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Paul Hamlyn Foundation
The Wellcome Trust
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University College London
National University of Ireland Galway
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Results

Complex Urban Systems for Sustainability and Health (London Hub) 30 Sep 2018

The London Hub for Urban Health, Sustainability and Equity aims to be the world’s foremost transdisciplinary hub for research, training and pubic engagement on urban health. It is founded on two constituent projects – Complex Urban Systems for Sustainability and Health (CUSSH) and Pathways to Equitable Healthy Cities (PEHC) – and involves leading London-based institutions and their global network of collaborating institutions. The Hub’s principal objective is to integrate and coordinate research and stakeholder engagement that support evidence-based policies aimed at improving population health, health equity and environmental sustainability in cities around the world. The Hub, and its projects, will achieve this objective through comparative studies that involve participatory research and coproduction of knowledge among academic researchers, policy makers and practitioners, and civil society; developing models for prospective policy evaluation and applying these models to data from our partner cities; and training the next generation of research and policy leaders in urban health, while establishing the foundations for sustaining and expanding the Hub beyond the Wellcome funding period. The CUSSH project focuses on how to transform cities to address vital environmental and population health imperatives, and entails partnership with the cities of London, Beijing, Kisumu, Nairobi, Ningbo and Rennes.

Amount: £5,150,000
Funder: The Wellcome Trust
Recipient: University College London

Biomaterial-based delivery of neurotrophic factors to the Parkinsonian brain 31 May 2018

The concept of cellular brain repair for Parkinson's disease is relatively simple - if brain cells die in this condition, then it should be possible to replace these cells through transplantation of healthy cells back into the brain. Over the past three decades, numerous animal studies and several clinical trials in human patients have shown that this concept has significant potential for repairing the brain affected by Parkinson's disease. However, poor survival of the healthy cells has limited the widespread roll-out of this cellular reparative approach to patients. Biomaterials, that is, materials that have been engineered to interact safety with living tissue for therapeutic purposes, have the potential to improve such cellular reparative therapies for Parkinson's disease. Specifically, injectable biomaterials gels have the potential to significantly improve cell survival by providing a physical scaffold and pro-survival environment for the implanted cells. Thus the aim of this proposal is to determine if biomaterial hydrogels can be used to improve cellular reparative therapies for Parkinson’s disease using animal models of the condition. We will specifically investigate the beneficial effect of biomaterials on stem cell-derived neuron cell transplantation approaches.

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

Impact of varied reperfusion approaches following middle cerebral artery occlusion on the subsequent development of reperfusion injury 31 May 2018

Timely reperfusion of the occluded cerebral vasculature can minimize brain damage and optimize positive patient outcome. Current therapeutic approaches include administration of tissue plasminogen activator to dissolve an occlusive clot pharmacologically. More recently, mechanical clot removal devices are becoming a favoured approach. However, reperfusion injury can develop and haemorrhagic transformation (HT) of recently ischaemic brain is a potentially fatal complication of thrombolytic and mechanical reperfusion therapy. MMP-9 and MMP-2 expression in brain tissue is indicative of disruption of the blood brain barrier [3]. Heightened MMP-2 is associated with more favourable outcomes than MMP-9; high expression of MMP-9 is associated with haemorrhagic transformation and poorer clinical outcomes [4, 5]. Specific objectives during summer placement: - To experience real science by integrating into a research team. - To learn and master the techniques implicit in immunohistochemistry and other histological measures, including tissue slicing, antibody staining and quantitative assessment of biomarkers. - To contribute to the on-going assessment in the host lab, of the impact of varied reperfusion approaches following middle cerebral artery occlusion on the subsequent development of reperfusion injury. In particular, MMP-9 and MMP-2 expression in rat brain will be quantitatively assessed.

