- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Young people in sub-Saharan Africa are central to ending the HIV epidemic. However, uptake of proven protective interventions is low and evidence on who does/does not engage is limited. Theory predicts that behaviours and intervention uptake cluster within social networks. Interventions in other settings have successfully leveraged social ties to improve intervention impact. I aim to: (1) use novel methods to identify how social networks pattern risk for HIV acquisition; and (2) test the feasibility of using such knowledge to improve intervention uptake. I will undertake this work at the Africa Health Research Institute in rural KwaZulu-Natal, South Africa. Following qualitative interviews with young people exploring their social networks and social norms, we will then quantitatively follow 600 15-24 year-olds, together with their close friends and family, for three years. Using these longitudinal data, we will statistically model how social contacts influence behaviour and HSV/HIV acquisition. We will then quantitatively and qualitatively evaluate the feasibility of using network-selected peer-educators to promote uptake of HIV self-tests and subsequent treatment. We will compare how influential peer-educators differ from randomly selected ones in terms of willingness to be involved, training dynamics and health impact.
Lung cancer development is an evolutionary process, involving accumulation of mutations within a given environment. However, although driver alterations and mutational processes in lung cancer evolution have been elucidated, an understanding of the constraints and selection pressures that govern cancer development and their evolution and genomic regulation is unclear. Moreover, while studies have revealed that driver alterations can be present in ‘normal’ tissue, the differences between such somatic genomic evolution and cancer evolution is unclear. I hypothesise that knowledge of the genomic and transcriptomic mechanisms underpinning tumour evolution, coupled with an understanding of constraints and selection pressures that shape tumour development, can inform approaches to tackle cancer. I have previously developed bioinformatics methods to disentangle a cancer’s life history from multi-region sequencing data (e.g. de Bruin and MCGRANAHAN, 2014 SCIENCE; McGRANAHAN et al., 2016 SCIENCE), and developed tools to elucidate immune escape (MCGRANAHAN et al., 2017 CELL). I propose to extend these methods using normal tissue sequencing, public and private data from collaborators, to obtain a pan-cancer database of the evolutionary trajectories of thousands of tumours. Evolutionary maps, including immune micro-environmental and therapeutic selection pressures over space and time, will provide a systems level understanding of cancer evolution.
Background Prescribing for bipolar disorder is a major clinical dilemma as long-term pharmacological treatment is often necessary. Lithium is the most effective mood stabiliser. However, only 30% of individuals have a good therapeutic response. Presently, there is no reliable way to predict response or adverse event risk, or if an alternative treatment would be better for that patient. Aim To personalise prescribing for people with bipolar disorder via prediction models that quantify potential benefits and risks of existing treatments based on clinical phenotypic characteristics of the individual. Objectives Identify individualised clinical predictors of lithium and second-generation antipsychotic response. Determine clinical predictors of chronic kidney disease in individuals taking lithium. Determine clinical predictors of pathological weight gain in individuals taking second-generation antipsychotics. Methodology Data sources Swedish population registers, Hong-Kong health registers, Taiwanese health insurance database, UK primary care data linked to secondary care admission records, and UK mental health care data. Analyses Traditional epidemiological and machine learning methods; drawing on the strengths of each approach. Prediction model generation I will combine predictors from different datasets; resulting in models predicting drug response, chronic kidney disease and weight gain. Application Prediction models will be presented as online and smartphone application clinician decision aids.
Lysosome turnover in health, aging and disease 17 Jul 2018
Lysosome dysfunction is implicated in lysosomal storage diseases, and multiple age-related neurodegenerative diseases, including Parkinson’s, Alzheimer’s and age-related macular disease. Lysosomes are signalling organelles central to maintaining cellular homeostasis. Nutrient sensing on the lysosome can lead to nuclear translocation of the transcription factor, TFEB, and lysosomal gene transcription. However, it remains unclear how newly synthesised lysosomal proteins are packaged into new lysosomes and how old/damaged lysosomes are cleared. We recently established models of lysosomal aging/dysfunction in retinal pigment epithelial cells, taking advantage of their huge degradative burden, and identified conditions that upregulate lysosome biogenesis/activity. We propose to identify the trafficking steps and molecular machinery underlying lysosome biogenesis and test the relative contributions of lysosome exocytosis and lysophagy (lysosome autophagy) to cellular clearance of aged/damaged lysosomes. Our ultimate goal is to exploit these mechanisms to promote damaged lysosome clearance or rejuvenation and/or promote lysosome biogenesis for the treatment of diseases where lysosome activity is compromised. Treatment efficacy in upregulating lysosome activity, whilst readily measurable in culture, is difficult to assess in vivo. We will establish a molecular signature of aged/damaged lysosomes in cultured RPE that can be used to identify damaged lysosomes in aged/diseased retinae.
