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

Results

Effects of sex on metabolic homeostasis in old age 31 May 2018

The main aim of our research is to determine the differences in the lifespan and physiology of male and female Drosophila melanogaster in response to increased levels of sugar (sucrose) in the diet. Current human diets are detrimental to health and obesogenic. The health outcomes are dependent on the sex of the individual, however the molecular and physiological mechanisms are not understood. The results of our study will help establish a Drosophila model that can be used to understand how nutrition and sex interact, which might contribute to a healthier lifestyle choices in humans leading to healthy ageing. The effects of diet on lifespan and diet-induced obesity of the two sexes will be recorded, as well as the feeding behaviour using the proboscis extension assay and blue-food assay. Gut morphology/function will also be examined since the gut appears to underlie the different response of the sexes to increased dietary protein. In particular, we will focus on age-induced hyperplasia by determining the number of proliferating cells (stained with anti-phospho-Histone 3). We will also monitor gut function by assessing the leakiness of the gut using a blue food. Finally, statistical analysis using suitable regression models will be performed in R.

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

Dynamical modelling of somatic genomes 28 Nov 2017

Cancers are complex and chaotic systems. It is becoming apparent that no two cells in a cancer are genetically identical or follow the same evolutionary trajectory. Chromosomal instability (CIN) is one way that cells generate this complexity and is a hallmark of all cancer and ageing. In cancer, it increases the level of variation available to cells and gives rise to intra-tumour genetic hetereogeneity, which makes the disease more agressive, drug tolerant, and harder to treat. We are still far from a complete understanding of how cells undergoing CIN evolve over time, in particular, we do not know how populations of cancer cells evolve and how selection acts to change these properties. Understanding this normal evolutionary behaviour will be key to separating the functional and non-functional aspects of intra-tumour heterogeneity. We will tackle this problem by understanding cancer as an emergent complex system, and use simple dynamic stochastic models to capture the essential biological features of the processes underlying CIN, including chromosome gain and loss, structural change, and genome doubling. We will use the vast amount of NGS data already available to fit these models using Bayesian inference and infer the evolutionary aspects of CIN in healthy and cancerous tissues.

Amount: £1,273,968
Funder: The Wellcome Trust
Recipient: University College London

Assessment of placental function in complicated pregnancy using advanced MRI 04 Dec 2017

Placental insufficiency underlies the major obstetric syndromes of fetal growth restriction (FGR) and pre-eclampsia and accounts for one third of stillbirths in high-income countries. There is an unmet clinical need for a method to properly characterise placental perfusion and determine if and when a placenta is likely to fail. The objective of this work is to develop an imaging method to assess placental function in complicated pregnancy. This work will help us to better understand placenta function in FGR. This project will compare placenta properties from appropriately developing and early-onset growth-restricted pregnancies to understand the differences in the appearance of the placenta in FGR. The key goals of this work are to assess a novel Magnetic Resonance (MR) Imaging method to measure fetal and maternal placental perfusion. This technique describes an MR signal that models the blood flow properties as they change between the maternal and fetal sides of the placenta. to link this to relevant clinical information including clinical ultrasound markers and fetal MRI. to use these results to establish a comprehensive imaging project for the placenta by providing an in vivo measurement of placenta function to complement information from ultrasound imaging and ex utero microCT.

Amount: £99,804
Funder: The Wellcome Trust
Recipient: University College London

The role of E2F targets in oncogene-induced replication stress tolerance as potential new targets for cancer therapy 31 May 2018

In human cells, deregulated G1/S transcription, the transcriptional wave that commits cells to the cell cycle, is at the basis of many cancers and it is governed by the transcription factor E2F2. Oncogenes such as c-myc, deregulate G1/S transcription leading to uncontrolled cellular proliferation. We will induce expression of the oncogene c-myc in epithelial human cells, that directly leads to the increase in levels of E2F transcription. Unscheduled S-phase entry leads to replication stress and DNA damage, and thus genomic instability, which may lead to cell death or drive cancer initiation if the DNA damage repair is impaired. Paradoxically, this increased E2F-dependent transcription provides also a mechanism for replication stress tolerance to protect cells from catastrophic genomic instability. Some cancers have very high levels of replication stress, and by understanding how these cells are able to tolerate such high levels, we may be able to target these buffers for new cancer therapeutics. A large scale screen is being performed in the lab to identify these targets. I will investigate the role of one of these targets. Preliminary work in the lab and previous work in yeast suggests that the Smc5/6 complex may be such a candidate for oncogene-induced tolerance.

