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Funders:
Paul Hamlyn Foundation
The Wellcome Trust
Recipients:
University College London
Amounts:
£0 - £500
£500 - £1,000

Results

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

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

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

Effects of Rab3a-Interacting Molecule 1a (RIM1a), linked to the enhancement of cognitive function, on presynaptic function and plasticity: a direct link from genes to cognition? 30 Sep 2018

Neurons communicate with each other via specialised junctions called synapses. The brain contains trillions of synapses where information is transferred and processed, which shapes neuronal network and brain function. Synaptic terminals contain small vesicles filled with neurotransmitters. When a nerve impulse invades the synaptic terminal, it triggers fusion of synaptic vesicles with the plasma membrane and release of transmitter molecules. Neurotransmitters quickly diffuse towards the target neuron, where they bind to specific receptors and evoke further electrical or chemical signalling. Very often mutations in proteins that regulate synaptic vesicle fusion lead to neurological disorders and cognitive impairment. RIM1alpha is one of the key proteins that regulate synaptic release of neurotransmitters by bringing together the key components of release machinery. Recently, a novel mutation in RIM1alpha was discovered that enhances cognitive function in humans. This "experiment of nature" represents a unique model to test how alterations in synaptic function shape high-level brain activity and cognition. In this project we aim to understand the effects of this RIM1alpha mutation in mouse neuronal model on synaptic transmission and use-dependent synaptic plasticity. We anticipate that our results will provide novel unparalleled insights into the cellular mechanisms that underlie cognitive processing in the brain.

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

Exploring the role of Genome Architecture in Neuronal Development using an in vitro model system 31 May 2018

The research aim is to explore the role of genome organisation and three-dimensional configuration in regulating transcriptional responses during neuronal differentiation. To do so, expression of co-regulated candidate genes during differentiation from neuronal progenitor cells (NPCs) to post-mitotic neurons (PMNs) will be identified with qRT-PCR. NPCs will be dissected from E12.5 mouse cortices and cultured in basic Fibroblast Growth Factor (bGFG). Differentiation into PMNs will be induced by adding neurotrophin-3 (NT-3). The nuclear localisation of pairs of co-regulated genes will be detected using double fluorescence in situ hybridisation (D-FISH), assessing whether these genes relocate to transcriptionally active regions, like transcription factories, or transcriptionally repressive regions, like the nuclear periphery. Results will also compare transcriptional changes in neuronal differentiation with nuclear re-organisation patterns in the expression of activity-regulated genes (ARGs), like c-Fos and Gadd45b. This will allow the identification of genome architecture changes specific to cortical development. Possible gene co-localisation, genomic-wide contacts and loci interactions will be studied with 4C technology, which combines chromosome conformation capture (3C) methodology with high-throughput sequencing.

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

Gene Editing using CRISPR/Cas9 for Gene Correction in Recessive Dystrophic Epidermolysis Bullosa (RDEB) 31 May 2018

Conventional gene therapy approaches rely on the addition of a corrected gene copy via viral vector transduction. Such strategies are currently being applied to recessive dystrophic epidermolysis bullosa (RDEB) where there is defective collagen type VII protein. However, use of constitutive exogenous promoters in viral vectors results in sustained gene expression that is not subject to the normal regulatory mechanisms of C7 expression. Integrating properties of vectors also pose risk for insertional mutagenic-derived events and efficiency of gene transfer has been challenging given the large size of COL7A1 cDNA. Whereas, gene-editing tools can be designed and engineered to target and repair specific defined regions of DNA, thereby alleviating genomic toxicity and maintaining endogenous gene expression control. Existence of well-known mutation hotspots within COL7A1 allows CRISPR reagents to be designed that would target the mutations found in the UK population with RDEB. Investigations outlined in this proposal aim to identify the most effective CRISPR reagent for a chosen mutation hotspot within COL7A1 gene. In skin, keratinocytes predominantly produce collagen type VII. Therefore, this project will evaluate feasibility of gene editing approaches using CRISPR/Cas9 system in HACAT keratinocytes cell line, and help address critical aspects of CRISPR/Cas9 efficiency at a chosen loci.

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

Irritability, Reward Processing and Adolescent Depression 30 Sep 2018

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

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

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

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

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

Investigation of protein CoAlation in the process of apoptosis 27 Apr 2017

CoAlation is a novel post-translational modification to proteins whereby Coenzyme A is covalently attached to proteins. It occurs as part of the oxidative stress response as an alternative mechanism to protein glutathionylation. It is specifically a modification of enzymes involved in cellular metabolism and protects catalytic thiol groups on active site cysteine residues from irreversible damage by reactive oxygen species and reactive nitrogen species. Applying oxidizing agents to cells results in induction of apoptosis. Such agents also induce protein CoAlation. The aims of this project are to monitor induction of apoptosis in HEK293 cells in response to treatment with oxidizing agents using anti-PARP3 and anti-Caspase 3 Western blot and Fluorescence-activated Cell Sorting and to analyse the pattern of CoAlation at different stages of apoptosis using anti-Coenzyme A Western blot.