Efficient and transparent methods for linking and analysing longitudinal population studies and administrative data 05 Jul 2018
The Wellcome Trust LPS Strategy states that research is needed to i) underpin efficient linkage of multiple datasets, ii) quantify potential biases resulting from linkage, and iii) to handle linkage error in data analyses. We propose a programme of methodological research to develop efficient and transparent methods for linkage and analysis, to help maximise the joint potential of existing longitudinal population studies and multiple administrative datasets. Our proposed work packages will focus on linkage of LPS and multiple administrative datasets: WP1: Facilitate development of innovative linkage methods for multiple datasets, by developing shareable software to generate synthetic datasets that are generalisable to a range of research settings. WP2: Develop methods for efficient linkage of multiple datasets by expanding existing probabilistic linkage methods to the setting in which multiple administrative or LPS datasets are to be linked dynamically, and where there are multiple sets of identifiers (e.g. collected at different time-points). WP3: Provide appropriate tools for analysis of linked data by extending existing imputation methods for handling linkage uncertainty and avoiding bias within analysis. WP4: Maximise the value of approaches developed in WP2-3 through evaluation using exemplar linkages and dissemination of methods to the LPS community and other key stakeholders.
Cellular mechanisms underlying the morphogenetic biomechanics of mammalian neural tube closure 30 Sep 2018
Primary neurulation is a biomechanical process whereby the flat neural plate folds into a closed neural tube (NT). Closure initiates at the hindbrain/cervical boundary and "zippers" bi-directionally to form the cephalic and spinal NT. Failure of NT closure results in defects including spina bifida, which continue to affect 1:1,000 pregnancies. Despite advances in delineating its genetic control, we lack an integrated understanding of neurulation as a biomechanical morphogenetic process. To this end I have combined mouse posterior neuropore (PNP) live-imaging, laser ablation, and novel strain-mapping workflows to describe the tissue-level biomechanics of spinal closure. These revealed that the PNP is biomechanically coupled by a far-reaching actomyosin network, identified teratogenic/genetic models in which altered PNP biomechanics predict spina bifida, and identified a novel closure-initiation point ("Closure 5") which forms at the embryo’s caudal extreme. We now propose to determine: Are mechanical forces which promote and oppose NT closure balanced through actomyosin-dependent contractility overcoming tissue rigidity, up to a failure threshold? Do biomechanical differences between spinal and cephalic closure account for the latter’s apparent predisposition to failure? Does Closure 5 formation critically facilitate completion of spinal neural tube closure in humans and mice, and how is its morphogenesis regulated?
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.
Understanding how nNOS signaling in the gut influences the development, maintenance and function of interstitial cells of Cajal. 21 May 2018
Loss of neuronal nitric oxide synthase (NOS1, a.k.a nNOS) neurons has been implicated in a range of gastrointestinal motility disorders including Achalasia, Gastroparesis and Diabetes. Recent studies have demonstrated that global knockout of Nos1 results in reduced populations of interstitial cells of Cajal (ICC). This key population is crucial for pacemaker function and neurotransmission within the gut wall. Interestingly, rescue of NOS1+ neurons in the Nos1-/- colon after transplantation of enteric neural stem cells leads to restoration of ICC numbers, suggesting NO signaling may be critical for the development of ICC. However, it is unclear whether such changes in ICC are a direct result of NO (nitric oxide) signaling or are a secondary consequence of other phenomena. The goal of this project is to: assess the effects of temporal perturbation of NO signaling on the functional development of ICC. The key aims of this project are to: i) develop an inducible Nos1 conditional knockout mouse model to allow temporal control of NO signaling. ii) assess neuronal composition and iii) the development/function of ICC after inducible knockout of Nos1. This study will provide key evidence as to NO-regulated ICC development, which might play a key role in normal motility and disease.
