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University College London

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Partnering for Equitable STEM Pathways for Youth from Minoritized Communities. 07 Nov 2016

Minoritized Youth, addresses fundamental equity issues in informal STEM learning (SL+ priority D, Equity, diversity and access to informal learning settings). The major goal of our Partnership is for practitioners and researchers, working with minoritized youth, to develop new understandings of how and under what conditions minoritized youth participate in Informal STEM Learning (ISL) over time and across settings, and how they may connect these experiences towards pathways into STEM. We will: 1) Develop new understandings of ISL pathways that are equitable and transformative for minoritized youth; 2) Co-develop high leverage practices and tools that support these equitable and transformative ISL pathways (and the agency youth need to path-make); and 3) Strengthen and increase professional capacity to broaden participation among youth from minoritized communities in STEM through ISL. Our work is grounded in longitudinal youth participatory ethnographies, surveys, and design-based implementation research methodologies. Our major goal responds to three challenges at the intersections of ISL research and practice in the US/UK: 1) lack of shared understanding of how minoritized youth perceive and experience ISL opportunities across the US/UK, and the practices and tools needed to support empowered movement through ISL; 2) limited shared understanding and evidence of core high-leverage practices that support minoritized youth in progressing within and across ISL, and 3) limited understanding of how ISL might be equitable and transformative for minoritized youth seeking to develop their own pathways into STEM. We focus on minoritized youth, ages 11-14, for whom there are wide and persistent gaps in representation in STEM, and for whom STEM careers and pursuits remain elusive. The project will be carried out by RPPs in 4 cities: London & Bristol, UK and Lansing, MI & Portland, OR, US, involving university researchers (Kings College, University College London, Michigan State University, Oregon State University) practitioners in science museums (@Bristol Science Centre, Brent Lodge Park Animal Centre, Impressions 5, OMSI) and community-based centers (STEMettes, Knowle West Media Centre, Boys & Girls Clubs of Lansing, and Girls, Inc.).

Amount: £621,873
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

Cellular and network mechanisms of hippocampal -prefrontal coordination during memory consolidation 09 Nov 2016

Consolidation of newly acquired memories takes place during sleep and involves the interaction of hippocampus and prefrontal cortex. The cellular mechanisms and synaptic pathways underlying this process are not fully understood but it has been hypothesized that synchronous hippocampal ripples and prefrontal cortex spindles mediate it. The present project proposes a multimodal approach to investigate these mechanisms in rodents. The first goal will be to dissect the fine-scale dynamics of memory reactivation in hippocampus and cortex during sleep after learning of a spatial memory task. This aim will be achieved with simultaneous large-scale recordings in both structures and advanced analysis of population activity. The second goal will be to unveil which anatomical regions and synaptic pathways are mediating this inter-regional synchronization. Simultaneous electrophysiological and functional magnetic resonance recordings will be performed in sleeping rats before and after the task and wide-brain activity will be assessed at times of high hippocampal-prefrontal synchrony. The last goal will be to causally verify the participation in inter-areal coordination and memory consolidation of the key synaptic pathway(s) pointed out in the previous stage. To achieve this, closed-loop optogenetic silencing of specific cellular populations would be performed at times of hippocampal-prefrontal synchrony during sleep memory consolidation.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

Molecular Control of Adhesion-Free Migration 09 Nov 2016

Many cells have the capacity of directed motion, which is essential for several physiological and pathological processes, including development, immune-response, and metastasis. During canonical, focal adhesion-based migration, actin dynamics are converted to traction force through integrin-based anchors to the substrate. However, integrins are dispensable for in vivo and 3D-confined migration of various cell types. Recently, an alternative migration mode was discovered, during which propulsion forces are generated through non-specific friction between the cell cortex and its substrate. However, nothing is known about the molecular mechanism underlying friction-driven migration. I will elucidate this process, first by performing a candidate-based screen and state-of-the-art microfabrication assays to identify the molecules responsible for generating friction. Next, I will create knock-out zebrafish lines to determine the in vivo relevance of friction-driven migration. Finally, I will study how cells transition between adhesive and adhesion-free migration, which is crucial e.g. during cancer progression. To identify the key processes underlying these transitions, I will perform live cell microscopy of friction-generating and adhesion molecules and integrate my findings into a mathematical model of cell migration. Ultimately, this project will shed light on a newly uncovered migration mode that is likely of fundamental importance for in vivo cell motility.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

