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Funders:
Paul Hamlyn Foundation
The Wellcome Trust
Scottish Council For Voluntary Organisations
Recipients:
University College London
University of Cambridge

Results

Clinical Characterisation of a Broad Spectrum of Genetic Variation in the General Population 30 Sep 2018

Inborn errors of metabolism (IEM) are severe and extreme changes in metabolism caused by mutations in a single gene. Recent large-scale human studies have shown that genes causal for IEM are associated with nutrients, or ‘metabolites’, in the blood. However, whether these associations cause disease or adverse health outcomes is unknown. In this project, I will use IEM genes identified in these studies to link genetic variation to clinical features in a large human population. To do this, I will assemble a list of IEM genes of interest that were identified in the literature and in large population datasets. I will then test for associations between the variants I find in these genes and a wide range of clinical features found in open-access population datasets. As the IEM genes used in this study have been associated with blood metabolites previously, linking variants in these genes to clinical features will shed light on the molecular mechanisms underlying genes and disease in the general population. Understanding how genetic variation affects disease will help identify novel therapeutic targets and enable health professionals to better manage disease risk.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

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

Investigating non-canonical programmed ribosomal frameshifting in porcine reproductive and respiratory syndrome virus 30 Sep 2018

RNA viruses are under selection pressure to maintain a small genome, however they still need to produce a variety of proteins. To overcome these conflicting pressures, many viruses use non-canonical methods of translation control. One example of this is programmed ribosomal frameshifting (PRF), in which a percentage of ribosomes, while translating a ‘slippery sequence’ slip one or two nucleotides out of frame, consequently translating the remainder of the mRNA in a different reading frame and allowing expression of more than one protein from a single gene. This is normally stimulated by a downstream secondary RNA structure, however there are two known examples of a trans-acting viral protein being used as the stimulatory element. One example is found in the genome of porcine reproductive and respiratory syndrome virus (PRRSV): an Arterivirus that infects pigs, causing an estimated annual cost to the US swine industry of $664m. I will use structural techniques such as X-ray crystallography to derive information about the RNA/protein complex, and will investigate the efficiency and mechanism of this non-canonical PRF using ribosomal profiling in parallel with RNASeq. The latter will also allow me to analyse host and viral gene expression, to examine host-virus interactions in this important pathogen.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Epigenetic inheritance: the influence of variable silencing of the repeat genome. 10 Apr 2018

Evidence from epidemiological studies and experiments in animal models suggests that effects of environment and lifestyle can be transmitted across generations via non-genetic mechanisms. Such mechanisms are challenging to unravel in mouse and man. In mammals, non-genetic inheritance is best exemplified by the Agouti viable yellow (Avy) mouse where phenotypic differences in genetically identical animals are caused by insertion of a retrotransposon - an endogenous retrovirus (ERV) that provides a cryptic promoter driving ectopic expression of agouti. This ERV is variably DNA methylated in different individuals causing inter-individual variation in coat colour – a non-genetic influence on phenotype. Remarkably, a memory of parental coat colour is transmitted to subsequent generations. Variable expressivity can be modulated by in utero environmental exposures. ERVs represent ~12% of the mouse genome. Inspired by Avy, we propose a research programme, supported by preliminary data, to address the following questions: Aim 1 – To what extent do mammalian ERVs exhibit variable epigenetic silencing and what is the mechanism? Aim 2 – Is this transmitted as non-genetic memory across generations? Aim 3 – Are they sensors of environmental compromise? Aim 4 – Are there implications for phenotype? Aim 5 – Does a related phenomenon occur in humans?

Amount: £2,929,851
Funder: The Wellcome Trust
Recipient: University of Cambridge

Gene Expression Heterogeneity in the Maintenance and Coordinated Differentiation of Neuromesodermal Progenitors in vivo 08 Aug 2018

Modern imaging data in biology is essentially multi-scalar in that raw image data undergoes a series of processing steps until it is at a manageable size to perform quantification and analysis. While this processing pipeline might be beneficial to one set of scientific questions, it may be inappropriate to others. Computational biologists may be interested in improving the pipeline itself, while other researchers may be interested in accessing the already processed data. Thus, a central road-block in the open sharing of large-scale imaging data is the fact that there is no one size fits all solution. This project aims to generate a web-based database that stores experimental and data descriptors together with links to the raw and processed data files. This will greatly enhance our ability to upload this data to repositories that are based placed to share the datasets in question, from the raw unprocessed data files down to feature extracted and processed data. Upon submission, the website will link to the deposited data and thereby act as an integrated platform for other researchers to access and explore the data that is available to them. Thus, researchers will be able to access our data at all levels. In built in the project is a second evaluation phase, whereby will we reach out to collaborating laboratories to assess the effectiveness of our open research platform. These will include computational biologists interested in accessing raw data files and processing pipelines, and other developmental biologists who will interact with processed datasets.