Our past experiences are captured in autobiographical memories that serve to sustain our sense of self, enable independent living and prolong survival. Despite their clear importance and the devastation wreaked when this capacity is compromised, the neural implementation of autobiographical memories has eluded detailed scrutiny. My goal is to understand precisely how autobiographical memories are built, how they are re-constructed during recollection and how these memory representations change over time. My aim is to identify the mechanisms involved in these processes and thereby establish a theoretically enriched account of their breakdown in pathology. This endeavour will be enabled by cutting-edge, multi-modal technology that includes a new wearable MEG system and ultra-high-resolution MRI. The ventromedial prefrontal cortex and hippocampus are heavily implicated in autobiographical memory. I will test a novel hierarchical model that specifies their distinct roles and how they interact to produce the seamless encoding and recollection of our lived experiences. Overall, this new extension of my work will expose autobiographical memories as never before, revealing the millisecond temporal dynamics, and the laminar-specific and hippocampal subfield processing that supports their evolution from the point of inception, through initial sleep cycles and then over longer timescales.
Lung cancer remains the leading cancer-related cause of death in the UK. Early detection and treatment are critical to improving outcomes. Our lab has collected a unique set of lung tissue samples from patients with pre-cancerous disease, some of whom have gone on to develop cancer. By studying the genetic and molecular profiles of these samples we aim to elucidate the mechanisms of progression from pre-cancerous disease to invasive cancer. By doing so we can identify future methods of treatment and prevention. My work focuses on analysis of vast quantities of data produced by this program. We have recently studied the genetics of these samples, including which genes are expressed, which are mutated, and how they are regulated. From these complex networks we identify key signals of instability in the genome, which we believe are driving progression to cancer. These data provide a snapshot of early cancer. The first aim of this project is to investigate the dynamics of this process using longitudinally collected samples, and new techniques which can probe these samples on a single-cell level. The second aim is to study the immunological mechanisms by which some pre-invasive lesions regress and do not become invasive cancer.
Genomic instability triggers catastrophic events that restructure parts of the genome and provide a proliferative advantage to the cancer cell (e.g. through oncogene amplification) in up to 30% of cancers. There is recent evidence that suggests these types of events may also impact immune responses, by affecting genes that are involved in the interaction between cancer cells and their microenvironment. This project aims to study the impact of two well defined catastrophic events, chromothripsis (massive chromosome-wide rearrangements) and kataegis (hypermutated regions), on genes involved in immune-related pathways in oesophageal adenocarcinoma. The student will work with whole-genome sequencing data from 120 samples of oesophageal tumours available from the International Cancer Genome Consortium and will employ bioinformatics approaches to address the following key goals: (1) identify chromothripsis and kataegis events using computational protocols previously established in the group; (2) identify the genes affected by these events via genomic overlap methods; (3) summarise the proportion of the genes affected that are involved in immune signalling pathways (as recorded in relevant pathway databases). This will enable us to assess the likely impact of such catastrophic events on immune system processes and further clarify their implication in immune evasion during cancer development.
Neural circuits in the brain underlie sensory perception and motor control, functions that are often impaired during neurological disorders. However, many aspects of circuit function remain unclear. These include how sensory and motor information is represented and transformed as it flows through neural circuits. In this project, I will study the properties of Golgi cells, a particular type of inhibitory neuron in the cerebellar cortex, a brain area that helps coordinate movements and predict thier sensory consequences. To do this I will use a new high speed 3-dimensional microscope technology that can measure signals as they rapidly flow through complex neural circuits deep within the brain of mice expressing fluorescence reporters of neural activity. By examining how the activity of populations of inhibitory neurons change during different behavioral tasks and during learning, I will determine how these neurons contribute to information processing in the cerebellum. By combining this imaging method with methods for manipulating neuronal activity and network models of circuit function I will identify the underlying mechanisms. This research will lead to fundamental new insights into cerebellar function and will provide a framework for understanding what goes wrong during neurological disorders.
The role of the Trem2 R47H mutation in the development of Alzheimer disease phenotypes in APP knock-in mice 31 May 2018
The field of research into Alzheimer’s disease is lacking a transgenic mouse model which shows progressive degeneration like in humans. Recently, there has been increased interest in the involvement of the immune system of the central nervous system, particularly microglia, which co-localise with amyloid-beta plaques, potentially limiting toxicity. TREM2 is a protein expressed by microglia and the R47H mutation is an identified risk-factor for Alzheimer’s disease. We propose that combining this microglial risk-factor with raising amyloid beta in APP knock-in mice may exacerbate the Alzheimer's phenotype, potentially leading to tau pathology. Initially I will be taught to perform whole-cell voltage-clamp in brain slices. I will then use a novel TREM2(R47H) knock-in mouse and examine variables previously reported as altered in transgenic APP/PSEN1 mice (and confirmed in APP knock-in mice, unpublished). In particular I will record spontaneous and miniature excitatory postsynaptic currents, the frequency of which is dependent on the probability of glutamate release and number of synapses; the amplitude dependant on the number of postsynaptic receptors. These experiments will help to elucidate the effects of microglia in early synaptic changes involved in AD and will provide initial characterisation of the TREM2 mice that will be crossed with APP knock-in mice.