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

Appraisal of LRG1 antibody internalisation and as a dual acting antibody-drug conjugate 30 Sep 2018

Abnormal blood vessel formation contributes to diseases such as cancer, and is the result of inappropriate angiogenic signalling. In recent years, it has been shown that in the presence of the transforming growth factor beta1 (TGFbeta1), leucine-rich alpha-2-glycoprotein 1 (LRG1) promotes the formation of new blood vessels, via a process known as angiogenesis. Blocking the activity of LRG1 by using an antibody against it leads to reduced blood vessel growth, and thus, could be exploited to inhibit cancer growth. We aim to combine the blood vessel normalisation achieved by LRG1 blockade with affecting cancer cell deterioration. To do this, we aim to modify the LRG1 antibody vehicle, using state-of-the-art biotechnology, with a suitable fluorophore to evaluate internalisation into a cancer cell (i.e. its ability to deliver cargo), followed by decoration with a suitable toxic drug to evaluate efficiency in cells.

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

Pre-configured and learned properties of hippocampal circuits 10 Apr 2018

Despite recent advances in systems and computational neuroscience, very little is known about how the brain’s functional complexity arises during ontogenesis and which developmental mechanisms determine the emergence of complex behaviour. The proposed research aims to bridge this gap between developmental neurobiology and systems neuroscience by defining the relative roles of early embryonic events and post-natal learning in the development of spatial and non-spatial coding in the hippocampal formation. Our key goals are to: 1) establish whether the functional diversity in hippocampal place cells is defined by early embryonic divergence; 2) test whether ‘non-place’ coding in the hippocampus is intrinsic to the network (as place coding appears to be), or whether it requires late post-natal learning; 3) discover the relative contributions of experience-dependent and independent processes in creating the specific neural architecture (‘continuous attractor') underlying codes for direction and distance. We will deliver these goals using chronic in vivo recording of neural activity (high density electrophysiology and calcium imaging) in developing animals coupled with neuronal birth tagging, behavioural testing and functional inactivation of crucial targets, to discover which self-organised embryonic events and instructive signals are necessary to organise hippocampal circuits.

Amount: £1,097,310
Funder: The Wellcome Trust
Recipient: University College London

Exploring glial roles in sculpting brain development 21 Feb 2018

Although two broad cell types, neurons and glia, compose the brain, neurobiologists have tended to focus on neurons, the electrically excitable cells that process information. Glia were thought of primarily as neuronal support cells. Recent work challenges this view and shows that glia play essential roles not just in supporting neuronal function but also in instructing their development. I propose three aims to address how glia regulate two key aspects of brain development, neuronal birth and neuronal identity: (i) A major challenge in neurobiology is defining the origin of neuronal identity (and thus diversity). I will investigate how signals sent by glia to naïve precursors determine the unique neuronal fates that these cells adopt. (ii) Although the brain has little regenerative potential, under restricted circumstances differentiated glia can act as stem cells to generate neurons. I have identified one such example and will probe the signals that reprogramme glia to generate neurons. (iii) I will explore how different glial types differ in their regulation of neural development. I will begin with a systematic survey of the signals released by different glial-subtypes and then manipulate these while evaluating their effect on neighbouring neural precursors and neurons.

