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Recipients:
University College London
Award Year:
2015

Results

Molecular mechanisms and therapeutic strategies in amyotrophic lateral sclerosis caused by mutations in the C9orf72 gene. 26 Feb 2015

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by motor neuron degeneration. A hexanucleotide expansion in the C9orf72 gene is a common cause of ALS and my supervisors (Isaacs and Partridge) recently published evidence from a Drosophila model in the journal Science that neurotoxicity is mediated by dipeptide repeat (DPR) proteins generated by repeat-associated non-ATG translation. Emerging evidence suggests that DPR proteins cause nucleolar dy sfunction and resolving this in relevant disease models will significantly increase our understanding of and ability to treat C9orf72-ALS. Aims: Using C9orf72-ALS models I will evaluate if DPR proteins cause nucleolar dysfunction and interact with RNA and whether promising novel small molecules which bind C9orf72 repeat RNA reduce DPR formation, nucleolar dysfunction and neurotoxicity. Methods: I propose a carefully integrated approach that will combine assessment of nucleolar function an d therapeutic potential of the small molecules in 1) novel in vivo Drosophila models, with subsequent validation in 2) C9orf72 mutation human induced pluripotent stem cell (iPSC)-derived spinal motor neurons. This approach across model systems will serve to rigorously validate the findings made. Implications: These experiments may provide novel mechanistic insights into a common form of ALS and deliver pre-clinical data on an exciting therapeutic approach.

Amount: £250,511
Funder: The Wellcome Trust
Recipient: University College London

Cohesin proteins bridge genome topology and function during development. . 01 Apr 2015

Spatial and temporal control of gene expression is essential for development of complex multicellular organisms. My research focuses on understanding fundamental mechanisms controlling gene expression in mammalian cells. We are investigating how cohesin-mediated three-dimensional chromosome architecture influences gene regulation which drives cell-specific gene programmes. Chromosome structure and function are intimately connected. Recent molecular methods have shed new light on our underst anding of chromosome topology and mechanisms which regulate gene activity. Recently, a modular organization of chromosomes has been discovered, embedding genes and regulatory elements into complex chromosomes in a simple way. This new layer of genome organization (termed chromosomal domains) provides a compelling framework whereby distal elements can interact to drive gene regulation. Cohesin is central to chromosomal topology. Cohesin exerts its effects on genes primarily by anchoring long -range chromatin loops. These loops are distributed throughout the genome, creating a network of long-range contacts which structure domains and also tether enhancers to promoters. The precise mechanisms by which specific cohesin sites are assembled and how this cohesin-based organization supports cell identity are not fully known, yet are fundamental to our understanding of gene regulation. We will deliver new mechanistic understanding of how cohesin-based genome organization influences gen e regulation. We will address the functional role and molecular determinants of cohesin-mediated structure during dynamic developmental transitions using powerful new genetic tools and systems. This work will lead to deeper insights of the molecular transitions which accompany normal lineage commitment and how topological configurations of chromatin collaborate with transcription factors to drive differentiation.

Amount: £1,648,520
Funder: The Wellcome Trust
Recipient: University College London

Genetics and biology of drug resistant HIV . 07 Jul 2015

Early treatment of HIV as a means of prevention is seen as the major component of future strategies aimed at controlling the epidemic. South Africa hosts the largest ART cohort in the world - a unique environment to explore the wider implications of universal ART. The move to early ART will confer unprecedented selection pressure on the virus, with serious implications for subsequent lines of therapy, and HIV pathogenesis/transmission. In particular resistance to a core drug class - protease in hibitors - is poorly understood but could involve 3 genes or more genes including gag, pol and env. Given two of these are structural proteins interacting directly with the host, escaping virus could have altered cell tropism, antibody sensitivity, innate immune interactions and transmissibility both between cells and across mucosal surfaces. I propose to work between WT Africa Centre and the UCL London campus to gain insight into the pathogenic features of escaping viruses, as well as identifyi ng more precisely than ever before the determinants of protease inhibitor failure and likely efficacy of salvage therapies for patients failing these core agents. In order to achieve this, we will perform whole genome viral sequencing from patients pre and post failure, and we will also sythesize 10 pairs of full-length infectious clones representing baseline and escaping viruses. These reagents will be used to generate viruses for use within primary cell (T cell, macrophage) as well as humanize d mouse models of pathogenesis to understand potential biological implications of resistant viruses.

