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Recipients:
Broadfield Primary School
University College London
Award Year:
2017

Results

Sir Henry Dale Extension: Inferring the selection history of world-wide populations in relation to phenotypes 31 May 2017

<p>I will construct efficient statistical algorithms to identify selection effects that have several advantages over current approaches, in particular:</p> <p>1)&nbsp;&nbsp;&nbsp; increased power from exploiting correlations (i.e. linkage disequilibrium) among nearby genetic variants</p> <p>2) &nbsp; &nbsp;no requirement for classification of individuals into discrete &quot;populations&quot; that may not have clear ancestral meaning</p> <p>3) &nbsp; &nbsp;robustness to variant ascertainment bias</p> <p>4) &nbsp; &nbsp;increased power to detect selection from standing variation</p> <p>5) &nbsp; &nbsp;ability to test selection in single individuals (e.g. single samples from ancient human remains, or aDNA)</p> <p>These new approaches will automatically identify genetic regions subjected to selection and the individuals affected when jointly analysing data from world-wide groups. Through application to novel genome-wide data obtained through the PI's Sir-Henry-Dale-Fellowship, including &gt;3700 African individuals from &gt;100 ethnicities spanning 15 countries, I will identify selection events both unique to and shared amongst geographic regions, pointing to shared past environmental pressures. Using collaborators' world-leading aDNA collections, I will furthermore unearth the timing of selection events. I will test for enrichment of selection signals in gene pathways and/or variants previously associated with phenotypes, elucidating how chronic and infectious disease have driven selection. Overall this fellowship will produce a comprehensive picture of selection effects in humans.<br> &nbsp;</p>

Amount: £519,660
Funder: The Wellcome Trust
Recipient: University College London
Amount: £2,814,500
Funder: The Wellcome Trust
Recipient: University College London

How do cells integrate signals? Roles of timing in neural induction 31 Jan 2017

<p>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 10<sup>4</sup>) 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&rsquo;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.</p>

Amount: £12,700
Funder: The Wellcome Trust
Recipient: University College London

Optimization of embryonic ESC-derived motor neuron grafts for restoration of lost muscle function 31 Jan 2017

<p>Damage to motor neurons due to traumatic injury or degenerative conditions typically results in permanent muscle denervation and paralysis. We recently described<sup>1</sup> 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.</p> <p>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.</p>

Amount: £16,673
Funder: The Wellcome Trust
Recipient: University College London

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

<p>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, <em>Drosophila melanogaster</em>. 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 <em>KCNMA1</em> BK potassium channel &ndash; the mammalian homologue of <em>Drosophila</em> <em>slowpoke</em> (<em>slo</em>). We will characterise changes in ion channel expression in GEPD <em>slo</em> 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.</p>

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

Vision, decision and navigation in mouse parietal cortex 31 Jan 2017

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. &nbsp;&nbsp;

Amount: £27,400
Funder: The Wellcome Trust
Recipient: University College London

Local control of ventral subicular circuitry and its alteration by social isolation 31 Jan 2017

<p>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 &ndash; a common route to affective disorders such as depression and anxiety.</p> <p>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.</p> <p><span>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.</span></p> <p>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&nbsp;provide more specific targets for <em>in vivo</em> manipulations aimed at reversing isolation-induced behavioural deficits.</p> <p>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.</p>

Amount: £30,524
Funder: The Wellcome Trust
Recipient: University College London

Investigating the role of microglia in shaping dorsal horn pain circuitry during normal development and after early postnatal injury 31 Jan 2017

<p>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.&nbsp; It has been therefore been proposed that early life pain experience may determine adult pain sensitivity.&nbsp; 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.&nbsp;&nbsp; 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. &nbsp;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.&nbsp;&nbsp;&nbsp;&nbsp; The following questions will be addressed</p> <ul> <li><strong></strong> How do nociceptive and tactile afferents become structurally and functionally organized in the postnatal dorsal horn (dorsal horn sensory connectome)?</li> <li>What role do microglia play in the development of dorsal horn sensory connections under normal conditions and after neonatal injury?</li> <li><strong></strong>How do microglia change over postnatal development under normal conditions and after neonatal injury?</li> <li><strong></strong>Is injury-induced priming of microglia due to changes in the dorsal horn environment, changes in microglial properties, or both?</li> </ul>

Amount: £21,633
Funder: The Wellcome Trust
Recipient: University College London

Roles of enhancer SINEs during mouse cortical development 31 Jan 2017

<p>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.</p> <p>The aims of my project are the following:</p> <ol> <li>To characterize eSINEs that regulate neural genes during cortical development, <em>in vitro</em>&nbsp;</li> <li>To analyse the role of selected eSINEs in cortical development using <em>in utero </em>electroporation</li> <li><strong></strong>Generation and analysis of a transgenic mouse lacking a selected eSINE</li> </ol>

Amount: £70,617
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

<p>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.</p> <p>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.</p>

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

Force Generation during Collective Chemotaxis in vivo 31 Jan 2017

<p>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<em> in vivo</em>.&nbsp; Furthermore, studies have focused mainly on epithelial cells. Another issue&nbsp; 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 <em>Xenopus</em>&nbsp;and zebrafish&nbsp;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.</p> <p>&nbsp;</p>

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

Toxin-Drug Conjugates: structural and functional studies of Protoxin-II 31 Jan 2017

