limited number of studies focusing on CCM, in absence of external cues, instead of the directional migration observed in vivo. Furthermore, studies have focused mainly on epithelial cells. Another issue relates to the forces involved in moving the cells as studies, to date, have produced contradictory results regarding whether leader or trailing cells generate propulsive forces. In this project, we will analyse the mechanical properties during the collective migration of Xenopus and zebrafish neural crest cells; a mesenchymal cell population which undergoes directional migration during development, giving rise to a range of cell types. Using traction force microscopy and FRET-tension sensors, we will identify which cells generate forces during CCM. Furthermore, we will address whether intercellular mechanocoupling is important for attaining coordination in CCM by measuring traction forces in cell cohorts with varying degrees of adhesion. Finally, we will elucidate the molecular mechanisms of CCM by disrupting proteins implicated in force generation and analysing the effect on generated forces. This study will thereby establish an understanding of the physical mechanisms driving CCM.

Amount: £14,399
Funder: The Wellcome Trust
Recipient: University College London

Investigating the role of RNA interference in retinal development and as an agent of degeneration 31 Jan 2017

Genetic diseases affecting the retina, are the leading cause of blindness in the developed world. Despite the wide knowledge of the genetic factors which result in retinal dystrophies, (more than 200 genes have been identified as playing a role) such conditions remain untreatable. In monogenic retinal dystrophies the age of onset of photoreceptor cell death and rate of sight loss varies, yet the pathogenic gene mutation is present throughout life. Why some cells die at a given point in time and others do not, is unknown. This project aims to investigate the role of endogenous micro RNAs (miRNA) in retinal development and the relationship between miRNA dysregulation and retinal dystrophy. Specific miRNAs will be inactivated using the CRISPR/Cas9 system and the effects on photoreceptor differentiation and optic cup lamination determined. Furthermore, retinal organoid cultures derived from Type I Usher (a syndromic retinopathy) patient induced-pluripotent stem cells (iPSC; derived by reprogramming skin fibroblasts), will be used to establish whether miRNA dysregulation is indicative of an early disease state and whether CRISPR/Cas9-based gene correction can return dysregulated miRNA levels to normal. Finally, the effects of delivering certain miRNAs to a mouse model of retinal dystrophy on early disease phenotype will be established.

Amount: £24,581
Funder: The Wellcome Trust
Recipient: University College London

Homeostatic gene networks in Drosophila models of epilepsy and dyskinesia 31 Jan 2017

Transcriptional and translation control in neurons is highly plastic, allowing firing frequency and synaptic output to be regulated with high temporal precision. Recent research has demonstrated that the complement of ion channels within a neuron can undergo homeostatic remodelling in response to altered neuronal excitability. However, the extent to which this occurs in neurological diseases is unknown, as are the alterations in ion channel expression that may buffer disease-linked mutations to the greatest degree. We aim to investigate these questions using the fruit fly, Drosophila melanogaster. Using homologous recombination, we will generate a novel knock-in fly model of Generalized Epilepsy and Paroxysmal Dyskinesia (GEPD). This disorder is caused by a gain-of-function mutation in the KCNMA1 BK potassium channel – the mammalian homologue of Drosophila slowpoke (slo). We will characterise changes in ion channel expression in GEPD slo knock-in flies through RNAseq, and using this data, perform a modifier screen to determine which alterations are compensatory or pathogenic. Genetic suppressors identified via this strategy will represent promising targets for future therapeutic interventions.

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

How do middle ear stem cells and the immune system interact in the pathogenesis of chronic otitis media? 30 Sep 2017

Chronic middle ear inflammation (otitis media) poses a significant global burden of disease in adults and children leading to permanent deafness. The middle ear mucosa maintains a well-ventilated middle ear but undergoes abnormal remodelling in disease. Similar to the adult upper airway, basal cells are hypothesised to be stem cells actively maintaining middle ear mucosa. Pathological remodelling via abnormal repair pathways may underlie chronic otitis media and studying these could help understand and treat the disease. Aim: To identify and characterise the stem cell population of the middle ear in health and how maintenance of middle ear mucosa is disrupted by the immune system leading to chronic inflammatory disease. Methods: Murine and human biopsies will be grown and characterised in vitro, in 3T3 co-culture, air-liquid interface and 3D spheroid models to study differentiation and proliferation mechanisms in health and confirm markers of stem cell and cell fate. These markers will be used to perform lineage tracing in mice in healthy mice and in crosses with Junbo mouse model of otitis media. Finally, the role of the immune system, specifically the aryl hydrocarbon receptor (AhR – responsible for detoxification of pollutants that are linked to otitis media) will be studied using AhR agonists/antagonists and Ahr deficient mice crossed with Junbo mice.