Amount: £2,067,756
Funder: The Wellcome Trust
Recipient: University College London

Characterising viral antibody evasion by conformational masking. . 27 May 2015

CM limits the availability of neutralisation targets; nevertheless, it does not prevent the emergence of antibodies against these sites. Rather, CM prevents antibodies from accessing their targets and inactivating virus particles in circulation. However, coordinated unmasking is necessary to enable functional domains to participate in virus entry. This imposes rate-limiting steps on the entry program, and introduces a phase in which the unmasked virus is vulnerable to antibodies. Using robus t in vitro models I will quantify the effect of CM on virus entry kinetics. I will also discover whether drugs that interrupt entry can extend the window of opportunity for antibodies. By limiting entry, CM confers a potential fitness cost; however, in natural infection this is likely offset by the benefits of antibody evasion. Exploiting deep sequencing analysis and phenotypic characterisation, I will perform in vitro and in vivo studies to establish the role of immune selection in maintaining CM. This will provide an important understanding of how immune responses shape viral evolution. Building on my expertise in cutting-edge microscopy, I will use a novel super-resolution virometry assay to directly measure antibody binding to defined model viruses and patient-derived variants; therefore quantifying the molecular consequences of CM.

Amount: £878,007
Funder: The Wellcome Trust
Recipient: University College London

Better understanding of affective behaviour through functional dissection of ventral subicular circuitry. 21 Oct 2015

The overall aim of the proposed work is to understand the control of affective behaviour, from the level of individual synaptic and cellular mechanisms through to the complex circuitry in which they are utilised. To achieve this I will investigate the ventral subiculum (vS). vS is considered crucial for affective behaviour, but due in part to its complex circuitry, how it carries out this important role is unknown. I will use a powerful combination of in vivo and in vitro circuit analysis to gai n a mechanistic understanding of how affective behaviour is controlled by vS circuitry, and altered by disease. I will first address the long-standing, but poorly tested hypothesis that distinct populations of projection neurons in vS have disparate and unique roles in the generation of affective behaviour using in vivo imaging and optogenetics. I will then investigate the afferent circuitry in vS that determines the activity of the different vS projection types, to provide a mechanistic m odel for how vS circuitry, and thus affective behaviour, is controlled. Finally, I will investigate cocaine-induced synaptic alterations in vS, and aim to provide a direct and mechanistic link between classically observed synaptic changes, circuit function and pathological behaviour.

Amount: £1,209,072
Funder: The Wellcome Trust
Recipient: University College London

Crowded growth: How volume and intracellular density relate to cell growth and proliferation. 11 Nov 2015

Significant amount of research, mostly focusing on signalling processes, has been carried out to understand the regulation of cell growth and proliferation. While some biological evidence is starting to emerge that cell volume or cell mass might regulate cell growth, the role of intracellular density has been largely overlooked. This is surprising, considering that mathematical and biophysical evidence suggests that intracellular density might be a critical regulator of various growth associated processes. I will investigate how changes in these fundamental biophysical properties of a cell, cell volume and intracellular density, affect growth and proliferation in human cells. My main goals are to (1) understand how protein synthesis and degradation scales with cell size and intracellular density, (2) study how cell division rate is dependent on cell size and intracellular density, (3) investigate potential regulation of intracellular density and (4) find translational research opportun ities for the work on cell volume and intracellular density. To achieve these goals, I will utilise flow cytometry, microscopy and microfluidic mass sensor based high throughput single-cell measurements together with my recently developed analysis method, which converts heterogeneous single-cell data to systems level information.

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

Neural substrates underlying auditory social cognition. 11 Nov 2015

How the mammalian brain recognizes and uses social cues to guide interactions with conspecifics is a central question in neuroscience. I propose to address this using a natural communicative behaviour in mice, in which males attract potential female mates by producing elaborate courtship songs in the ultrasonic range. This project proposes a unique research approach to study where and how auditory social signals are encoded in the mouse brain, and how these representations are used to guide beha vioural responses during social interactions. This will be achieved by combining an ethologically valid assay of natural female approach to males during courtship with large-scale neuronal ensemble recordings in auditory cortex to assess the neuronal representation of behaviourally relevant vocal sounds. Finally, the neuronal circuits causally involved in generating this social behaviour will be identified using molecular-genetic manipulations. Together, these three synergistic approaches will h elp clarify the neuronal substrates of auditory social cognition, and establish a mouse model of vocal interactions with important implications for the study and potential remediation of psychiatric disorders affecting social communication.