Amount: £1,198,593
Funder: The Wellcome Trust
Recipient: University College London

Impact of missense mutations in recessive Mendelian disease: insight from ciliopathies 10 Apr 2018

Background: Over 1,800 autosomal recessive (AR) Mendelian-disease genes have been identified. Missense mutations account for 59% of protein coding region mutations, yet their precise functional effects remain largely uncharacterized. Two important questions in human genetics aim to explain interindividual variation in phenotypic severity and assign pathogenic mechanisms to different disease phenotypes (including independent phenotypes within the same syndrome). For AR disorders, it is thought that many missense mutations cause protein instability. For these hypomorphic mutations, disease phenotypes are defined according to quantitative genetic threshold effects within a protein interaction network. Project: We will focus on a subset of AR ciliopathies which are strongly enriched for missense mutations, where complete gene knockout is thought to be lethal (see Rationale-below). We will use gene-editing and quantitative protein-protein interaction analyses to systematically compare the phenotypic effects of frameshift (likely knockout/null) and missense mutations. We will test our hypothesis that these missense mutations disrupt only a subset of gene functions/protein interactions, using phenomics algorithms we have developed and unbiased phenotyping in cell lines and mouse models, allowing us to assign pathogenic mechanisms to disease phenotypes. In future, this approach could be extended to the estimated 10-20% of > 3,000 Mendelian-disorders enriched for missense mutations.

Amount: £1,706,863
Funder: The Wellcome Trust
Recipient: University College London

Investigating the effect and impact of binding RSV-G protein on pneumococcal growth and antibiotic sensitivity 21 May 2018

The pneumococcus (Streptococcus pneumoniae) is a global pathogen associated with high mortality rates in young children and the elderly. My research has shown that pneumococci rapidly increase their virulence by binding to the G protein encoded by human respiratory syncytial virus (RSV), the leading cause of viral pneumonia. This is thought to be mediated by the pneumococcal receptor for RSV, penicillin binding protein 1a (PBP1a), an important protein involved in bacteria cell wall synthesis and cell division. However, the mechanism behind the increase in virulence remains unknown. This proposal builds on my recent observations and brings together world-leaders in the fields of virology and bacterial cell wall biosynthesis to determine the immediate phenotypic and genotypic consequences of the pneumococcus binding to RSV-G protein. To do this I will: Determine whether binding RSV-G protein affects pneumococcal growth and increases pneumococcal cell lysis. Determine the effect of RSV-G on PBP1a gene expression and the enzymatic activity of pneumococcal PBP1a. Determine whether binding to RSV-G protein increases pneumococcal antibiotic sensitivity. These findings will help direct a larger study to determine the mechanisms of virulence enhancement during co-infection and the impact this has on inflammation, the host cell response and, importantly, antimicrobial therapy.

Amount: £99,958
Funder: The Wellcome Trust
Recipient: University College London

Exploring gene therapy approaches for neuroblastoma using a patient's own gamma delta T cells. 13 Nov 2014

Neuroblastoma is a rare childhood malignancy with tumours developing from the sympathetic nervous system. Approximately 50% of patients are affected by high-risk disease characterised by widespread metastasis. Five-year survival is only 40% despite highly aggressive multi-modal treatment regimes. Novel therapies that effectively target malignant cells whilst sparing normal tissues are therefore a research priority. Adoptive cellular therapy with T-cells engineered to express a Chimeric Antigen R eceptor (CAR) combine the antigen specificity of a monoclonal antibody together with T-lymphocyte cytotoxicity. Current approaches utilise alpha-beta T-cells due there abundance in the peripheral circulation and ease of expansion ex vivo. Gamma delta T-cells (gdT) however have many unique and advantageous properties, including innate killing ability, antibody-dependent cytotoxicity and professional antigen presenting function. When engineered with a CAR, gdT-cells may therefore may confer therap eutic advantage as we hypothesise they will give better tumour responses and better long-lived protection. This pre-clinical project investigates CAR-gdT-cells as a potential novel therapy for high-risk neuroblastoma. The ultimate aim is to engineer gdT-cells that have greater specific cytotoxcity, reduced off-target effects, and the ability to generate secondary immune responses leading to long-lasting anti-tumour surveillance. If successful, we will look to opening a CAR-gdT-cell phase 1 clini cal trial.