Healthcare environments across the globe are encountering new challenges as they respond to changing populations, global austerity, rapid technological advances, personalised medicine, and demands for more patient involvement. We believe that qualitative health research (QHR) can contribute to our understanding and responses to these challenges, and we have developed a proposal which aims to expand and improve the work of this field. This proposed work will be conducted through our UCL Qualitative Health Research Network (QHRN) and will include the following activities: 1) a networking and brainstorming event to create a forum for the critical analysis and improvement of QHR; 2) the fourth QHRN symposium, a two-day event with 200 delegates, 20 oral presentations and 40 posters; and 3) our quarterly seminar series, which showcases presentations from leading scholars in QHR. The main outputs generated through these events and activities will include: A position paper detailing recommendations for the improvement of QHR, publication of our proceedings from the symposium in a peer-reviewed journal, workshops and other training opportunities at the QHRN Symposium, the continuation of communication channels for members of the network (website, email listserv, and Twitter account), and dissemination of findings of QHR to patient organisations, practitioners and policymakers.
Our new UCL Unit for Stigma Research (UCLUS) will be a hub for innovative high quality research and theory production in the field of stigma research. UCLUS brings together research across diverse fields, including intellectual disability, mental health and dementia, and explores cross-cutting themes and opportunities for research. We are seeking funding to support UCLUS activities and explore areas for new research on stigma resistance and disclosure decision making, two novel areas in which we are piloting work. A better understanding of what makes some members of highly stigmatised groups more vulnerable/resistant to stigma, and how they manage disclosure offers the potential for innovative contributions to broader theorising on responses to adversity. It can also inform the development of interventions that enhance wellbeing via capacity to resist stigma among members of highly stigmatised groups. Funding will allow us to (a) explore this area further, (b) develop a research agenda, (c) build capacity for high quality research, and (d) extend existing and form new partnerships to take this work forward through the public launch of UCLUS, a seminar series, development of the research unit's social media presence, a UCLUS led session at the 2018 IASSID European Congress, and international collaborative visits.
Aim: Investigating the relationship between genotype, gene expression and phenotype of microphthalmia, anophthalmia and ocular coloboma (MAC), which collectively causes one-third of life-long blindness and severe visual impairment in children worldwide. Research questions: What are the pathogenic variants underlying MAC? How do molecular subtypes correlate with phenotype and stratify clinical risk? What molecular pathways are involved in human eye development? What is the relationship between genotype and gene expression in microphthalmia? Key goals and methodology: 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. 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. 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. Outcomes: 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.
Thanks to the Wellcome Trust and other leading international institutions, we have developed and proved the viability of a new generation of recording probes that will transform electrophysiology. These "Neuropixels" probes transcend past approaches, recording hundreds to thousands of neurons simultaneously. Several key steps are now necessary to maximize the impact of this new technology, enabling its widespread use in the neuroscience community. We must develop radically new recording equipment and software, provide training, and build a collaborative community of users (Aim 1). To allow this community to fully exploit the potential of this technology, we must extend it to a larger range of applications: multi-shank probes, wireless recording for freely moving animals, and optrodes for use with optogenetics (Aim 2). Meanwhile, we will obtain ground-truth data to calibrate error rates, and begin the development of a tool to automatically identify brain regions based on electrophysiological characteristics (Aim 3). This project integrates software and hardware engineering, fabrication efforts, neurophysiology tests, and behavioral and anatomical techniques. It thus requires a collaboration between laboratories with different skill sets, and a unique nanoelectronics research partner, IMEC. The results of this collaboration will transform the field of neuroscience.