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

The mechanism controlling sorting and axonal retrograde transport in neurons. 01 Apr 2015

Neurons have unique morphologies, which are maintained by transport events allowing precise communication over long distances. Fast axonal transport constitutes the backbone of these trafficking pathways and is required for neuronal development and survival. Accordingly, several neurodegenerative diseases are associated with deficits in axonal transport, suggesting a causal role for axonal transport dysfunction in disease pathogenesis. Multiple evidence link fast axonal transport and neuronal homeostasis, yet the mechanisms responsible for long-term transport and sorting of physiological ligands, such as neurotrophins and their receptors, are still unclear. Our overall aim is therefore to define: What are the molecular mechanisms controlling cargo uptake and sorting along the axonal transport route? We uncover an essential role for nidogens, key components of the synaptic basement membrane, in the uptake and axonal transport of tetanus neurotoxin (TeNT), and clinical tetanus. Bas ed on our findings that TeNT exploits a trafficking route used by neurotrophins for their long-range transport and signalling, this proposal aims to uncover the role of nidogens in axonal retrograde transport and neuronal survival. Using a combination of biochemistry, cell biology and intravital imaging and taking advantage of our ability to analyse axonal transport in-vitro and in-vivo, we will address the following questions: i) Do nidogens undergo axonal retrograde transport and trans- synaptic transfer in neurons? ii) What is the nature of the receptor complex targeting nidogens to this route? iii) Which signals modulate axonal transport of nidogens? iv) What is the physiological function of nidogens undergoing axonal transport?

Amount: £1,747,223
Funder: The Wellcome Trust
Recipient: University College London

A reappraisal of peripheral pain pathways 08 Dec 2015

Action potential propagation velocity provided a useful system for categorising peripheral nerves for 75 years. Now, genetic definition of sensory neuron subsets is providing a more precise functional distinction; individual sensory neurons and their target dorsal horn neurons can be activated, silenced or killed genetically and defined in terms of their transcriptomes, and linked to behavioural changes. In addition, physiological stimuli can be used to drive activity dependent reporters allowing further definition of neuronal subtypes. In this proposal, we show how the exploitation of these methods will inform our knowledge of peripheral pain pathways, the key element in almost all chronic pain syndromes, and identify cell types and molecular targets that are critical for distinct types of pain sensation. Our work will encompass human and animal genetics and should provide clinically significant information.

Amount: £3,631,275
Funder: The Wellcome Trust
Recipient: University College London

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

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

Amount: £275,628
Funder: The Wellcome Trust
Recipient: University College London

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

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

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

Characterisation of cell types obtained from mixed cell cultures of the human olfactory mucosa, for the application of central nerve repair 23 Nov 2015

Spinal cord and root injuries are commonly due to road traffic accidents and can result in permanent paralysis with major physical, psychological and economic impacts. Although surgical repair of spinal root and cord injuries can restore some movement, patients seldom report good functional outcome. Olfactory ensheathing cells (OECs) are a promising cell candidate for nerve repair and can be obtained from the olfactory mucosa of the nose, where they normally induce repair of damaged olfactory nerve fibres for the sense of smell. They can be obtained by a simple biopsy of the olfactory mucosa using an endoscope. Through funding from the Health Innovation Challenge Fund, Mr David Choi and colleagues at UCL aim to better understand the cell quality attributes and final product formulation to ensure a robust, well-characterised cell product that is effective in laboratory assay systems and satisfies regulatory requirements. With this information the team can then proceed with production of cells for transplantation and plan to start a phase 1 clinical trial involving transplanting a patient's own OECs during the surgical repair of brachial plexus avulsion, within three years. Positive results would impact not only patients with brachial plexus injuries, but also patients with spinal cord injury or stroke.

Amount: £1,163,250
Funder: The Wellcome Trust
Recipient: University College London

Learning as Bayesian inference. 02 Dec 2015

Organisms face a hard problem: based on noisy sensory input, they must set a large number of synaptic weights. However, they do not receive enough information in their lifetime to learn the optimal weights (i.e., the weights that ensure that the circuit, system, and ultimately organism, functions as effectively as possible). In this kind of high noise regime, it is advantageous to compute a probability distribution over the weights, rather than just a point estimate (as is done under standard le arning rules). This would allow synapses to efficiently use incoming information, greatly improving learning. In addition, it would allow organisms to match learning rates to incoming information -- speeding up learning when the rate of new information is high, and slowing it down when the rate is low. Here we explore the hypothesis that synapses do compute, approximately, probability distributions over their weights. This leads to three specific questions: 1. What are the learning rules u nder the assumption that synaptic weights keep track of probability distributions? 2. What is the effect of these learning rules on large networks of spiking neurons? 3. How can we test experimentally whether these learning rules are the ones used by the brain? To address these questions, we will derive update rules for the probability distribution over synaptic weights using rules of probabilistic inference, and analyze, both theoretically and through simulations, the effect of those l earning rules on network behavior. We will then generate specific hypotheses, with the goal of collaborating closely with experimentalists to test them; those tests should result in further refinement.