Amount: £114,615
Funder: The Wellcome Trust
Recipient: University College London

Neurobiology of speech communication:cognition, plasticity and social interactions 03 Dec 2014

Functional imaging studies (PET and fMRI) have revealed that human speech is processed along distinct (though interacting) streams, in ways that are analogous to the functional and anatomical auditory streams seen in animal primate studies. I am proposing a series of studies in which aspects of human speech perception and production are investigated, to identify the neural basis of low level and higher-order control of speech perception, the neural basis of production and perception of speech in different masking contexts, and plasticity and individual differences in speech processing. I am particularly interested in how we can apply these results to the understanding of clinical issues (e.g. aphasic stroke and cochlear implantation), and will address the latter with studies of cochlear implant users and simulations. I also aim to extend this work to consider how the importance of social factors, such as how communicative intent affects the neural regions recruited in addition to those involved in the linguistic processing of speech. This is an attempt to integrate the neurobiology of speech perception and production with themes in social neuroscience, and important link to establish, given the central role of speech as a communication tool.

Amount: £311,157
Funder: The Wellcome Trust
Recipient: University College London

Mechanisms underlying spoken language production: facilitating frontal brain networks following aphasic stroke. . 03 Dec 2014

Word-finding difficulties (anomia) are the most common and chronically disabling impairment after aphasic stroke. However, surprisingly little is understood about the contributions that different frontal brain areas make to anomia recovery, and how these areas function together as a network. The frontal language network overlaps considerably with those supporting other diverse cognitive functions such as cognitive control; both are likely involved in language learning/recovery. Here I seek to pl ace spoken word production in the context of wider cognition and its underlying neural mechanisms to understand how common brain areas, and possibly common processes, support such disparate functions in the damaged brain. To address this I will use whole-brain high-resolution structural and functional magnetic resonance imaging (fMRI) together with high-definition transcranial direct current stimulation (HD-tDCS), plus neuropsychological examination and behavioural training of aphasic strok e patients. Using factorial neuroimaging experimental paradigms paired with 'real-life' anomia training procedures I will examine brain-behaviour relationships. My first series of experiments will use fMRI in aphasic patients both with and without damage to left frontal cortices (Broca's area). I will investigate the immediate modulatory effects of HD-tDCS on patient's residual frontal brain effective connectivity during easy and hard naming and cognitive control tasks. The second experimental series will investigate longer-term changes (consolidation) in these frontal brain networks after extended anomia training (hard becomes easy) and will correlate effective connectivity parameters with speech relearning success. This approach will provide a powerful platform to understand the neural basis of cognitive and spoken language change following brain damage.

Amount: £1,276,036
Funder: The Wellcome Trust
Recipient: University College London

Natural killer cell subsets in the liver: phenotype, function and role in obesity-induced liver disease. 29 Oct 2014

Organ-specific natural killer (NK) cells form a distinct lineage from their circulating counterparts and have specialist physiological functions. In the last year, a liver-specific NK subset has been identified in mice. Whether an equivalent population exists in human liver is not yet known, nor is the function of these cells known in either humans or mice. My goal is to address these questions with specific reference to NASH. I will examine liver transplant perfusates by flow cytometry for the transcription factors that define the liver-specific NK subset, and for relevant surface markers. I will then investigate whether any of the subsets identified are liver-specific using in vitro lymphocyte differentiation assays and by comparing their representation in donor- versus recipient-derived NK cells from explanted livers. I will perform ex vivo assays for expected functions such as cytokine production and cytotoxicity. Microarray analysis will also be used to identify any novel function s. Using marginal tissue from liver resections, I will determine whether NK subset frequency and function differs between NASH livers and controls. To test the hypothesis that liver-specific NK cells affect the progression of NASH, I will examine disease severity in Tbx21[fl/fl]Ncr1[icre] mice, which specifically lack these cells.

Amount: £782,599
Funder: The Wellcome Trust
Recipient: University College London

How to promote positive physical activity behaviour in parents and their preschool-aged children: using cohort data to inform interventions. 13 Apr 2015

Physical activity is beneficial for adults and children alike, yet activity levels decrease throughout childhood into adulthood. Parents of preschool-aged children are at particularly high risk of insufficient activity, and their activity levels are associated with those of their young children. Low activity levels may therefore be detrimental to parents' and their child's health. Understanding what influences physical activity in these groups is important to determine who and what influences ch ange in activity, and when, to develop successful interventions to promote higher activity levels in preschoolers and their parents. This fellowship aims to establish determinants of change in activity in parents and their young children. First I will synthesize evidence of determinants and mechanisms of change from existing family-based interventions (phase 1). This will inform subsequent analyses of objectively measured physical activity data from UK and US cohort studies which aims to de termine: what individual, social and environmental factors are associated with change in activity in mothers (phase 2) and preschool-aged children (phase 3), and how maternal-child physical activity is associated over time (phase 4). This will provide important new information to aid development of population health interventions to positively impact the activity levels and subsequent health of families.