Amount: £48,563
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

Lineage tracing and early embryonic dynamics using mosaic somatic mutations 30 Sep 2018

Every cell in the human body descends from the fertilised egg cell, and during the journey from zygote to adult cell, many mutations are acquired. The mutations that happen early enough during embryonic development will be present in some parts of the body, but absent in others. One of the difficulties of this project is the discovery of these early embryonic mutations, as they are hard to distinguish from mutations that happened later in life, noise from experimental procedures, and mutations that were already present at fertilisation. Here, we cut out small pieces of various tissues from multiple individuals using a laser and sequence its DNA. Mutations shared between different samples from the same individual are candidate embryonic mutations. Each mosaic mutation gives us information on the development of the human body and with enough mutations, we can construct and visualise the human body as a large evolutionary tree, with the fertilised egg cell as the single root, and all the adult cells as its leaves. This can give us many new insights on the developmental relationship between different organs, how many different early embryonic cells give rise to one tissue or organ and developmental lineages of different cell types.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

The effect of nutrients on maximal fat oxidation rates in adult humans measured using indirect calorimetry. 31 May 2018

I aim to study the effects of nutrient availability and mitochondrial transport capacity on the variability of maximal fat oxidation (MFO) during exercise in healthy adults. Less than half of MFO can be predicted by variables such as gender, VO2max and body composition. There are two possible reasons for this. First, nutrient availability may have a large effect on MFO and current protocols may not adequately control for it. Second, VO2max - which combines two variables with opposite effects on MFO (oxygen uptake and fat mass) - may not be the optimal predictor. Here, I will test whether heart rates at a given power are a better predictor of MFO and whether short-term fluctuations in nutrient availability can explain some of the variability of MFO seen within the general population. Nutrient availability will be altered using a glucose meal and by glycogen depletion. I will also use nitrate supplementation to test whether MFO can be increased by induced-expression of fat oxidation enzymes. The key goals are to determine to what extent short-term changes in nutrients and the expression of fat oxidation enzymes can alter MFO and whether the resultant fat oxidation rates can be predicted using simple heart rate data.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding the Initiation of Viral Replication & its Role in Influenza Virus Pathogenicity 31 May 2018

The development of novel strategies against influenza viruses depends on our understanding of influenza virus replication and pathogenicity. Both are directly linked to the activity of the viral RNA polymerase, which copies and transcribes the viral genome, and generate aberrant RNA products that are non-contiguous in the viral genome and strong inducers of the interferon response. Despite recent crystal structures of the RNA polymerase, we only poorly understand how it interacts with and copies the viral genome, or how it generates aberrant RNA products. This project aims to use i) structure-guided mutagenesis, ii) in vitro and in vivo activity assays, iii) cell culture-based interferon production assays, to ask if RNA polymerase residues that bind and guide the viral genome are important for the initiation of viral replication and the formation of aberrant RNA products and thereby the pathology of influenza virus infections. The project will contribute to our understanding of the mechanics of influenza virus replication and the identification of putative targets for the development of new anti-influenza virus drugs.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

Molecular mechanisms of alternative splicing regulation 28 Nov 2017

Alternative pre-mRNA splicing (AS) is a widespread regulatory mechanism enabling individual genes to generate multiple protein isoforms. We have investigated the mechanisms controlling AS events that are regulated during the transition of smooth muscle cells (SMCs) between contractile and proliferative phenotypes. We have shown how the widely-expressed RNA binding proteins (RBPs) PTBP1 and MBNL1 regulate SMC splicing events. Recently, we identified RBPMS as a potential "master" regulator of SMC AS. RBPMS is sufficient to switch AS events to the SMC pattern and its activity is strongly modulated by its own AS and by phosphorylation. Critically, RBPMS is sufficient to switch AS to the SMC pattern in vitro. This offers a unique opportunity to determine the molecular anatomy of regulated splicing complexes. We will carry out detailed mechanistic analyses of RBPMS-regulated splicing using a combination of biochemical, proteomic, single-molecule, and structural approaches including Cryo-EM. We will identify critical regulatory interactions between regulatory RBPs and core splicing factors, and test their importance by genome editing and mRNA-Seq. In a complementary aim, we will investigate how peptide-ligand interactions equip PTBP1 to regulate AS and a range of other post-transcriptional processes, and whether a family of such peptide-mediated interactions extends to related RBPs.