Amount: £835,839
Funder: The Wellcome Trust
Recipient: University College London

Avoiding on-target off-tumour toxicity in cancer immunotherapy. 19 Nov 2015

Chimeric antigen receptors link MHC-unrestricted antigen specificity with T-cell signalling, facilitating potent and regulatable antigen-specific cancer recognition and killing. Clinical trials of CAR gene modified T-cells show unprecedented clinical responses, with the major limitation of on-target off-tumour toxicity due to expression of most cancer antigens on some normal tissues. In my Wellcome clinical training fellowship I identified a novel method of avoiding such toxicity by designing CA Rs for use in gdT-cells. These gdT-CAR cells combine innate killing limited to sites of cancer or injury with CARs providing co-stimulation to overcome the immunoinhibitory tumour microenvironment. I demonstrated proof of concept using two model antigens, GD2 and CD33, applicable to solid cancers (e.g. neuroblastoma) and myeloid leukaemias (e.g. AML) respectively. In my fellowship I will develop this by: 1) Identifying mechanism and relative efficacy of different co-stimulatory CAR endodomains in gdT cells 2) Investigate selectivity of co-stimulatory CARs in gdT against acute myeloid leukaemia compared with healthy blood cells bearing the same tissue antigen. 3) Investigate the use of mass cytometry for high-dimensional signalling analysis to inform CAR design. Efficacy, toxicity and mechanism will be assessed in a staged manner using cell lines and primary tissue.

Amount: £275,672
Funder: The Wellcome Trust
Recipient: University College London

The consequences of, and relationship between, amyloid deposition, grey matter microstructural change and atrophy in the MRC NSHD 1946 birth cohort 19 Nov 2015

The development of disease modifying therapies to delay the clinical onset of Alzheimer’s disease (AD) is of the highest public health importance. Robust biomarkers of the long pre-symptomatic period between the first appearance of the histopathological hallmarks of AD and the onset of clinical symptoms will be crucial for recruitment and monitoring in drug trials and clinical practice. I will analyse the multi modal MRI and amyloid PET imaging data of 500 individuals from the MRC National Survey for Health and Development (NSHD; the British 1946 birth cohort) to address the following key objectives: 1. Investigate whether amyloid deposition leads to microstructural grey matter change utilising diffusion based MRI and a new and novel multi-shell acquisition technique (NODDI).2. Investigate the extent and pattern of grey matter atrophy associated with amyloid deposition and compare sensitivity of diffusion based/NODDI metrics with measures of grey matter atrophy.3. Evaluate the sensitivity of tests of cognition, audition and olfaction in assessing early impairment of cortical function and the relationship with the the neuroimaging data.4. Investigate the relationship between neuroimaging metrics and cognitive trajectory throughout life.

Amount: £174,791
Funder: The Wellcome Trust
Recipient: University College London

Supportive supervision of mid level health workers in rural Nepal for improved job satisfaction, motivation and quality of care. 25 Mar 2015

Many low-income countries are suffering from a shortage of health workers in rural areas. In response to this, tasks are being shifted to mid level cadres who are often working without adequate management and support mechanisms. These cadres require emotional and clinical support in order to develop and retain their skills, and an enabling environment to provide good quality care. The evidence base about the impact of supportive supervision on primary health care is weak, and there is a need to develop the theory about how supportive supervisions may work. We will conduct action research with central and district level stakeholders, and health workers to describe and explore the difficulties facing mid level health workers, and discuss current weaknesses in existing supervisory mechanisms. We will also explore supervision preferences of mid level health workers, and the effect of gender and difference in cadre on supervisory needs through qualitative interviews in three districts. We will critically examine pilot interventions and conduct a realist review of the national and international literature to identify potential interventions which could be implemented for mid level health workers in rural Nepal. Findings will be fed back and discussed in a working group, and interventions presented to a wider group of stakeholders at a workshop. Cost information will also be prepared and presented at this workshop. After participatory prioritisation of interventions, we will develop an evaluation methodology and theories of change, which we will present at a dissemination meeting. We will seek funding for the implementation and evaluation of the prioritised supportive supervision interventions, and identify pilot districts in which to test interventions. We will disseminate our methodology and interventions among academic and practitioner audiences.