Amount: £309,724
Funder: The Wellcome Trust
Recipient: University College London

Genetic background effects in human iPSCs and iPSC-derived cell types 12 May 2017

Human induced pluripotent stem cells (iPSC) have emerged as a key model system to study the function of genetic variants, as they provide access to relevant cell types and developmental lineages through cellular differentiation. However, while it has been shown that the genetic background of the donor individual has an effect on molecular phenotypes measured from iPSCs, it is currently not known how much the genetic background influences studies that use iPSCs to model rare disease mutations, making interpretation of results challenging. In this project, I will use CRISPR-Cas9 technology to study specific rare disease mutations in different genetic backgrounds. Specifically, I will focus on loss-of-function mutations causing Kabuki syndrome, a disorder of the epigenetic machinery, and use patient-derived iPSCs together with engineered mutant and control lines to quantify the contribution of the genetic background on the transcriptome and epigenome of the iPSCs as well as neuronal precursor cells derived from them. This project will establish the value of using patient-derived iPSCs over generic iPSC lines with engineered mutations. This information is critical for the design of any subsequent studies in which iPSCs serve as the baseline, such as directed differentiation experiments and therapeutic targeting of the mutation.

Amount: £99,935
Funder: The Wellcome Trust
Recipient: University College London

Complex Urban Systems for Sustainability and Health (London Hub) 30 Sep 2018

The London Hub for Urban Health, Sustainability and Equity aims to be the world’s foremost transdisciplinary hub for research, training and pubic engagement on urban health. It is founded on two constituent projects – Complex Urban Systems for Sustainability and Health (CUSSH) and Pathways to Equitable Healthy Cities (PEHC) – and involves leading London-based institutions and their global network of collaborating institutions. The Hub’s principal objective is to integrate and coordinate research and stakeholder engagement that support evidence-based policies aimed at improving population health, health equity and environmental sustainability in cities around the world. The Hub, and its projects, will achieve this objective through comparative studies that involve participatory research and coproduction of knowledge among academic researchers, policy makers and practitioners, and civil society; developing models for prospective policy evaluation and applying these models to data from our partner cities; and training the next generation of research and policy leaders in urban health, while establishing the foundations for sustaining and expanding the Hub beyond the Wellcome funding period. The CUSSH project focuses on how to transform cities to address vital environmental and population health imperatives, and entails partnership with the cities of London, Beijing, Kisumu, Nairobi, Ningbo and Rennes.

Amount: £5,150,000
Funder: The Wellcome Trust
Recipient: University College London

Integrated interdisciplinary approaches to design new anti-bacterials with novel mechanisms of action to tackle antimicrobial resistance in Tuberculosis 30 Sep 2018

Tuberculosis (TB) remains a serious threat to global health. The World Health Organisation estimate that 10.4 million new cases were contracted in 2015, and that over 500,000 of those cases were resistant to at least one of the antibiotics currently used to treat this condition. The spread of such resistance is a serious concern and as a result there is a need for the development of new drugs to combat TB. Recent work has identified two classes of molecule which have promising anti-tubercular properties: tetrahydroisoquinolines and non-steroidal anti-inflammatory drugs. My project will focus on the development of new anti-bacterials from these classes of molecule while exploring the reasons behind their anti-tubercular properties. This will be achieved through a combination of chemistry and molecular microbiology, making use of both laboratory and computational techniques.

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

Co-evolution of tumour mutational and CD4 T-cell differentiation landscapes 30 Sep 2018

Lung cancer is the second most commonly diagnosed cancer in the UK and the greatest cause of cancer-related death. A type of this disease called non-small cell lung cancer (NSCLC) accounts for the majority (85%) of cases. T-lymphocyte cells (T-cells) of the immune system patrol the body and can recognise and destroy cancer cells by recognising mutated proteins (neoantigens) on them. Despite this, the majority of patients with advanced lung cancer die of the disease, indicating the ineffective function of the immune system. In particular, little is known about the role of a particular group of immune cells called T-helper cells that are thought to be important. In chronic infections where T-cells are constantly exposed to their targets, they become less responsive as younger cells are driven to turn into later ones more rapidly. As younger cells are lost, the body's ability to fight the infection reduces. In cancer, it is possible that mutations drive a similar problem. Using lung cancer specimens from patients on a clinical trial and animal models of cancer, we propose to study the question of whether and how mutations can paralyse the ability of T-helper cells to fight the disease.