Africa Health Research Institute (GBP record) 6 month partial award 30 Jun 2016

Our aim is to reduce the huge burden of HIV and TB in KwaZulu-Natal as a precursor to the eradication of these diseases. This will be facilitated by merging the population based research excellence of the Wellcome Trust (WT)-funded Africa Centre (AC), with the cutting edge laboratory science and experimental medicine approaches of the Howard Hughes Medical Institute (HHMI)- funded KwaZulu-Natal Institute for Research in TB and HIV (K-RITH) to create an exciting, interdisciplinary South African based research initiative. Our 5-year vision is to use basic science, systems biology, health systems and social science research to undertake fundamental discoveries into the susceptibility, transmission and cure of HIV and TB. Our specific questions are: 1. How can new HIV infections best be eliminated? 2. How can TB transmission be interrupted and how can drug-resistance be contained? 3. How can the health of pregnant women with HIV and their offspring be improved? 4. How can we improve the health-system delivery and population-level impact of HIV treatment and other chronic disease care? 5. How is health and wellbeing affected by migration, economic and other inequalities

Amount: £472,230
Funder: The Wellcome Trust
Recipient: University College London

Understanding cellular organisation: from archaea to eukaryotes 05 Jul 2016

We know surprisingly little about the basic logic, topology or origins of eukaryotic cell architecture even though such an understanding is fundamental to most biomedical research. Until recently, the proteins responsible for shaping eukaryotic cells (including Actin/Tubulin/coatamers/ESCRTIII) were thought to be unique to eukaryotes. This changed with the discovery of close homologues in TACK/Loki-family archaea. Despite the important part played by these proteins during eukaryogenesis, we know little about their functions in the context of archaea. To determine how these cytoskeletal systems with origins in archaea contributed to the emergence of internal compartments that define eukaryotes, our team will use metagenomic sampling and phylogenomics to trace their evolutionary history, and a combination of approaches, including live super-resolution microscopy and electron tomography to carry out a comparative analysis of their ultrastructure, dynamics and function in both archaea and eukaryotes. Ultimately, we expect this evolutionary cell biological analysis to make a start towards an understanding of archaeal cell biology, to reveal the likely path of eukaryogenesis, and to reveal underlying principles of eukaryotic cell biology that so far have eluded us. In doing so, we expect this fundamental research to have a signficant impact in the future on human health and disease.

Amount: £1,122,019
Funder: The Wellcome Trust
Recipient: University College London

TREAT-HD: targeting neurodegeneration in Huntington's disease 08 Dec 2015

Despite their immense public health burden, and after considerable investment in therapeutics research, the pathobiology of neurodegenerative diseases remains poorly understood and we lack treatments to prevent or slow their progression. Our vision is to provide a step-change in the understanding of mechanisms underlying neurodegeneration – and recovery – using Huntington’s Disease (HD) as a model. Our three key goals are to: further understanding of HD neuropathology and its response to gene-silencing treatment. We will exploit a unique opportunity to link with the first human trial of an antisense oligonucleotide (ASO) to reduce levels of huntingtin protein. develop a new generation of ASO treatments by targeting levels of the highly pathogenic exon 1 mutant huntingtin protein. determine the earliest potential time window for therapeutic intervention. We will study a novel cohort of young adult HD gene-carriers decades before expected symptom onset to characterise the earliest signs of disease-related brain changes and identify early functional impairment. By examining this model disease in patients, we will gain understanding of general pathological processes shared across protein-misfolding neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Consequently, this work has fundamental implications for the development of treatment strategies beyond HD to more prevalent neurodegenerative diseases.