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

The development of neuronal circuits controlling sleep/wake behaviour in zebrafish models of autism. 19 Nov 2014

The main goal of the proposed research is to understand how the development of hypothalamic neuronal circuits that control complex behaviours such as sleep is disturbed in zebrafish models of autism. For this purpose I will harness a combination of powerful genetic tools available in zebrafish, cutting edge neuroimaging techniques and high-throughput behavioural analysis. The Rihel lab, in collaboration with the Giraldez labs at Yale, has identified diverse sleep/wake phenotypes in zebrafis h mutants harbouring mutations in genes associated with autism. I will test the hypothesis that these sleep phenotypes are due to the altered development and functionality of hypothalamic sleep circuits. I will examine the specification, patterning and connectivity of sleep relevant neuron population located in the hypothalamus, basal forebrain and brain stem using in situ hybridisation, immunostaining and transgenic zebrafish lines. Furthermore, I will image and compare the dynamic activity of developing zebrafish brains of wild-type and mutant larvae to determine the functional integrity of sleep circuits. Differentially active neurons will then be laser-ablated or optogentically/pharmacologically manipulated to directly test their specific sleep/wake circuit function and their contribution to the autism sleep phenotype.

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

Functional neuromics of the cerebral cortex. 21 Jul 2015

Cortical circuits comprise multiple classes of neurons and glia, whose interactions govern perception, behaviour, and thought. We propose to combine several new techniques to probe this circuitry with unprecedented precision by identifying, monitoring, and controlling the participating cells. We will: 1. Provide a definitive taxonomy of cortical cell classes. By applying single-cell RNA sequencing to tens of thousands of neocortical and hippocampal cells, we will identify cell classes and su bclasses, together with marker genes that in combination identify them. 2. Understand the anatomical organization of these classes. By applying in situ transcriptomics to cortical tissue, we will understand the position of each class in the circuit, and determine the molecular identity of selected projection classes. 3. Understand how these classes participate in sensory processing and behaviour. We will record the activity of neurons and glia in the neocortex and hippocampus of behaving mice, then classify the recorded cells by retrospective in situ transcriptomics. 4. Identify causal interactions among cell classes in vivo. We will reveal the causal influence of molecularly identified cells on the network by stimulating them using 2-photon optogenetics, while recording population activity. These data will constrain mechanistic models of the underlying circuit.

Amount: £4,189,482
Funder: The Wellcome Trust
Recipient: University College London

2 month costed extension 20 Jul 2015

Not available

Amount: £252,519
Funder: The Wellcome Trust
Recipient: University College London

Neuronal integration in sensory cortex: New paths to discovery. 04 Apr 2014

The cortex is known to process images and sounds through the activity of neurons in visual and auditory areas. However, little is known about how cortical populations integrate multiple sensory streams and modalities into coherent pattern, and how sensory-driven activity interacts with non-sensory, endogenous patterns of activity. These patterns may provide the context needed to interpret sensory signals and act upon them. We seek a unified view of how the cortex integrates multiple external and endogenous signals into the activity of neuronal populations. To this end, we will address a series of related questions within a common experimental framework: (1) What is the structure of population activity in sensory areas of the awake cortex? (2) What are the rules of interaction of multiple signals in awake cortex? (3) How does the structure of population responses change with cortical state? (4) How does cortical population activity relate to sensory-driven behavior? (5) What mechanisms control brain state and the structure of population activity? By answering these questions we seek to uncover fundamental laws that predict the population activity from sensory input and internal state, and that predict perceptual choice from population activity, and to provide insight into the underlying circuits and mechanisms.

Amount: £160,000
Funder: The Wellcome Trust
Recipient: University College London