<p>Chronic pain affects a large number of patients worldwide but the available treatment options are often far from adequate. The voltage-gated sodium channel Na<sub>v</sub>1.7 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 Na<sub>v</sub>1.7; it is therefore a promising lead as a drug for chronic pain.&nbsp;</p> <p>However, many crucial aspects of the interaction of Protoxin-II with Na<sub>v</sub>1.7 remain unknown: it is not known where the toxin binds to Na<sub>v</sub>1.7 and how this binding mode effects inhibition of the channel, or how Protoxin-II is able to select for Na<sub>v</sub>1.7 over other voltage-gated sodium channels.</p> <p>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 Na<sub>v</sub>1.7, and to design &lsquo;toxin-drug conjugates&rsquo;, analogous with antibody-drug conjugates used as treatments for cancer, with high therapeutic potential.</p>

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

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

<p>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 &ndash; chemical shift changes are observed over 28 &Aring; 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.</p>

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

Unravelling the molecular complexity behind ocular maldevelopment 30 Sep 2017

<p><strong>Aim:</strong> Investigating the relationship between genotype, gene expression and phenotype of <u>m</u>icrophthalmia, <u>a</u>nophthalmia&nbsp;and ocular <u>c</u>oloboma&nbsp;(MAC), which collectively causes one-third of life-long blindness and severe visual impairment in children worldwide.</p> <p>&nbsp;</p> <p><strong>Research questions: </strong>What are the pathogenic variants underlying MAC? How do molecular subtypes correlate with phenotype and stratify clinical risk?&nbsp; What molecular pathways are involved in human eye development? What is the relationship between genotype and gene expression in microphthalmia?</p> <p>&nbsp;</p> <p><strong>Key goals and methodology:</strong></p> <ol> <li>Whole genome sequencing of 30 parent-offspring trios with isolated MAC and longitudinal phenotyping. Establish an international reference network to stratify a well-defined cohort to improve care pathways and future research.</li> <li>Temporal comparative analysis of DNA methylome (bisulfite conversion and Illumina Infinium EPIC BeadChips) and transcriptome (65 million reads per sample using Illumina HiSeq-2500) in the developing human eye between 4-9 weeks gestation.</li> <li>Model 3D human microphthalmic optic cups using iPSC technology with isogenic controls using CRISPR/Cas9 gene-editing. DNA methylome and transcriptome analysis to assess disruption of molecular pathways.</li> </ol> <p>&nbsp;</p> <p><strong>Outcomes:</strong> Establish a molecular framework for ocular maldevelopment. Identify drug targets and develop therapeutics. Improve genetic diagnosis, counselling and management. Elucidate shared molecular mechanisms between embryonic tissue fusion defects and late-onset visual sensory disorders.&nbsp;</p>

Amount: £25,000
Funder: The Wellcome Trust
Recipient: University College London

4 year PhD in Neuroscience 30 Sep 2017

Not available

Amount: £2,850,000
Funder: The Wellcome Trust
Recipient: University College London

Arts, Society and Public Health: An Exploration of the Major UK Cohort Studies 24 Jan 2017

<p>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:</p> <ul> <li>Diagnosed mental health conditions, self-reported mental health and wellbeing</li> <li>Diagnosed physical health conditions, self-reported health and somatic symptoms (such as pain)</li> <li>Physiological measures (e.g. stress hormones/inflammation/lung function/cardiovascular measures)</li> <li>Cognitive measures (e.g. memory/mood/reasoning)</li> <li>Psychosocial measures (e.g. self-esteem/social support/quality of life/life satisfaction)</li> </ul> <p>&nbsp;</p> <p>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:</p> <ul> <li>Peer-reviewed papers and conference presentations aimed at academics</li> <li>Presentations at industry conferences for cultural organisations to explain the implications of findings for practice</li> <li>Reports and meetings with stakeholders in public health, politics and commissioning to explore the implications for policy</li> <li>A suite of activities to raise awareness amongst the public of the effects of arts engagement.</li> </ul>

Amount: £241,889
Funder: The Wellcome Trust
Recipient: University College London

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

<p>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.</p> <p>&nbsp;</p> <p>We will use linked primary care, hospitalisation, disease registry and mortality data in England (the CALIBER programme), [1] 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.&nbsp;</p>

Amount: £253,846
Funder: The Wellcome Trust
Recipient: University College London

The putative propriospinal contribution to feedforward control mechanisms during skilled grasp 27 Apr 2017

<p>The corticospinal pathway is the major direct pathway contributing to hand and motor function, after stroke or spinal cord injury this pathway can become irreversibly damaged. However, other parallel pathways may still function and are accessible to the motor system. The propriospinal network is an interneuronal system that is located at the mid-cervical levels (C3-C4), which transmits and alters descending commands for targeted reaching and grasping. Lesion studies have illuminated the role of this system in the recovery of reach and grasp movements.The aim of this project is to investigate the role of this connection in healthy humans. Specifically, our objective is to show the contribution of this system in feedforward grasping mechanisms. We will employ a motor task that involves grasping an object between the index finger and thumb where the task demands change prior&nbsp;to contact. Paired low-intensity peripheral nerve stimulation (PNS) and transcranial magnetic stimulation (TMS) will be used to probe the propriospinal modulation of corticospinal output during the task. Studying the propriospinal system in healthy humans will show how motor commands are updated at a spinal premotoneuronal level and could provide a&nbsp;novel pathway to target for neurorehabilitation after lesions of the central nervous system.</p>

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