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

Inhibition in the Periaqueductal Gray 30 Sep 2018

Deciding which action to take, such as whether to cross a busy road, is a critical survival skill. Making decisions requires integrating complex information and identifying the cellular mechanisms of this process is critical for understanding how the brain computes decisions. In this project will investigate neurons that control defensive decisions in mice and focus on inhibitory neurons in the midbrain Periaqueductal Grey (PAG), which have the ability to veto defensive behaviours.The first main goal of the project is to use electrophysiological and advanced molecular techniques, such as RNA sequencing and gene knock-down, to identify the genes and ion channels that control the firing of PAG inhibitory neurons. The second goal is to determine key regulators of the activity of these neurons, in particular neuromodulators and long-range synaptic connections from other brain areas, using techniques such as optogenetics in combination with behavioural assays that exploit the innate defensive behaviours of mice. The results of this work will reveal new the biophysical principles that drive firing in a key population controlling a critical behavioural decision, and provide an entry point for understanding how pathological states such as anxiety lead to maladaptive decisions.

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

Non-local computations in hippocampal circuits: neural mechanisms 17 Jul 2018

The overall goal of this proposal is to build a neural-level understanding of how non-local cortico-hippocampal communication mediates memory consolidation and spatial computations. The well-studied network of spatially modulated neurons in the hippocampus and associated regions provides the pre-eminent cellular-model of memory for events and places. However, the activity of these neurons mainly encodes local information, that is, the current configuration of an animal in its environment. Work conducted by us, and others, have identified transient reactivations of hippocampal neurons and cortical counterparts as a key mechanism supporting systems consolidation and spatial planning. These brief ‘non-local’ events provide a means by which remembered experiences can gradually update memory networks, equally they are theorised to support the calculations necessary for route planning. Our aims are: 1) to understand how hippocampus and cortex interacts during reactivations; 2) determine how reactivated information affects existing representations; 3) precisely define the spatial computations that guide navigation; 4) investigate how neuromodulation controls the occurrence of reactivations. To this end, our approach is to combine computational modelling, machine learning, and state-of-the-art experimental techniques. Developing a basic understanding of these processes opens the way to understand how they fail in disease and may ultimately deliver tremendous therapeutic benefits.

Amount: £1,670,136
Funder: The Wellcome Trust
Recipient: University College London

Investigating the energy homeostasis of cellular calcium signalling 31 May 2018

Cellular calcium signalling is a ubiquitous and fundamental mechanism driving many processes in cell physiology. However it carries a significant energetic cost: calcium that enters the cytosol must be removed or sequestered by ATPases. In this project we propose to explore the mechanisms involved in maintaining energetic homeostasis in the face of this energy demand. The transfer of calcium signals to mitochondria is thought to support energy production, as it upregulates the rate limiting enzymes of the TCA cycle, increasing the rate of ATP production, although extrusion of calcium from the mitochondria also carries an energetic cost. The recent development of new targeted fluorescent reporters allows detailed exploration of compartmental ATP generation, making these questions accessible. We will therefore use fluorescence microscopy and imaging of a novel mitochondrial targeted ATP reporter to measure changes in cytosolic and mitochondrial ATP in response to changes in cytosolic and/or mitochondrial calcium signals to address these fundamental questions in cell biology. It is important to understand the fundamental mechanisms of cellular energy homeostasis so that we can better understand how mitochondrial dysfunction, associated with many disease states, undermines the ability to match energy demand with energy production.

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

New methods to predict gene function in fission yeast 30 Sep 2018

Computational biology aims to answer some of biology’s most complex questions using computational and statistical methods. The field has successfully identified genes involved in disease and has helped to discover drugs for their treatment. My PhD research takes this approach to understand the processes by which we age. Aging is a complex disease — characterised by the progressive loss of function in an organism over time — with huge social and financial cost. Faced with an aging population, breakthroughs in this area are desperately needed. I am attempting to do this using data collected from experiments that measure the lifespan of yeast in different environmental conditions. Whilst we are only distantly related to yeast, it is a useful model of human aging as it shares many cellular processes, but lives for a fraction of the time. Ultimately, I aim to use these data to predict the genes that cause yeast to age. Whilst a handful of aging genes have been identified, more genes are likely to contribute. I use networks and machine learning approaches to make my predictions. Going forward, these will help to deepen our understanding of aging and aid the development of treatments to eventually cure this disease.

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