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

Investigating the sleep modulating effect of oxytocin in zebrafish models of autism. 27 Apr 2017

In this project I will test the hypothesis that oxytocin expression and development of oxytocin-expressing neurons are altered in zebrafish with mutations in the ASD risk genes cntnap2 and chd8. I hope to find evidence for the sleep modulating effects of oxytocin, and posit whether deficiencies in oxytocin signalling pathways may contribute to sleep disorders in autism mutants. I will examine oxytocin mRNA levels across the day/night cycle for both wild-type and mutant fish established in the Rihel lab. I will then analyse the pattern of oxytocin expression in the brains of mutant embryos and their wild-type siblings. From the findings in related studies with cntnap2 mutant mice and the Rihel lab zebrafish models of autism (see references [3] and [6]), I expect to see an alteration in the amount of oxytocin mRNA for day/night between the wild-type and mutant embryos, and a change in the number of neurons expressing oxytocin. If such changes are found, they could explain the sleep phenotype observed in cntnap2 autism mutants, and elucidate a link between neuronal circuit dysfunction and behavioural perturbation in this animal model.

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

Evaluation of antimicrobial resistance and intrahospital transmission of respiratory pathogens in antibody-deficient patients. 27 Apr 2017

I will be studying the respiratory microbiome of antibody-deficient patients to determine whether the number of bacterial species that are resistant to common antibiotics correlates with antibiotic usage, and whether transmission of these bacteria occurs between patients whilst attending hospital for immunoglobulin infusions. Immunocompromised patients provide a highly permissive environment for pathogen evolution as the lack of immune pressure allows resistance to develop without an associated fitness cost. Many of these patients take long-term prophylactic antibiotics together with frequent treatment courses, which we hypothesise acts as a selection pressure to further increase the number of resistant bacterial species in their microbiome. By analysing sputum samples with conventional microbiology techniques and MALDI-TOFF mass spectrometry, I will identify the bacterial species present in each sample and determine how many are resistant to common antibiotics, comparing this to questionnaires detailing the patients’ antibiotic usage. Additionally, for any resistant species identified in multiple patients, I will compare the antibiograms from each sample and extract DNA for 16S next generation sequencing to determine whether the presence of these species is due to intrahospital transmission. This project could inform clinical management of these patients as well as other situations where immunocompromised patients share hospital facilities.

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

No time for panic: British responses to influenza in peace and war, 1889-1919 29 Aug 2008

The 1918 influenza pandemic represents the worst outbreak of infectious disease in Britain in modern times. Although the virus swept the world in three waves between March 1918 and April 1919, in Britain the majority of the estimated 228,000 fatalities occurred in the autumn of 1918. In London alone deaths at the peak of the epidemic were 55.5 per 1,000- the highest since the 1849 cholera epidemic. Yet in the capital as in other great cities and towns throughout Britain, there was none of the panic that had accompanied earlier 19th century outbreaks of infectious disease at the heart of urban populations. Instead, the British response to the 'Spanish Lady' as the pandemic strain of flu was familiarly known was remarkably sanguine. As The Times commented at the height of the pandemic: 'Never since the Black Death has such a plague swept over the face of the world, [and] never, perhaps, has a plague been more stoically accepted.' The apparent absence of marked social responses to the 1918 influenza is a phenomenon much remarked on in the literature of the pandemic, as is the apparent paradox that despite the widespread morbidity and high mortality the pandemic had little apparent impact on public institutions and left few traces in public memory. However, to date no one has explored the deeper cultural 'narratives' that informed and conditioned these responses. Was Britain really a more stoical and robust nation in 1918, or was the absence of medical and other social responses a reflection of the particular social and political conditions that prevailed in Britain during the First World War and then medical nosologies and cultural perceptions of influenza? And if the 1918 pandemic was 'overshadowed,' as one writer puts it, by the war and the peace that followed the Armistice, what explains the similarly muted response to the Russian flu pandemic of the early 1890's, a disease outbreak that coincided with a long period of peace and stability in Britain? In this project I aim to show that, contrary to previous studies, both the 1918 and the 1889-92 Russian flu pandemic were the objects of much deeper public concern and anxiety than has previously been acknowledged and that the morbidity of prominent members of British society, coupled with the high mortality, occasioned widespread 'dread' and in some cases alarm. However, in 1918 at least, government departments and public institutions actively suppressed these concerns for the sake of the war effort and the maintenance of national morale.

Amount: £657
Funder: The Wellcome Trust
Recipient: University College London

Developing gene therapy for the inherited childhood epilepsy, Dravet Syndrome 27 Apr 2017

Dravet syndrome is a rare, incurable epilepsy which affects young children. Before two years of age they have seizures, incoordination and cognitive impairment. They carry mutations in the SCN1A gene, which codes for voltage-gated sodium channel NaV1.1. This protein is expressed in hippocampal inhibitory interneurons. Gene therapy offers several advantages over conventional drugs. It is a treatment which targets the cause of the disease by delivering the corrected copies of the SCN1A directly to brain cells. Our hypothesis is that we can incorporate a promoter to achieve persistent expression specifically in inhibitory interneurons of the hippocampus. We aim to compare two novel promoters against a pan-neuronal promoter, synapsin. The first is a truncated endogenous promoter, Gad67. The second is a synthetic promoter identified by in silico analysis. Before the project commences, we will clone these two promoters into lentiviral vectors. These, and a synapsin vector, will be injected intracranially into neonatal mice. At the start of the project the brains from four mice will be co-stained with antibodies directed against GFP and inhibitory interneurons to assess colocalisation. To measure persistence of expression from these promoters, the four remaining mice will be subject to whole-body bioluminescence imaging twice-weekly.