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

Neuronal encoding of complex three-dimensional environments 31 May 2018

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

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

Identification and Validation of the Determinants of Variation in T cell Immunity in Health and in Inherited Immunodeficiency Syndromes 30 Sep 2018

Vaccination is a powerful strategy to prevent infectious diseases, by stimulating our immune system to produce antibodies. However, vaccines have not been as successful in boosting immunity against infections that require a different defence called T-cells. This problem is exemplified by tuberculosis, which causes more deaths than any other infection despite the use of the Bacillus Calmette-Guérin (BCG) vaccine, because the protection provided by BCG is variable. I aim to understand why BCG only works in some people. I will investigate the idea that differences in T-cell activation in different people are responsible for differences in the protective effects of BCG. In healthy individuals, I will test T-cell activation in response to a general stimulus. Using these data, I will develop a mathematical model to understand how variation in T-cell responses comes about. I will then In BCG-vaccinate the same individuals and test if my model explains all the variability in responses to BCG and in T-cell control of tuberculosis. These experiments may reveal the molecular switches that are responsible for differences in BCG efficacy. By testing cells from patients with genetic abnormalities in some of these molecules, I will validate their role in providing effective T-cell immunity.

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

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

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

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

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

Investigating acetylation control of MutSbeta protein (Msh2-Msh3) in DNA triplet repeat expansions. 31 May 2018

Huntington’s disease (HD) is a debilitating, relentlessly fatal neurodegenerative disease. HD is caused by inheritance of an expanded CAG repeat tract in the HTT gene. The CAG repeat continues expanding in the brain of HD patients, and these somatic expansions contribute to disease progression and age of onset. It is known from model systems that the DNA repair protein MutSbeta (Msh2-Msh3 complex) is essential to drive expansions, as knockout of either Msh2 or Msh3 blocks nearly all expansions. Recent work from the supervisor’s laboratory suggests that MutSbeta expansion activity is regulated by post-translational acetylation. This link to protein acetylation is noteworthy with regard to potential therapy, in light of the supervisor’s recent demonstration that inhibiting histone deacetylase 3 in HD mice blocked disease onset. Using cultured human cells, I will test potential acetylation control of the Msh2 subunit of MutSbeta by mutating a putative acetylation site, lysine 73, to convert it to the non-acetylatable arginine (Msh2K73R). I will then test Msh2K73R protein expression and its ability to form MutSbeta complex. I will assist in genetic assays to measure CAG repeat expansions in cells expressing Msh2K73R, compared to wild type. My prediction is Msh2K73R will drive expansions in an acetylation-independent manner.

Investigation of the structural and conformational preferences of ribosome-bound nascent chains using NMR paramagnetic relaxation enhancement measurements 31 May 2018

Co-translational folding is best studied by providing high-resolution structural descriptions of nascent polypeptides (NCs) as they emerge from the ribosome. This is achieved by producing snapshots of the process using ribosome-associated-nascent chains(RNCs) and developing 3D structural models by combining NMR spectroscopy as experimental restraints within MD simulations. The emerging NC is a dynamic entity that searches conformational space in its quest for acquiring its correct structure; it undergoes both transient interactions with itself and the external surface of its ribosome. This Scholarship aims to develop novel distance-based, PRE (paramagnetic-relaxation-enhancement) NMR measurements of RNCs to evaluate these transient processes. Over 8 weeks, this project will enable us to develop strategies to selectively label RNCs with the MTSL "spin-labels" at a single cysteine site, by adapting well-established RNC technology. We will study two RNCs "snapshots" which capture early folding transition for an immunoglobulin protein. We will characterise the structural properties of the modified RNCs using 2D NMR spectroscopy, and quantitate possible transient interactions/compaction events by collecting PRE measurements. We will also initiate MD simulations with the new experimental restraints that have been acquired. These approaches will advance our current 3D structural models to dissect further molecular details of co-translational protein folding.

