- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
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.
Chronic pain affects a large number of patients worldwide but the available treatment options are often far from adequate. The voltage-gated sodium channel Nav1.7 has been identified as a target for drugs to treat nociceptive chronic pain, but as yet no clinical candidates have been identified. Protoxin-II is a small protein found in the venom of the Peruvian green velvet tarantula, and is a potent and specific inhibitor of Nav1.7; it is therefore a promising lead as a drug for chronic pain. However, many crucial aspects of the interaction of Protoxin-II with Nav1.7 remain unknown: it is not known where the toxin binds to Nav1.7 and how this binding mode effects inhibition of the channel, or how Protoxin-II is able to select for Nav1.7 over other voltage-gated sodium channels. This project will attempt to develop an efficient and versatile synthetic route to Protoxin-II and analogues, and to use these analogues to test the structure-function relationship in Protoxin-II. This information will be used to probe its method and site of action against Nav1.7, and to design ‘toxin-drug conjugates’, analogous with antibody-drug conjugates used as treatments for cancer, with high therapeutic potential.
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.
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.
Mammalian brain development relies on the sequential generation of neurons that form the cortical and subcortical structures. Spatiotemporal control of cell behaviours and sequential production of neurons expressing layer-specific genes is achieved through tight control of transcription. The Riccio laboratory recently identified a subset of Short Interspersed Elements (SINEs) that control the expression of activity-regulated genes in cortical neurons. We discovered that these specific SINEs function as enhancers, and are transcribed from their internal RNA Polymerase III promoters to produce enhancer RNAs (eRNA). Importantly, SINE eRNA is necessary for enhancing the expression of RNAPII-dependent genes proximal to enhancer SINEs in the genome. It has been reported that specific SINEs can recapitulate expression patterns of neuronal genes and, through evolution, may have gained new functions as developmentally regulated enhancers. In this project I will select candidates from the enhancer SINEs previously identified by the Riccio laboratory and characterise their role in cortical development. The aims of my project are the following: To characterize eSINEs that regulate neural genes during cortical development, in vitro To analyse the role of selected eSINEs in cortical development using in utero electroporation Generation and analysis of a transgenic mouse lacking a selected eSINE
Investigating the role of microglia in shaping dorsal horn pain circuitry during normal development and after early postnatal injury 31 Jan 2017
The neonatal CNS is highly responsive to noxious stimulation and early pain exposure, such as neonatal surgery or routine clinical procedures, cause persistent changes in somatosensory processing. It has been therefore been proposed that early life pain experience may determine adult pain sensitivity. Thus, an understanding of the postnatal development of the somatosensory and nociceptive system, and how it is influenced by early pain experience is an important neurobiological question. This project focusses upon developing nociceptive circuits within the dorsal horn of the mouse spinal cord and the interaction between microglia and neurons in this process. I plan to investigate how microglia shape nociceptive synaptic connections during normal postnatal development and their role in altering nociceptive circuitry after early life injury. The following questions will be addressed How do nociceptive and tactile afferents become structurally and functionally organized in the postnatal dorsal horn (dorsal horn sensory connectome)? What role do microglia play in the development of dorsal horn sensory connections under normal conditions and after neonatal injury? How do microglia change over postnatal development under normal conditions and after neonatal injury? Is injury-induced priming of microglia due to changes in the dorsal horn environment, changes in microglial properties, or both?
The overall aim of this project is to use viral tracing, electrophysiology and optogenetics to investigate the local circuitry of the ventral subiculum (vS), and how this circuit is altered by social isolation stress – a common route to affective disorders such as depression and anxiety. I will first investigate the anatomical distribution of neurons in vS that project to the prefrontal cortex or the NAc. These have been shown to be distinct parallel populations with unique circuit functions, but very little is known about their detailed local circuit organisation. Next I will use optogenetics, electrophysiology and viral tracing to determine the functional connectivity of the local circuit that defines the differential activity of these projections. Despite strong hypotheses that local control is key in this circuit, how this is acheived mechanistically remains unknown. Finally, I will determine how this detailed projection-specific circuitry is altered by social isolation - a manipulation that drammatically alters vS circuitry - and aim to provide more specific targets for in vivo manipulations aimed at reversing isolation-induced behavioural deficits. Overall, these experiments will provide for the first time mechanistic insight into the function and organisation of vS circuitry, from individual synaptic connections, to circuit function.