Amount: £33,367
Funder: The Wellcome Trust
Recipient: University College London

A novel biomarker platform for dementia research with single molecule sensitivity. 11 Jun 2015

Identification of biomarkers is increasingly important in diagnosis and therapeutic decision making in most areas of medicine and particularly so in neurological conditions due to difficulties of direct visualisation and tissue sampling of the central nervous system. Biomarkers are also critically important for clinical trial inclusion criteria and as outcome measures. Sensitive methods to measure markers are constantly sought and in clinical neuroscience cerebrospinal fluid (CSF) is one of the most promising biomarker matrices, although CSF volumes are often limited and not easily resampled. Biomarkers in CSF are at low concentration and so are not easily measured. A key objective is to develop novel biomarkers for core neuropathological changes in neurological diseases using ultrasensitive Simoa technology. The equipment requested is a fully automated analyser manufactured by Quanterix , the Simoa HD-1. Simoa (single molecule array) technology is based on standard immunochemical tec hniques and uses paramagnetic beads and standard reagents but is able to achieve much greater sensitivity than standard techniques due to the ability to trap single molecules in femtolitre volume wells allowing for a digital readout. measuring at the single molecule level. This can lead to up to 1000-fold better analytical sensitivity, compared to traditional ELISA techniques.

Amount: £119,531
Funder: The Wellcome Trust
Recipient: University College London

A preclinical magnetic resonance imaging system for neurology and oncology. 11 Jun 2015

This application is for a high-field (9.4T), preclinical MRI scanner. The key objective of the proposal is to increase the capacity for preclinical MRI at UCL, in order to support a research programme focussing on excellence in neuroscience and oncology. Currently, access to preclinical MRI at the UCL Centre for Advanced Biomedical Imaging (CABI) is limited to a single scanner, which was funded in 2008 by the British Heart Foundation to develop cardiac imaging. This system is used at full cap acity and is typically booked up to three months in advance. Many requests that the Centre receives for collaborative research cannot currently be facilitated, despite their potential for scientific excellence and for generating novel, highly impacting results, or must be tailored to the constraints of the currently available infrastructure. If funded, this proposal would enable cutting-edge research projects (including research into neurodegeneration, optogenetics and non-invasive tumour his topathlogy) to be undertaken robustly and without compromise. Several of the projects outlined in this application have elements of 'blue-skies' research that are highly novel and could generate data that is impacting, important and could provide benefit across numerous disciplines.

Amount: £870,000
Funder: The Wellcome Trust
Recipient: University College London

Novel metabolite based therapeutics for improved cholesterol, glucose and reduced weight gain 25 Aug 2015

Obesity, high cholesterol, increased glucose and insulin resistance contribute to a major and growing healthcare threat globally and represent a risk for the development of liver, renal and cardiovascular diseases, as well as Type 2 diabetes. Our project focuses on a new approach to tackling these aberrant metabolic conditions. It is based on studies of a knockout mouse with a remarkable phenotype: lean, resistant to high fat diet weight gain, increased insulin sensitivity and reduced cholesterol. Parallel metabonomic studies led to the discovery of key microbiomederived biomarkers in the knockout mouse. We will test the hypothesis that a microbiome-derived biomarker can be used as a therapeutic to moderate weight gain, plasma cholesterol and glucose and to improve insulin sensitivity.

Amount: £167,160
Funder: The Wellcome Trust
Recipient: University College London

Engineered Treg Therapy for Multiple Sclerosis 25 Aug 2015

Multiple sclerosis is an inflammatory demyelinating condition of the central nervous system. Although several disease-modifying treatments (DMTs) have been approved to reduce the frequency of clinical relapses, most patients continue to clinically deteriorate under current therapy schedules. Autologous haematopoietic stem cell transplantation can have lasting beneficial effects for patients, but the procedure requires aggressive myelo-ablative conditioning which is associated with substantial toxicity. Neither DMTs nor stem cell transplantation can mediate antigen-specific suppression of the immunopathology of MS. Regulatory T cells (Treg) have the ability to suppress unwanted immune responses of T cells, 8 cells and inflammatory myeloid cells. We have previously shown in a murine model that T cell receptor (TCR) gene transfer is a robust technology to generate antigen-specific Treg. In this project, we will use cell engineering technologies to produce Treg that specifically suppress inflammation in the CNS. The planned preclinical work is expected to provide the basis for clinical trials in patients with MS.

Amount: £227,006
Funder: The Wellcome Trust
Recipient: University College London