Amount: £796,863
Funder: The Wellcome Trust
Recipient: University College London

Novel multichannel "SMART" neuroprobe - Enhancement 08 Apr 2016

Neuroscience is entering an exciting period when it will be possible to decipher the neural codes underlying perception and cognition. Novel genetic, molecular, physiological, optical and behavioural approaches will allow the monitoring of activity across ensembles of neurons in behaving rodents, and the manipulation of this activity in a temporally and spatially precise manner. For the first time we will establish causal links between patterns of neural activity and behaviour, and carry out decisive tests of both new and long-standing hypotheses about the computational properties of neural circuits. Members of the consortia seek to understand the patterns of neural activity underlying sensory, motor and cognitive representations, and the rules by which they are assembled. The core of the present proposal is the development and testing of a major stepchange in silicon-based electrode technology to rapidly accelerate the pace of this work by greatly increasing the simultaneous sampling of extracellular electrical signals within and across multiple brain regions.

Amount: £273,651
Funder: The Wellcome Trust
Recipient: University College London

Public health data science to investigate and improve migrant health. 25 May 2017

Migration is a defining political challenge of our time and a global health priority. Internationally there is a lack of epidemiological data on new migrants including the prevalence of high morbidity conditions and estimates of risk factors for disease. The overarching aim of this research is to generate evidence that will improve the health of migrants moving from low and middle-income to high-income countries. Key goals: Million migrant study: Create an electronic cohort that will establish the first national rates of age-specific morbidity and risk factors for disease in migrants. Migrant eCohort: Investigate the migrant exposome and how this changes over time since migration, using digital technologies (smart phones and apps) for data collection. Personalised public health intervention: Develop and test the feasibility of a tailored health advice website to improve migrant health. Outcomes: These studies will transform how we conduct digital cohorts in mobile populations and have wide application for efficient study design. The detailed epidemiological and health service data produced will provide the first national evidence of the health effects of rapid epidemiological transition as a result of UK migration, and a platform from which to carry out digitally enabled personalised public health interventions.

Amount: £1,164,786
Funder: The Wellcome Trust
Recipient: University College London

Analysis of cytomegalovirus pathogenesis in a human challenge system 30 Nov 2016

Our research has made major contributions to understanding the natural history and pathogenesis of human cytomegalovirus (HCMV) in allograft recipients. Critically, we have demonstrated that biomarkers can be applied to stratify patients most at risk of HCMV disease and thus inform clinical practice to reduce HCMV end-organ disease. This clinical approach of administration of antivirals to individuals with elevated viraemia above designated levels provides a unique opportunity to gain fundamental insight into disease processes in a human challenge model of HCMV infection. A multi-disciplinary consortium has been recruited to apply next generation DNA sequencing, molecular virology and functional immunological assays to identify virus and host cell determinants of disease susceptibility. Whole genome sequencing of virus in organ donors (live and cadaveric) and recipients will be used to track the source, replication kinetics and evolution of HCMV strains in seronegative and seropositive recipients. We will then define in vitro humoral, cell-mediated immunity and natural killer responses against HCMV that correlate with protective immunity against primary infection, reinfection and reactivation in these patient groups. This approach has the potential to provide unique insights into the natural history and pathogenesis of HCMV and identify innovative therapeutic approaches against it.

Amount: £2,669,767
Funder: The Wellcome Trust
Recipient: University College London

A cell culture model to find drugs that may be useful to treat dementia. 15 May 2017

