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Recipients:
University College London
Award Year:
2017

Results

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

Global Health 50/50: Towards accountability for gender equality in global health 04 Dec 2017

We propose to establish Global Health 50/50, a new initiative seeking to advance action and accountability for gender-equality in global health. Gender is a key driver of power to exercise the right to health, including exposure to risks of poor health, health seeking behaviours, and access to quality health care. Gender inequalities continue to define and drive career pathways and opportunities for people working in global health organizations. While some progress has been made, major gaps and challenges remain. We seek to raise awareness of persistent inequality and identify pathways to change. We will establish a network of experts in gender and global health, working with an advisory body drawn from the realms of politics, development, management, advocacy, human rights, social justice. Global Health 50/50 will publish an annual report on the state of gender-related policies and practices of 150 major organizations working in the field of global health.

Amount: £29,764
Funder: The Wellcome Trust
Recipient: University College London

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.

Amount: £1,998,000
Funder: The Wellcome Trust
Recipient: University College London

Integrative structural biology of protein folding during biosynthesis on the ribosome 05 Apr 2017

Central to the activity of all living systems is the need for polypeptide chains to acquire their biologically-active structures and avoid the competing events of misfolding. It is well established that the majority of proteins begin to acquire structure as highly-dynamic nascent chains during biosynthesis on the cell’s protein biosynthesis machinery, the ribosome. A detailed molecular understanding of how this native structure is acquired and how misfolding is avoided during biosynthesis is sparse. We will build on our capacity to derive structural and dynamic mechanistic information of the fundamental process of co-translational folding: we will produce a multi-scalar analysis extending from in vitro to in vivo to provide a comprehensive, high-resolution description of emerging nascent chains (NC) during biosynthesis. Our research will integrate NMR and cryo-EM to answer emerging questions regarding the observation that the ribosome itself can modulate folding processes, and also act as a hub for the recruitment and co-ordination of auxiliary proteins that can assist NC folding and modification processes. Structure-based design, incorporating protein engineering and ribosome modification will dissect NC folding mechanisms and understand how misfolding is avoided. This underpins aims to reshape co-translational folding, targeting the ribosome and NC at the earliest stages of protein-biosynthesis.

Amount: £2,034,461
Funder: The Wellcome Trust
Recipient: University College London

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

The neonatal CNS is highly responsive to noxious stimulation and early pain exposure, such as neonatal surgery or routine clinical procedures, cause persistent changes in somatosensory processing. It has been therefore been proposed that early life pain experience may determine adult pain sensitivity. Thus, an understanding of the postnatal development of the somatosensory and nociceptive system, and how it is influenced by early pain experience is an important neurobiological question. This project focusses upon developing nociceptive circuits within the dorsal horn of the mouse spinal cord and the interaction between microglia and neurons in this process. I plan to investigate how microglia shape nociceptive synaptic connections during normal postnatal development and their role in altering nociceptive circuitry after early life injury. The following questions will be addressed How do nociceptive and tactile afferents become structurally and functionally organized in the postnatal dorsal horn (dorsal horn sensory connectome)? What role do microglia play in the development of dorsal horn sensory connections under normal conditions and after neonatal injury? How do microglia change over postnatal development under normal conditions and after neonatal injury? Is injury-induced priming of microglia due to changes in the dorsal horn environment, changes in microglial properties, or both?

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

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

The overall aim of this project is to use viral tracing, electrophysiology and optogenetics to investigate the local circuitry of the ventral subiculum (vS), and how this circuit is altered by social isolation stress – a common route to affective disorders such as depression and anxiety. I will first investigate the anatomical distribution of neurons in vS that project to the prefrontal cortex or the NAc. These have been shown to be distinct parallel populations with unique circuit functions, but very little is known about their detailed local circuit organisation. Next I will use optogenetics, electrophysiology and viral tracing to determine the functional connectivity of the local circuit that defines the differential activity of these projections. Despite strong hypotheses that local control is key in this circuit, how this is acheived mechanistically remains unknown. Finally, I will determine how this detailed projection-specific circuitry is altered by social isolation - a manipulation that drammatically alters vS circuitry - and aim to provide more specific targets for in vivo manipulations aimed at reversing isolation-induced behavioural deficits. Overall, these experiments will provide for the first time mechanistic insight into the function and organisation of vS circuitry, from individual synaptic connections, to circuit function.