Posterior parietal cortex (PPC) in humans and other animals is considered to be a nexus of sensory, motor, and cognitive functions. The underlying circuits and computations are increasingly studied in mice, a species that affords unparalleled resources such as genetic tools and behavioral tasks. Studies of mouse PPC, however, have focused on distinct functions: visual processing, decision making, and spatial navigation. It is not clear whether the same neurons and populations participate in these three functions, and whether they play similar roles in different behavioral contexts. We will first establish how the anatomical definition of mouse PPC used in studies of decision and navigation relates to functional maps of visual cortex established in studies of vision. We will then train head-fixed mice to perform two visual decision tasks: one of which involves navigation in virtual reality, and we will use two-photon calcium imaging to track the activity of populations of PPC neurons over weeks. These data will reveal whether the activity of the same PPC neurons stays fixed or varies to meet the variable demands of these two tasks, and thus establish the role of mouse PPC in functions that are typically combined in daily life: vision, decision, and navigation.
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.
Optimization of embryonic ESC-derived motor neuron grafts for restoration of lost muscle function 31 Jan 2017
Damage to motor neurons due to traumatic injury or degenerative conditions typically results in permanent muscle denervation and paralysis. We recently described1 a novel strategy to artificially restore functional control of paralyzed muscles, which employs embryonic stem cell-derived motor neurons (ESC-MNs), modified to express channelrhodopsin-2 and glial derived neurotrophic factor, to confer optogenetic control of neural activity and promote long-term survival, respectively. These ESC-MNs, contained within embryoid bodies (EBs), were engrafted into injured peripheral nerves of mice, resulting in reinnervation of paralyzed muscles and optical control of their function. Unfortunately, EBs contain pluripotent cells with an inherent potential to form teratomas, limiting their clinical utility. However, purified ESC-MN grafts have a limited to capacity to functionally reinnervate muscle targets because other cell types within EBs, particularly excitatory interneurons, appear necessary for successful reinnervation of target muscles by engrafted ESC-MNs. The aims of this project are to i) optimize the ESC-MN graft identity, by investigating the effect of interneurons on motor neuron maturation and muscle innervation; ii) to use the optimized grafts to reinnervate opposable flexor and extensor muscles, to demonstrate the therapeutic utility of this approach in the restoration of complex functions, such as hand grasping.
During embryonic development cells have to integrate up to eight molecular pathways in order to choose between alternative fates or behaviours. However, even in combination, these eight pathways cannot provide enough information to specify the many (perhaps as many as 104) cell types that comprise the adult body. Timing seems to be important. One of the earliest fate decisions in embryonic development occurs soon after gastrulation during neural induction when one part of the epiblast is set apart, acquiring neural identity in response to signals from the organiser, Hensen’s node. A recent view is that neural induction is highly regulated in time and that it involves several steps. Competent cells, capable of responding to signals from the organiser, go through different states of specification before committing to the neural fate. Here we aim to understand how timing orchestrates neural induction. Specifically, we will uncover whether competence to respond to inducing signals is regulated by a cell-autonomous clock or by external instructions, how competent cells can sense exposure to signals of different duration and how this signal changes over time to generate an appropriately regionalised neural plate.
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.
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.
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.
Central nervous system compartmentalisation and drug resistance in HIV-1 sub-type C infection 30 Sep 2017
My research proposes to study HIV compartment shifts from the CNS to the peripheral blood, the evolution of drug resistance in the CNS and the relationship between CNS co-infection with other neurotropic organisms and CNS compartmentalisation in HIV-1 subtype C. Within a longitudinal cohort I will conduct a proof-of-principle study with the aim of testing the hypothesis that the CNS is a reservoir for HIV, where independent replication with the possibility of developing drug resistant mutations that may seed into plasma on treatment interruption. I will track the dynamics of compartment shifts and the evolution of drug resistance in paired plasma and CSF before and during the course of ART over 2 years. I will follow-up patients in this cohort initiating first-line therapy, and go on to repeat paired sampling of plasma and CSF in those with low level viraemia (LLV), where I expect 20% to have CNS compartmentalised HIV. Finally, I will capitalize on collaboration with an ongoing therapeutic clinical trial of cryptococcal meningitis (CM) (the ACTA trial) to examine HIV CNS compartmentalisation and the emergence of ART resistance in the brain in patients with CM. I will benefit from having access to stored samples of paired CSF and plasma from 680 patients in this multi-centre trial in Africa. Phenotypic drug susceptibility using pseudotyped viruses with patients’ derived gag-pol in a single cycle infection assay system and genotypic assessments of compartmentalised viruses will be performed, using next generation sequencing and single genome amplification. The project builds upon the continuing close collaboration between Dr Ravi Gupta’s group at UCL and Professor Deenan Pillay at the Africa Health Health Research Institute in KZN, South Africa. The proposal complements and extends the research programs in both centres. I will have access to superb experimental science facilities in Durban where there is a major focus on HIV drug resistance and with clinical and population based research excellence at the epicentre of the HIV epidemic. The Gupta laboratory at UCL specializes in HIV drug resistance, HIV reservoirs, particularly within macrophages, with complementary skills and interests in Durban.