I am an undergraduate Neuroscience Msci student studying at the University of Bristol. I am undergoing an industrial trainee year, with Alzheimer’s Research UK University College London drug discovery institute (AR-UK UCL DDI), as part of my course. The AR-UK UCL DDI is a newly established unit in UCL, with core funding from Alzheimer’s Research UK. Its goal is to discover new approaches and therapies for dementia, a core symptom of a number of important diseases ("neurodegenerative diseases" of the brain such as Alzheimer’s disease). With the increasing aging population these neurodegenerative diseases are becoming a huge individual, societal and economic problem. The AR-UK UCL DDI currently has 12 scientists and will increase to about 24, and is equipped to enable the scientific experiments and studies to be performed.My industrial trainee year with the AR-UK UCL DDI will allow me to experience neuroscience in the research setting with an opportunity to use techniques commonly used in the field. The placement will provide a very practical learning in a professional environment, challenging me both personally and academically. It will also expose me to the process of working towards developing new therapies. I will be able to develop my interpersonal skills alongside vital experience working in lab with experienced colleagues. I will take the confidence and skills built during the placement into my final year and in my future studies and career as I hope to do a PhD after my undergraduate course.Project details: Neurons are key cells of the brain. Synapses are the key points that neurons communicate to each other, and are thought to be the basis of learning and memory. In neurodegeneration the neurons and the synapses decrease in number and ability to function, leading to progressive memory loss, dementia and eventually, death. Therefore ways of protecting the neurons and synapses, and maintaining their function, could be useful therapeutic approaches. The project will involve growing neurons in a cell culture dish; it is possible to do this by obtaining the neurons from mouse brains. The neurons are able to form synapses in the culture dish, which mimic the synapses that would be naturally formed in the mouse brain. I will use these cultured neurons to develop ways of measuring the number of synapses. It will be possible to measure the number of synapses by using fluorescently tagged antibodies that bind specifically to neuronal proteins that localise to synapses, and then use microscopy to count the number of those synapses. Once I have set up this system, I will be able to add various small molecules (compounds) and drugs and identify any that are able to increase the number of the synapses. Such small molecules or drugs could be the starting point for developing new therapies for dementia.

Amount: £7,000
Funder: The Wellcome Trust
Recipient: University College London

Advancing Psychiatric Mapping Translated into Innovations for Care: PsyMaptic-A 05 Dec 2016

My current and previous Wellcome Trust Fellowships (Henry Wellcome, 2009-13; Henry Dale 2014- present) focus on important aetiological questions about psychotic disorders, using epidemiological data. Psychotic disorders are a debilitating set of mental health disorders, characterised by hallucinations, delusions and cognitive deficits. My research demonstrates that these disorders have a robust, replicable social aetiology, with higher incidence rates observed in young people,1–3 men,1–3 ethnic minorities2–7 and people exposed to greater social disadvantage.8–11 In my previous fellowship, I established the largest epidemiological study of first episode psychosis [FEP] in England since 1999, to demonstrate that these substantial mental health inequalities also exist in more rural populations (East Anglia)3,12; rates are over twice as high as expected,3,13 with deprived rural communities experiencing the highest psychosis incidence. This study has generated new Page 5 of 18 aetiological clues, for example by showing that people at "ultra-high risk" of psychosis are exposed to similar social and spatial markers of social disadvantage as FEP patients,14 implicating an aetiological role for social adversities prior to onset. I have also demonstrated that migrants face greatest FEP risk when immigrating in childhood,15 an important period of sociocognitive development. I am attempting to replicate this in my current Fellowship, in a larger longitudinal cohort using Swedish national register data. Using this data, I have already shown that refugees are at elevated psychosis risk compared with other migrants from the same region of origin,7 providing further insights into the possible social determinants of psychosis. Epidemiological data can also inform mental health service planning. In England, Early Intervention in Psychosis [EIP] services assess and treat people with suspected FEP, offering evidence-based multidisciplinary care to improve downstream clinical and social outcomes, shown to be highly costeffective.16 Unfortunately, original policy implementation guidance17 made no provision for the heterogeneity in incidence described above, with services commissioned on a uniform expectation of 15 new cases per 100,000 people-per-year. This was at least half the true incidence,1,3 and over three times lower than the overall referral rate for all suspected FEP, including "false positive" (nonFEP) referrals,3 who still require appropriate psychiatric triage and signposting, and consume additional EIP resources not factored into original guidance. In response, I demonstrated that epidemiological estimates of psychosis risk could be used to better predict the expected FEP incidence in the population at-risk in England,13 nationally and regionally. The tool, known as PsyMaptic, has had substantial impact on policy and commissioning since it was freely-released in 2012 (www.psymaptic.org).16,18–22 Most recently, it has been used to inform national EIP workforce calculations23 following the introduction of Access and Waiting time standards,19 as part of the Department of Health’s commitment to achieving parity of esteem between mental and physical health by 2020.24 Whilst I have demonstrated, via PsyMaptic, that it is possible to translate epidemiological data into effective public mental health,25 some vital methodological limitations require empirical attention. I therefore seek Wellcome Trust enhancement funding to answer four empirical questions to develop and apply novel statistical prediction methodologies to generate sustainable, dynamic populationbased models of future mental health need.