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

Water resistance: a study of environmental justice, resilience and citizen science activism in Mexico City 02 May 2017

This research will explore resilience in the context of environmental justice, with a focus on water insecurity in Mexico City. The concept of resilience is central to public health and climate change discourse, but is rarely critiqued. Addressing this omission is crucial: resilience frameworks can conceal social inequalities, uphold political status quo, and overlook local experience. Equally, few anthropological studies have examined resilience and urban water insecurity. In Mexico City these gaps are especially prescient. The third most water-stressed city in the world, low-income neighbourhoods have limited access to water. Communities often protest in response. Drawing together an ethnographic study with the digital participatory methods of citizen science, the goals of this research are to: Understand the meaning and practices of resilience amongst people who experience water insecurity. Investigate the role of digital technology and citizen science in this space. Inform future uses of resilience in environmental justice research, design and policy. Through these objectives, the research acts at the intersection of social inequality, public health and the environment. The outcomes will contribute to anthropological theory and knowledge, open the potential for trans-disciplinary collaborations, and bring a more sensitive and ethical perspective to the overlap of climate change and health.

Amount: £96,532
Funder: The Wellcome Trust
Recipient: University College London

Antibiotic resistance in urinary tract infections in a primary care cohort in East London 30 Sep 2017

Antimicrobial resistance (AMR) is an alarming global issue causing difficulties for individual patient management and health systems. Antimicrobial use and misuse is the main driver behind AMR, and prescribing interventions such as antimicrobial stewardship programmes are our our main defense against it. We currently have a limited understanding of who is at most risk and how specific prescribing patterns drive resistance. This PhD will build on the unique resource of the East London Data Linkage Project that has already linked primary and secondary care records across two Clinical Commissioning Groups, by establishing further linkages with microbiology data on resistance patterns across a highly diverse population of more than a million people. This will enable a broad range of analyses identifying how risk factors such as ethnicity, social deprivation, age, gender and co-morbidities affect prescribing patterns and resistance. It will allow individual-level analyses of how resistance is related to exposure of specific antibiotics, how prescribing of one antibiotic class may lead to co-selection of resistance in other antibiotic classes, and the temporal relationships between antibiotic exposure and resistance. Analyses will inform our scientific understanding of resistance, and also present opportunities for personalised prescribing based on individualised risk rather than area-based blanket antibiotic policies.

Amount: £290,622
Funder: The Wellcome Trust
Recipient: University College London

Vacation Scholarships 2017 - University College London 16 Jun 2017

Vacation Scholarships 2017 - University College London

Amount: £25,500
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

Optimisation of carrier materials for the delivery of olfactory ensheathing cells in spinal cord injury 27 Apr 2017

Transplant-mediated repair is a promising method in spinal cord injury (SCI) treatment. This involves transplanting therapeutic cells that promote nerve regeneration at the site of injury. For SCI, one promising therapeutic cell type is olfactory ensheathing cells (OECs). These have been shown to remyelinate demyelinated axons and promote new synapses following injury. They are also easily accessible clinically via trans-nasal endoscopic biopsy, and compelling pre-clinical evidence means that they are now close to being formally tested as part of a first-in-man clinical trial. However, currently these cells are delivered as a simple cell suspension, and this is unlikely to be optimal for creating a permissive and optimised repair environment. Thus, the objective of this project will be to develop and engineer optimised biomaterial scaffolds for OEC delivery. In doing so, it is hoped that a permissive 3D extracellular environment can be created, and the phenotype and behaviour of OECs optimised for spinal cord repair. Promising prospective biomaterials include fibrin, collagen and collagen-fibrin blends. To this end, we will investigate the effect of these promising carrier materials on OEC survival and phenotype, particularly with a focus on changes they may cause on 3D cell morphology.

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

Somatic adaptation and sex differences in human endocrine development and disease 28 Nov 2017

Our work focusses on new genetic mechanisms affecting human adrenal and reproductive function. We have recently described a multisystem growth restriction disorder caused by gain-of-function of SAMD9, where somatic adaptation can modify phenotype and mask detection of the genotype. In parallel, we developed a transcriptomic atlas of human adrenal and gonad development, mapping out sex-specific effects of organogenesis. We now plan to develop these insights to address several related fundamental questions: 1) How extensive is SAMD9 variability in endocrine and growth phenotypes and does dynamic somatic adaptation play a wider role in human disease mechanisms; 2) What are the dynamic roles of sex chromosomes and sex hormones in development (focussing on brain, adrenal gland and genital tubercle), and how does genetic variability of the X-chromosome contribute to phenotype in Turner syndrome (45,X); 3) Can we apply these concepts to discover new genetic mechanisms underlying adrenal and reproductive disorders. This work would provide novel disease models and approaches to analysis, could link the dynamics of development and sex-differences to common conditions (e.g. neurodevelopment, stress, early-onset hypertension), and would continue to elucidate the causes of human adrenal and reproductive disorders, with important implications for personalised management and development of new therapies.