Amount: £1,503,005
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

Investigation into the role of RBM8A/Y14 in the development and function of megakaryocytes and platelets using a human pluripotent stem cell model of haematopoiesis 30 Sep 2018

Platelets are small blood cells, which cause blood to clot, preventing bleeding after injury. They are produced by megakaryocytes, large cells in the bone marrow. In people with low platelet counts (thrombocytopenia), life-threatening bleeding occurs spontaneously or after injury. Studying platelet and megakaryocyte development and function is important in understanding a) diseases causing thrombocytopenia, such as genetic disorders and other conditions, particularly cancer (and chemotherapy) and b) strokes and heart attacks, where platelets are excessively activated, forming clots that block vessels. Using stem cells (special cells capable of becoming any cell type) derived from adult skin or blood samples we grow & study megakaryocytes and platelets in the laboratory. We study a rare genetic disease, Thrombocytopenia with Absent Radii (TAR) syndrome, in which babies are born with very few platelets and abnormal bone formation (particularly the radius in the forearm). Our group discovered the cause of TAR, due to abnormalities in a gene called RBM8A, which helps cells control what proteins are produced; however precisely why this causes TAR is unclear. We believe our research will uncover the mechanism of this condition, helping to treat patients with TAR and improve wider understanding of how megakaryocytes & platelets develop and function.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Modeling cell differentiation dynamics from single cell genomics data 30 Sep 2018

We aim to understand in detail the dynamics of how white blood cells (specifically T helper cells) react to infections by multiplying rapidly and at the same time adapting their cell state to fight the infection. In particular, we focus on a mouse model of malaria where T helper cells differentiate into two subtypes: Th1 and Tfh. By quantitatively profiling the T helper cell population at different time points during a malaria infection, we expect to improve our understanding of the mechanisms which are responsible for the cell proliferation and specialisation. We study the cell population by detecting RNA expression, surface markers and cell divisions at the single cell level. The RNA expression will provide clues as to genes which are driving this process, and we will test a subset of genes using CRISPR knock outs. In addition to a better knowledge of the immune system, we hope to develop new mathematical and computational methods that will be widely applicable to modeling cell proliferation and differentiation data in diverse biological contexts.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Principles of human development and germ cell program 28 Nov 2017

Specification of human primordial germ cells (hPGCs) occurs around gastrulation, a critical juncture when the specification of the primary somatic lineages also occurs. In combination with human preimplantation embryos, in vitro models and hPGCs from aborted fetuses, our objective is to elucidate the origin and properties of the early human germline. For the mechanism of the hPGC fate, we will use experimental models that simulate early human development. We aim to investigate how cells gain competence for germ cell fate, and then respond to combinatorial effects of the critical transcription factors, which induce hPGC specification. Altogether, this study will reveal the organisation of the very early human embryo, and mechanisms of hPGC and somatic outcomes, which is essential for advances in regenerative medicine. Following hPGC specification, epigenetic resetting of the early human germline leads to extensive erasure of DNA methylation and epimutations in response to the critical regulators of chromatin organisation and nuclear architecture towards the epigenetic ground state. Some conserved resistant loci ('escapees') evade reprogramming. We will explore if some escapees have been exapted to function as regulatory elements. If so, this may have a crucial influence on human development, including brain development and neuronal diseases.

Amount: £2,750,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Metabolic magnetic resonance imaging across the human heart 18 Oct 2017

During my fellowship, I proved the feasibility of measuring cardiac energetics in volunteers and patients using ultra-high field (7T) MRI scanners. The sensitivity and the separation of signals from different metabolites both improved significantly compared to standard research scanners. I recently secured £340k funding to fit a new phosphorus coil on the Oxford 7T scanner, which I am now testing in volunteers. Theory predicts that this coil will have several complementary technical advantages. These will enable mapping of cardiac energy metabolism across the whole heart, with sufficient spatial resolution to distinguish signals from healthy from diseased tissue. It will also enable quantification of cardiac energy metabolism with high precision to study single subjects rather than groups. I request funding to validate these new whole-heart methods, proving their value in three carefully-targeted groups of patients, via an extension of my fellowship. My goals are (A) to study patients in which the metabolic pattern is known by other means; (B) others where the metabolic pattern will reveal previously-inaccessible aspects of disease mechanism; and (C) to prove I can resolve metabolic changes in single patients. Success in each of these studies will give me the pilot data needed for competitive Senior Fellowship applications.

Amount: £584,259
Funder: The Wellcome Trust
Recipient: University of Cambridge

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