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

Developing a behavioural task for measuring the ability of listeners to perform auditory scene analysis. 27 Apr 2017

The auditory brain separates simultaneous sounds arriving at the ear into identifiable and localisable sources by a process known as Auditory Scene Analysis (ASA). The two steps that are involved in ASA are i) segregation of the simultaneous auditory information and ii) the integration of the sounds from the same source into one stream. To understand how these two steps are connected and how different auditory cues interact to shape the scene, this project will develop a behavioural task and analyse the performance of human listeners. A target vowel will be presented alongside with a distractor vowel, and human listeners will identify what the target is. Listeners will only be able to identify the target if they can separate the two sounds: changing the location and pitch of target and distractor will help this. In order find out whether the separation of competing sounds is facilitated by the formation of perceptual streams, the vowels will also be presented as part of a sound sequence. Our hypothesis is that the ability to identify a target vowel will be improved by the formation of two perceptual streams. The long-term goal is to develop a behavioural paradigm suitable for humans and animals.

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

Microtubule organisation and role of LL5-beta in lymphoid stromal fibroblasts 27 Apr 2017

The lymph node is a meeting point for lymphocytes with antigen-presenting cells, and rapidly expands during immune responses. Lymph node structure is highly compartmentalised, and the complex internal architecture is maintained during lymph node expansion. Therefore, mechanisms must exist to balance lymph node integrity with the need to remodel very rapidly. Fibroblastic reticular cells (FRCs) are the most abundant lymphoid stromal cell population, and span the full volume of the tissue. They provide structural support and are highly contractile. FRCs ensheathes bundles of extracellular matrix, termed the conduit, which filters draining lymph. The Acton lab works to understand how lymph nodes are remodeled during expansion and has shown that interaction between FRCs and dendritic cells change FRC behaviour. This project asks how the microtubule networks within FRCs are reorganised as the FRC network expands. Phosphoproteomic screening has revealed that LL5-beta, a protein targetting microtubules to adhesion sites is regulated by interactions between FRCs and dendritic cells. This may provide a mechanism by which FRCs uncouple from underlying matrix, and target secretion of proteases or new matrix to the expanding network. This project will investigate whether LL5-beta coordinates organization of microtubules in FRCs and whether dendritic cell contact changes LL5-beta activity.

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

Neuronal encoding of complex three-dimensional environments 31 May 2018

This proposed research intends to investigate the brain representation of complex, multilayered three-dimensional environments in free-roaming rodents by detecting electrical neuronal activities. With the assumption that the grid cell can form a lattice representation in a volumetric space, the main goal of this project is to test this hypothesis and construct more detailed mosaic neuronal models. From the previous experimental evidence, the grid cell plays a pivotal role in distance-measuring by forming a grid-like array on a flat surface, however, how this array is remodelled in vertical or tilled surface remains debatable. In this project, rats will be allowed to explore in a giant lattice model with options of climbing up or down, dwelling forwards or backwards while looking for rewards. The neuronal activities in rat's hippocampus will be collected, reconstructed into a 3D model. If the hypothesis is to be correct, the 3D cognition map is suggested to be a multiple evenly-spaced neuron filed distributed volumetrically (figure1, D and E). Otherwise, the field might be distributed in parallel columns vertical to the ground, as the extension of the 2D hexagonal array (figure 1, C).

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

Investigating the role of mtch-1 in age-related proteostasis collapse 31 May 2018

The loss of protein homeostasis (proteostasis) is associated with many age-associated diseases, most notably Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Despite this, the factors that control the vulnerability of cells to proteostasis collapse with age are poorly understood. Using the nematode worm Caenorhabditis elegans as a model system, we have identified the highly conserved gene mtch-1, as a new proteostasis regulator. mtch-1 encodes a mitochondrial outer membrane protein of unknown function, the knockdown of which, enhances resistance to environmental stress, maintains cytosolic proteostasis with age, and extends lifespan. However, it is unknown how these beneficial effects are mediated. This project will determine which protein quality control (PQC) components are necessary for mtch-1 to influence protein aggregation. We will use fluorescent reporters to determine the effects of mtch-1 on the activity of PQC pathways, and perform an RNA interference screen of known PQC components to determine which, if any, are necessary for the loss of mtch-1 to suppress protein aggregation. These experiments will allow us to build a picture of the previously unexplored link between mtch-1 and changes in cytosolic proteostasis with age, thereby highlighting a new aspect of PQC that could be manipulated to promote long-term health.

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