Amount: £1,561,134
Funder: The Wellcome Trust
Recipient: University College London
Amount: £2,814,500
Funder: The Wellcome Trust
Recipient: University College London

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

Posterior parietal cortex (PPC) in humans and other animals is considered to be a nexus of sensory, motor, and cognitive functions. The underlying circuits and computations are increasingly studied in mice, a species that affords unparalleled resources such as genetic tools and behavioral tasks. Studies of mouse PPC, however, have focused on distinct functions: visual processing, decision making, and spatial navigation. It is not clear whether the same neurons and populations participate in these three functions, and whether they play similar roles in different behavioral contexts. We will first establish how the anatomical definition of mouse PPC used in studies of decision and navigation relates to functional maps of visual cortex established in studies of vision. We will then train head-fixed mice to perform two visual decision tasks: one of which involves navigation in virtual reality, and we will use two-photon calcium imaging to track the activity of populations of PPC neurons over weeks. These data will reveal whether the activity of the same PPC neurons stays fixed or varies to meet the variable demands of these two tasks, and thus establish the role of mouse PPC in functions that are typically combined in daily life: vision, decision, and navigation.

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

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

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

Damage to motor neurons due to traumatic injury or degenerative conditions typically results in permanent muscle denervation and paralysis. We recently described1 a novel strategy to artificially restore functional control of paralyzed muscles, which employs embryonic stem cell-derived motor neurons (ESC-MNs), modified to express channelrhodopsin-2 and glial derived neurotrophic factor, to confer optogenetic control of neural activity and promote long-term survival, respectively. These ESC-MNs, contained within embryoid bodies (EBs), were engrafted into injured peripheral nerves of mice, resulting in reinnervation of paralyzed muscles and optical control of their function. Unfortunately, EBs contain pluripotent cells with an inherent potential to form teratomas, limiting their clinical utility. However, purified ESC-MN grafts have a limited to capacity to functionally reinnervate muscle targets because other cell types within EBs, particularly excitatory interneurons, appear necessary for successful reinnervation of target muscles by engrafted ESC-MNs. The aims of this project are to i) optimize the ESC-MN graft identity, by investigating the effect of interneurons on motor neuron maturation and muscle innervation; ii) to use the optimized grafts to reinnervate opposable flexor and extensor muscles, to demonstrate the therapeutic utility of this approach in the restoration of complex functions, such as hand grasping.

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

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

During embryonic development cells have to integrate up to eight molecular pathways in order to choose between alternative fates or behaviours. However, even in combination, these eight pathways cannot provide enough information to specify the many (perhaps as many as 104) cell types that comprise the adult body. Timing seems to be important. One of the earliest fate decisions in embryonic development occurs soon after gastrulation during neural induction when one part of the epiblast is set apart, acquiring neural identity in response to signals from the organiser, Hensen’s node. A recent view is that neural induction is highly regulated in time and that it involves several steps. Competent cells, capable of responding to signals from the organiser, go through different states of specification before committing to the neural fate. Here we aim to understand how timing orchestrates neural induction. Specifically, we will uncover whether competence to respond to inducing signals is regulated by a cell-autonomous clock or by external instructions, how competent cells can sense exposure to signals of different duration and how this signal changes over time to generate an appropriately regionalised neural plate.

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

How do middle ear stem cells and the immune system interact in the pathogenesis of chronic otitis media? 30 Sep 2017

Chronic middle ear inflammation (otitis media) poses a significant global burden of disease in adults and children leading to permanent deafness. The middle ear mucosa maintains a well-ventilated middle ear but undergoes abnormal remodelling in disease. Similar to the adult upper airway, basal cells are hypothesised to be stem cells actively maintaining middle ear mucosa. Pathological remodelling via abnormal repair pathways may underlie chronic otitis media and studying these could help understand and treat the disease. Aim: To identify and characterise the stem cell population of the middle ear in health and how maintenance of middle ear mucosa is disrupted by the immune system leading to chronic inflammatory disease. Methods: Murine and human biopsies will be grown and characterised in vitro, in 3T3 co-culture, air-liquid interface and 3D spheroid models to study differentiation and proliferation mechanisms in health and confirm markers of stem cell and cell fate. These markers will be used to perform lineage tracing in mice in healthy mice and in crosses with Junbo mouse model of otitis media. Finally, the role of the immune system, specifically the aryl hydrocarbon receptor (AhR – responsible for detoxification of pollutants that are linked to otitis media) will be studied using AhR agonists/antagonists and Ahr deficient mice crossed with Junbo mice.

Amount: £309,724
Funder: The Wellcome Trust
Recipient: University College London