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

Integrated interdisciplinary approaches to design new anti-bacterials with novel mechanisms of action to tackle antimicrobial resistance in Tuberculosis 30 Sep 2018

Tuberculosis (TB) remains a serious threat to global health. The World Health Organisation estimate that 10.4 million new cases were contracted in 2015, and that over 500,000 of those cases were resistant to at least one of the antibiotics currently used to treat this condition. The spread of such resistance is a serious concern and as a result there is a need for the development of new drugs to combat TB. Recent work has identified two classes of molecule which have promising anti-tubercular properties: tetrahydroisoquinolines and non-steroidal anti-inflammatory drugs. My project will focus on the development of new anti-bacterials from these classes of molecule while exploring the reasons behind their anti-tubercular properties. This will be achieved through a combination of chemistry and molecular microbiology, making use of both laboratory and computational techniques.

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

Feasibility and acceptability of a decision aid to facilitate involvement of people with type 2 diabetes in decisions about medication intensification in an Irish setting 31 May 2018

The primary goal of this study is to assess the feasibility and acceptability of using the Diabetes Medication Choice Decision Aid in decisions about medication intensification in an Irish setting using a mixed methods approach. The extent to which patients are involved in the decision-making process about medication intensification will be measured using a validated tool (OPTION) in audio-taped consultations where the decision aid is used and not used. Health care professionals and patients will also be interviewed about how useful they found the decision-aid in involving patients in decisions about changes to medication.The quantitative analysis of the consultations will allow us to assess the level of patient involvement in the decision-making process around medication intensification. The qualitative interviews will provide us with a greater understanding of how useful the decision-making tool is in facilitating shared decision-making. The findings from this feasibility study will inform a future pilot randomised controlled trial of the decision aid in people with type 2 diabetes requiring medication intensification.

Co-evolution of tumour mutational and CD4 T-cell differentiation landscapes 30 Sep 2018

Lung cancer is the second most commonly diagnosed cancer in the UK and the greatest cause of cancer-related death. A type of this disease called non-small cell lung cancer (NSCLC) accounts for the majority (85%) of cases. T-lymphocyte cells (T-cells) of the immune system patrol the body and can recognise and destroy cancer cells by recognising mutated proteins (neoantigens) on them. Despite this, the majority of patients with advanced lung cancer die of the disease, indicating the ineffective function of the immune system. In particular, little is known about the role of a particular group of immune cells called T-helper cells that are thought to be important. In chronic infections where T-cells are constantly exposed to their targets, they become less responsive as younger cells are driven to turn into later ones more rapidly. As younger cells are lost, the body's ability to fight the infection reduces. In cancer, it is possible that mutations drive a similar problem. Using lung cancer specimens from patients on a clinical trial and animal models of cancer, we propose to study the question of whether and how mutations can paralyse the ability of T-helper cells to fight the disease.

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

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

UCL/WT Translational Partnership 2018 - Widening Participation and Enhancing Translational Culture 30 Sep 2018

The biomedical translational strategy of UCL and its partner hospitals is based upon harnessing the wealth of talent and ideas across disciplines to make a difference to patients and their families. The WT Translational Partnership Award supports the pursuit of excellence in the universities tripartite mission "Research, Education and Innovation" and will enhance the knowledge, culture and support available for translation: • Provide funding to develop pilot data enabling progression of projects to our internal Therapeutic Acceleration Fund. Aimed at encouraging Early Career Scientists to take the first step along the translational pathway (RESEARCH) • Enable a greater understanding of translation amongst early career researchers through a mixture of on-line training material and workshops (EDUCATION) • Supporting our Therapeutic Innovation Networks (TINs) in small molecule, biologics, cell, gene & regenerative medicine, devices, diagnostics and repurposing. These "early discovery therapeutic accelerators" will identify and address barriers encountered, share knowledge/best practice and use Industry expertise to progress specific projects (INNOVATION)

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

The use of plasma treated graphene oxide in critical limb schema 31 May 2018

The aim of this project will be to determine the angiogenic potential of plasma-coated graphene oxide sheets and their effect on cell viability. The objectives will be to place human umbilical cord endothelial cells(HUVECs) in Matrigel with graphene oxides with varying surface coatings on the graphene oxide. First we will use a plasma reactor to modify the surface properties by increasing the O2 and N2 groups on the surface. HUVECs will then be cultured using EGM-2 complete media before being placed onto Matrigel, along with surface treated graphene oxide. In order to determine the cytotoxic effect of each coating, a Live/Dead assay will be carried out on HUVECs that have been cultured in the presence of plasma-treated graphene oxide sheets after a 48hr culture, using fluorescent detection, while the angiogenic properties of each surface coating will be compared against an uncoated control, with complete media with growth factors being used as a positive control, using ImageJ software which will quantify the number/density and size of the vessels compared to the uncoated control. The ideal result would be a coating that has strong angiogenic properties with minimal cytotoxic properties, which would set the ground work for further in-vitro studies.