Amount: £204,479
Funder: The Wellcome Trust
Recipient: University College London

Human Immune Response Variation in Tuberulosis 11 Jul 2017

I aim to discover novel mechanisms by which differences in human immune responses influence the outcome of Mycobacterium tuberculosis (Mtb) infection. I hypothesise that host-genetic polymorphisms lead to variation in immune responses that determine the clinical outcome of Mtb infection by affecting host-cell restriction of mycobacterial growth. We will use transcriptional profiling at the site of tuberculin skin tests (TST) to make comprehensive molecular and systems level assessments of in vivo human immune responses to a standardised mycobacterial challenge. In order to identify human immune responses that increase risk of disease in people exposed to Mtb, we will test the hypothesis that the TST transcriptome will reveal immune phenotypes associated with progression of LTBI to active TB. We will test the role of host genetics by identifying genome-wide expression quantitative trait loci (eQTL) associated with variation in the TST transcriptome. We will then recall participants by genotypes associated with selected traits to undertake in vitro mechanistic studies in primay immune cells. We will validate the causal association between genetic and phenotypic variations, and test their impact on Mtb restriction by macrophages. The findings will inform clinical risk stratification, vaccine design and development of host directed therapies for TB.

Amount: £1,660,537
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

Endothelial cell behaviours in vascular health and disease 30 Nov 2016

At the interface between blood and tissues, vascular endothelial cells (ECs) provide signalling hubs for vascular adaptation to physiological needs. Quiescent ECs form a non-thrombotic surface that facilitates the exchange of gases, molecules and cells between blood and tissues, but they respond to hypoxia-induced signals with vascular expansion and regulate leukocyte extravasation in response to injury. Our unpublished observations indicate that the cell surface receptor neuropilin 1 (NRP1) relays signals from the extracellular environment to the endothelial nucleus to enable such context-dependent responses. Thus, we hypothesise that NRP1 integrates growth factor and extracellular matrix signalling with gene transcription programmes to balance EC behaviours that enable vascular growth and to prevent the senescent and proinflammatory endothelial phenotype common to many chronic diseases. To determine how vascular growth and homeostasis depend on NRP1-mediated pathways, we will investigate novel mechanisms by which NRP1 conveys signals for tissue vascularisation, protects ECs from premature senescence and regulates gene transcription for vascular growth and homeostasis. The knowledge gained will significantly advance our understanding of how extracellular signals are integrated with gene regulation to control EC behaviour, and will likely uncover pathways for therapeutic intervention in diseases with vascular dysfunction.

Amount: £1,436,838
Funder: The Wellcome Trust
Recipient: University College London

Determining the allosteric network in HDAC8 using NMR and molecular dynamics. 31 Jan 2017

The main goal of this project is to study the allosteric regulation of Histone deacetylase 8 (HDAC8). HDAC8 is an enzyme involved in transcriptional regulation and diseases such as acute myeloid leukaemia. Recent work in the group has shown that there are changes in chemical shifts in the helix 1, loop 1 and helix 2 region of HDAC8 when the inhibitor TSA binds to the active site – chemical shift changes are observed over 28 Å from the inhibitor binding site. This is of particular interest as recent work by J. Schwabe's group has shown that this region binds co-repressors in other class 1 HDACs modulating their activity. This suggests that the information transfer between the active site and the region around helix 1, loop 1 and helix 2 is a general allosteric pathway in class 1 HDACs and is important for their regulation. In order to derive a mechanism for the allosteric regulation we will use side-chains as probes in NMR experiments. In conjunction with this we hope to characterise the transition between the drug-bound structure and the apo HDAC8 using meta-dynamics. In doing so we hope to identify key motions and residues, which mediate this transfer of information.