Utilising electronic health records and Mendelian randomisation to investigate the relationship between liver function biomarkers and gastrointestinal disease; an example of bilirubin 30 Sep 2017
Liver function tests (LFTs) are commonly performed in clinical practice and are often associated with malignant and inflammatory diseases. Bilirubin has an anti-oxidant, cytoprotective function, and reported inverse associations with conditions including cardiovascular disease, inflammatory bowel disease, colorectal cancer and overall mortality. We will use linked primary care, hospitalisation, disease registry and mortality data in England (the CALIBER programme),  and include people aged 18 or older with no underlying gastrointestinal disease at baseline. We will use Cox models to estimate cause-specific hazard ratios (HRs) for the association of baseline bilirubin with onset of gastrointestinal disease. We will further compare outcomes in gastrointestinal disease and malignancy cohorts including hospitalisation rates, relapse-free survival, net survival and mortality. Finally, we will determine whether the associations detected (with serum bilirubin) are likely to be causal by utilising a Mendelian randomisation approach.
My aim is to develop a theoretical model of language processing that explains inter-patient variability in outcome after stroke. My hypotheses are that the same language task (e.g. describing a picture) can be sustained by different sets of brain regions (and neuronal pathways) and that inter-subject variability in neuronal pathways for the same language task reflect an individual’s inherent potential and prior experience. My investigations will (1) use functional neuroimaging to characterize inter-subject variability in neuronal pathways in a range of language tasks; (2) cluster healthy individuals and stroke patients into different groups according to the neural systems used for the same task; and (3) compare the identified groups on a multitude of demographic, behavioural and structural imaging measures. The results will identify the factors that distinguish which neuronal pathways a subject typically uses and which neural pathways are available to support recovery. The work will provide: (i) greater understanding of the neuronal pathways sustaining recovery; (ii) improved accuracy and precision in our prognoses for whether and when patients with aphasia will recover after stroke, and (iii) a new patient stratification system that can be used to design effective, individualised therapeutic interventions.
What's in a voice? 30 May 2017
Why do we sound the way we do? "What’s in a voice", is an exhibit which aims to start conversations about voices, and which illustrates the evolution, complexity and meanings associated with the human voice – which is simultaneously a musical instrument without peer in terms of flexibility and range, and also a powerful social instrument with which we express who we are, how we are, and who we would like to be. This project will tell the story of the human voice – from evolution to acoustics, from anatomy to emotion – in novel and engaging ways. We will illustrate this with a strong scientific background into our work on voices, and also with demonstrations of why and how our voices can change, as well as the use of different kinds of vocal performance to allow us to illustrate the different kinds of vocal mechanisms live. The performances will involve voice professionals, including beat boxers, actors, poets, rappers and singers. We are also working with people who have more ‘difficult’ voices, (e.g. people who stammer), and children from a local Camden primary school (St George the Martyr, Camden), with whom we are working to produce some vocal demonstrations.
This fellowship will explore the impact of arts and cultural engagement on health and wellbeing at a population level, using the outstanding longitudinal cohort data that have been collected in the UK. Research will examine the effects of (i) cultural engagement (e.g. attending concerts/museums/galleries/cinemas/theatre); (ii) active arts participation (e.g. music/dance/crafts/drama); (iii) passive arts consumption (e.g. music listening/watching TV/reading) on: Diagnosed mental health conditions, self-reported mental health and wellbeing Diagnosed physical health conditions, self-reported health and somatic symptoms (such as pain) Physiological measures (e.g. stress hormones/inflammation/lung function/cardiovascular measures) Cognitive measures (e.g. memory/mood/reasoning) Psychosocial measures (e.g. self-esteem/social support/quality of life/life satisfaction) A key focus will be on how different populations within society, including people of varying ages, socioeconomic status, ethnicities and education attainment, might be differently affected. In order to maximise the impact of this research on society, there will be a four-pronged engagement programme, including: Peer-reviewed papers and conference presentations aimed at academics Presentations at industry conferences for cultural organisations to explain the implications of findings for practice Reports and meetings with stakeholders in public health, politics and commissioning to explore the implications for policy A suite of activities to raise awareness amongst the public of the effects of arts engagement.
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.).