Behavioural and Histopathological Characterisation of APP-KI Alzheimer Mice Models 31 May 2018

The project would involve behavioural and histopathological studies of a mouse model of Alzheimer's Disease. The transgenic mouse, Amyloid Precursor Protein Knock-In (APP-KI) expresses human-like amyloid plaques in the absence of other APP fragments and, hence, represents the best APP model currently available. They will be injected with tau, in order to mimic the combination of pathological changes that occur in human Alzheimer's-disease-affected brains. The main goals of the project involve establishing the exact time-course over which the Alzheimer's-like phenotype develops, correlating the number of human-like amyloid plaques with the extent of the memory deficit in the APP-KI mice with and without tau, and finally establishing whether there is any underlying neuronal cell death in the tau-injected mice. The first four weeks of the project would involve a battery of behavioural tests to include Open Field activity, Novel Object Recognition, Object Location and spatial T-maze testing in order to identify behavioural changes/memory deficits in the APP-KI and the APP-KI + tau animals when compared to wild type litter-mates. Afterwards the animals would be sacrificed, their brains removed and sectioned. The brain sections would be stained and histopathological changes (e.g. amyloid plaque volume and tau filaments) correlated with behavioural changes.

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

Investigating prevention of cervical cancer, disease burden, and opportunities for improvement in inclusion health women (IHW) 30 Sep 2018

Cervical cancer is preventable due to screening and vaccination against human papillomavirus (HPV), the main cause of cervical cancer. However, there were 3,224 new cases and 890 deaths in the UK in 2014. By 2035, this is predicted to rise by 43% due to screening non-attendance. Living in a deprived area increases cervical cancer rates and non-attendance at screening. Inclusion health addresses needs of groups frequently underserved by health services who have worse overall health than people in deprived areas. These include homeless people, migrants, substance misusers, prisoners, and sex workers. It is likely that they engage the least with cervical cancer prevention and have the greatest need for intervention. Unfortunately, they are rarely included in cervical cancer prevention research. This fellowship will fill this knowledge gap. I will measure disease levels, engagement in prevention, and find ways to improve outcomes in inclusion health women. This is needed to eliminate cervical cancer. I will achieve this in three ways: (1) a review of existing studies on inclusion health and cervical cancer (2) a study linking information on 1.6 million migrants to cervical screening and vaccination data and (3) a survey and HPV testing of inclusion health women attending outreach services.

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

Inhibition in the Periaqueductal Gray 30 Sep 2018

Deciding which action to take, such as whether to cross a busy road, is a critical survival skill. Making decisions requires integrating complex information and identifying the cellular mechanisms of this process is critical for understanding how the brain computes decisions. In this project will investigate neurons that control defensive decisions in mice and focus on inhibitory neurons in the midbrain Periaqueductal Grey (PAG), which have the ability to veto defensive behaviours.The first main goal of the project is to use electrophysiological and advanced molecular techniques, such as RNA sequencing and gene knock-down, to identify the genes and ion channels that control the firing of PAG inhibitory neurons. The second goal is to determine key regulators of the activity of these neurons, in particular neuromodulators and long-range synaptic connections from other brain areas, using techniques such as optogenetics in combination with behavioural assays that exploit the innate defensive behaviours of mice. The results of this work will reveal new the biophysical principles that drive firing in a key population controlling a critical behavioural decision, and provide an entry point for understanding how pathological states such as anxiety lead to maladaptive decisions.

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