International Brain Laboratory 30 Sep 2017
Understanding mechanisms of brain function is a scientific frontier with enormous potential benefits which is now within reach, thanks to recent exciting technical innovations. However, given the brain’s extraordinary complexity, effectively harnessing these tools is beyond the reach of single laboratories pursuing problems in isolation. This initiative - the International Brain Laboratory - will focus the efforts of 20 laboratories to understand the neural mechanisms supporting decision-making behavior in mice. As in real-world foraging contexts, mice will combine information from sensory stimuli with internal estimates of evolving reward availability. To understand how sensory signals are integrated across the brain and combined with an internal, dynamic understanding of reward structure, we will measure brain-wide neuronal activity using 2-photon imaging and high-yield electrophysiology with Neuropixels probes. Theorists and experimentalists will work closely together to interpret data, making use of standardized data processing pipelines and immediate cloud-based data sharing. This is a paradigm-shifting approach in terms of its large-scale collaborative structure and its aim to provide a mechanistic explanation of decision-making behavior across brain structures. Further, by harnessing strategies for sharing data and analyses to ensure tight collaboration and improved reproducibility, we aim to provide a new template for global neuroscience collaborations.
I am an undergraduate Neuroscience Msci student studying at the University of Bristol. I am undergoing an industrial trainee year, with Alzheimer’s Research UK University College London drug discovery institute (AR-UK UCL DDI), as part of my course. The AR-UK UCL DDI is a newly established unit in UCL, with core funding from Alzheimer’s Research UK. Its goal is to discover new approaches and therapies for dementia, a core symptom of a number of important diseases ("neurodegenerative diseases" of the brain such as Alzheimer’s disease). With the increasing aging population these neurodegenerative diseases are becoming a huge individual, societal and economic problem. The AR-UK UCL DDI currently has 12 scientists and will increase to about 24, and is equipped to enable the scientific experiments and studies to be performed.My industrial trainee year with the AR-UK UCL DDI will allow me to experience neuroscience in the research setting with an opportunity to use techniques commonly used in the field. The placement will provide a very practical learning in a professional environment, challenging me both personally and academically. It will also expose me to the process of working towards developing new therapies. I will be able to develop my interpersonal skills alongside vital experience working in lab with experienced colleagues. I will take the confidence and skills built during the placement into my final year and in my future studies and career as I hope to do a PhD after my undergraduate course.Project details: Neurons are key cells of the brain. Synapses are the key points that neurons communicate to each other, and are thought to be the basis of learning and memory. In neurodegeneration the neurons and the synapses decrease in number and ability to function, leading to progressive memory loss, dementia and eventually, death. Therefore ways of protecting the neurons and synapses, and maintaining their function, could be useful therapeutic approaches. The project will involve growing neurons in a cell culture dish; it is possible to do this by obtaining the neurons from mouse brains. The neurons are able to form synapses in the culture dish, which mimic the synapses that would be naturally formed in the mouse brain. I will use these cultured neurons to develop ways of measuring the number of synapses. It will be possible to measure the number of synapses by using fluorescently tagged antibodies that bind specifically to neuronal proteins that localise to synapses, and then use microscopy to count the number of those synapses. Once I have set up this system, I will be able to add various small molecules (compounds) and drugs and identify any that are able to increase the number of the synapses. Such small molecules or drugs could be the starting point for developing new therapies for dementia.
Mechanisms and Regulation of RNAP transcription 11 Jul 2017
This grant focuses on four lines of scientific enquiry converging on RNAP function Characterisation of the molecular mechanisms underlying RNA polymerase and basal factors that facilitate transcription initiation, elongation and termination by using multidisciplinary approaches in vivo and in vitro. This includes using bespoke transcription assays, structure elucidation and a global characterization of the occupancy and transcriptomes. Identification of novel gene-specific factors and characterization of the proteomes of transcription preinitiation- and elongation complexes in vivo. Identification and characterization of RNAP-associated proteinaceous- and RNA regulators. Characterisation of the structure and function of archaeal chromatin formed by A3 and 1647 histone variants. A biophysical characterization of protein-DNA interactions and a whole-genome view of histone occupancy. Focus on the impact of chromatin on RNAP as it progresses through the transcription cycle, and the role of elongation factors to overcome the inhibitory effect of chromatin. Characterisation of factors that modulate RNAP during virus-host interactions. Virus (RIP)- and host (TFS4)-encoded RNAP-binding factors function as global inhibitors of transcription and their mechanism is reminiscent of antibiotics. Using two virus libraries of we want to screen for novel RNAP-binding regulators and use them as molecular probes to dissect RNAP function.