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

Water resistance: a study of environmental justice, resilience and citizen science activism in Mexico City 02 May 2017

This research will explore resilience in the context of environmental justice, with a focus on water insecurity in Mexico City. The concept of resilience is central to public health and climate change discourse, but is rarely critiqued. Addressing this omission is crucial: resilience frameworks can conceal social inequalities, uphold political status quo, and overlook local experience. Equally, few anthropological studies have examined resilience and urban water insecurity. In Mexico City these gaps are especially prescient. The third most water-stressed city in the world, low-income neighbourhoods have limited access to water. Communities often protest in response. Drawing together an ethnographic study with the digital participatory methods of citizen science, the goals of this research are to: Understand the meaning and practices of resilience amongst people who experience water insecurity. Investigate the role of digital technology and citizen science in this space. Inform future uses of resilience in environmental justice research, design and policy. Through these objectives, the research acts at the intersection of social inequality, public health and the environment. The outcomes will contribute to anthropological theory and knowledge, open the potential for trans-disciplinary collaborations, and bring a more sensitive and ethical perspective to the overlap of climate change and health.

Amount: £96,532
Funder: The Wellcome Trust
Recipient: University College London

Antibiotic resistance in urinary tract infections in a primary care cohort in East London 30 Sep 2017

Antimicrobial resistance (AMR) is an alarming global issue causing difficulties for individual patient management and health systems. Antimicrobial use and misuse is the main driver behind AMR, and prescribing interventions such as antimicrobial stewardship programmes are our our main defense against it. We currently have a limited understanding of who is at most risk and how specific prescribing patterns drive resistance. This PhD will build on the unique resource of the East London Data Linkage Project that has already linked primary and secondary care records across two Clinical Commissioning Groups, by establishing further linkages with microbiology data on resistance patterns across a highly diverse population of more than a million people. This will enable a broad range of analyses identifying how risk factors such as ethnicity, social deprivation, age, gender and co-morbidities affect prescribing patterns and resistance. It will allow individual-level analyses of how resistance is related to exposure of specific antibiotics, how prescribing of one antibiotic class may lead to co-selection of resistance in other antibiotic classes, and the temporal relationships between antibiotic exposure and resistance. Analyses will inform our scientific understanding of resistance, and also present opportunities for personalised prescribing based on individualised risk rather than area-based blanket antibiotic policies.

Amount: £290,622
Funder: The Wellcome Trust
Recipient: University College London

Neural mechanisms of spatial and episodic memory 05 Jul 2016

Episodic memory is a crucial function and its loss devastating. Research into its neural mechanisms is hindered by the knowledge gap between the molecular biology and pharmacology of neurons and synapses and behaviour/symptoms. To begin closing this gap I have developed a neural-level computational model of remembering the spatial context of an event. This model, including formation and use of place, grid, boundary and head-direction cells in spatial memory, will be tested, refined and extended to episodic memory, by experiments in humans and mice performing similar mnemonic tasks, such as virtual-reality navigation. Optogenetic, 2-photon microscopy and electrophysiological experiments in mice, will be combined with fMRI, MEG and intracranial recordings in humans to acquire the data across neuronal, circuits, systems, and behavioural levels, needed to test the model. Model predictions will be tested in patients with memory disorders. Key goals will be to test the model’s main neural-level mechanisms: how information can either be stored as a new memory or trigger reconstruction of an entire previous event, i.e. hippocampal pattern separation/completion; how egocentric perception and imagery interface with long-term allocentric representations, i.e. coordinate transformations in retrosplenial cortex; and how movement-related inputs update spatial representations in memory, mental imagery and planning.

Amount: £2,242,793
Funder: The Wellcome Trust
Recipient: University College London