- 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
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.
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.
Genetic association studies focusing on common variation have uncovered only a fraction of proposed trait heritability. Some of this so-called missing heritability will be found within rare variation in the population. This hypothesis is supported by the facts that recent explosive population growth has increased the population burden of rare variants and deleterious variants are kept at low allele frequencies. All genetic susceptibility to disease is caused by alterations to the genes or their expression and for this reason it seems fruitful to focus an association study on the genes themselves. Any associations found are then directly informative about the molecular basis of disease without the need for fine mapping. The proposed project aims to develop a statistical method to find genes associated with disease by analysing the rare variation present in a case-control cohort. We aim to extend existing methods by including a previously unconsidered parameter; the position of the variants in a gene. In scenarios where differences in clustering or distribution of variants are observed between cases and controls, this method will have a substantial increase in power. This technique will be useful for elucidating the molecular mechanisms causing the disease and thus discovering new therapeutic targets.
Design and evaluation of a modified vaccinia Ankara vector therapeutic vaccine for hepatitis B immunotherapy 30 Sep 2018
Hepatitis B virus (HBV) is a serious global health problem, with approximately 240 million people chronically infected. Long-term infection can lead liver failure, cancer and death. Current therapy controls but does not eradicate the infection. T cells are a type of immune cell necessary to fight HBV. During chronic hepatitis B these cells become less active. Checkpoint inhibitors are a form of immunotherapy that enables T cells to function again. In a study of woodchucks infected with a similar virus to HBV, treatment with vaccine and checkpoint inhibitor lead to better control of the virus. This project aims to use this combination of vaccine and checkpoint inhibitor, to treat patients with chronic HBV. A vaccine using a virus to carry the HBV proteins has been developed and shown to generate good immune responses in mice. We plan to develop a second vaccine to boost this response and test the vaccines together with checkpoint inhibitors in mice infected with the HBV virus. This will allow us to assess how effective this is at eradicating HBV. If the results from this study are promising, this could pave the way for clinical trials in humans with chronic HBV.
The ATP-sensitive potassium (KATP) channel is a plasma membrane protein present in beta cells of the pacreas which plays a key role in insulin secretion. KATP acts as a metabolic sensor, alerting the beta cells when blood glucose raises too high and stimulating them to release insulin. In diabetes, normal KATP function is disrupted and beta cells no longer secrete insulin properly in response to blood glucose levels. The molecular structure of the channel is closely linked to its function; there have been several genetic studies linking various mutations (which often only affect one molecule in the channel!) to neonatal diabetes or increased propensity to type II diabetes. Our research aims to identify precisely how these small mutations can have such drastic changes in the activity of the channel by using a combination of fluorescent labels and channel current measurements to watch the KATP channel move in real time. We can then try to construct a model of how the channel converts different stimuli into movements, and how this is affected in mutations linked to diabetes.
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.
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).
Learning the Signatures of Cancer 30 Sep 2018
Cancer is a genetic disease that is the second leading cause of death worldwide. Developing effective personalised therapies requires characterisation of the genetic factors driving malignancy. This is challenging as cancer is highly complex, heterogeneous, and dependent on cellular context. Cancer stratification aims to group cancers that share similar features, and are therefore likely to respond similarly to treatment, however, current stratification methods ignore many important genetic and epigenetic markers that likely influence cancer pathology, which would result in sub-optimal treatment. We propose to use whole genome-and-epigenome profiling and machine learning to extract clinically meaningful features of the host and cancer genomes that can be used to improve patient stratification and reveal novel cancer subtypes. As a proof of principle, we will apply these methods to predict the site of origin in patients with metastatic cancer but unknown primary (CUP), which could help improve diagnosis and prognosis for patients with this complex disease. We envision the robust stratification of cancer patients using genome profiling could lead to direct prediction of optimal treatment decision for all cancer patients.
Spontaneous and induced network dynamics across cortical layers during waking and sleep in mice 30 Sep 2018
No one can live without sleep. Even if we try very hard to stay awake, we ultimately can’t resist to fall asleep. Various brain functions, such as the abilities to remember and concentrate, decline when we get tired and improve with sleep. Therefore, it is thought that especially the brain needs sleep and determines when it is time to disconnect and recover. The goal of my research is to understand the brain machinery, which controls sleep and wakefulness. My research requires working with mice as I need to use a genetic tool to switch on and off specific brain cells for a short period of time to find out their role in sleep regulation. I will observe whether the brain can still coordinate its systematic shut down when we turn off cells, which are thought to measure the duration of wakefulness and initiate sleep. I aim to find out whether specific cells can measure how long the brain has been awake and send out signals to coordinate the systematic shut down of many brain regions when falling asleep. I hope that my experiments contribute to an understanding of healthy and disturbed sleep.
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.
Leveraging genetic variation to understand chromosome pairing, meiosis and the evolution of human disease risk 17 Jul 2018
We have the following specific aims: To discover how normal pairing (synapsis) of homologous chromosomes during mammalian meiosis is genetically controlled in fertile and infertile individuals, and how synapsis first initiates, and then spreads. To do this, we will leverage naturally occurring genetic variation. Errors in recombination, and in synapsis, result in aneuploidy events, and chromosomal rearrangements due to NAHR, that cause many human disorders including infertility, pregnancy loss, cancer, and developmental syndromes. To quantify how the chromatin accessibility and gene expression environments change during meiosis, using single-cell ATAC and RNA sequencing, and learn how proteins binding to DNA coordinate the onset and progression of meiosis, recombination, synapsis and impact fertility, and are impacted by genetic variation and chance. To build from our existing approaches to understand population structure, in order to infer trees revealing the historical relationships relating hundreds of thousands of modern and ancient individuals, in humans and other recombining species. We will use these trees, which change along the genome due to recombination, to investigate how variation impacting complex diseases and other traits has arisen and been acted upon by natural selection, how selection changes through time, and how the rate of evolution itself evolves through time.
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.
Antiviral iminosugars inhibit endoplasmic reticulum (ER) a-glucosidases I and II (a-Glu), which induces misfolding of viral N-linked glycoproteins. ER a-GluII inhibition leads to the release of fewer infectious viruses in vitro and in vivo, and can protect mice from DENV- and influenza lethal challenge. We observed that inhibition of ER a-GluI can lead to similar life-saving effects in mice, even if enzyme inhibition is short lived and achieved by administration of a single dose of the drug. This is sufficient to create long-lived triglucosylated protein species that can prevent secretion of infectious virus for some time. We aim to understand this process. I first will establish cell lines that can be hosts for the viruses I am investigating in which to re-capitulate in vivo observations. I shall then proceed to identify which protein(s) are responsible for the long-lasting antiviral effect, why they are not degraded, and how they can exert an antiviral effect for longer than enzyme inhibition. This work may lead to new ways of treating viral diseases such as dengue, influenza and hepatitis B, prophylactically and/or therapeutically. Moreover, a field trip to Vietnam is planned to take advantage of clinical samples.
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.
Understanding how the billions of varied cells in the human brain develop from a small number of neural stem cells (NSCs) is a central question in biology and medicine. This highly complex process has largely been explained by transcriptional regulation dictating the levels of protein expression in stem cells and their progeny. Using novel single molecule approaches to quantitate transcription and protein levels, we have discovered functionally important conserved examples where the levels of transcription and protein expression do not correlate. These include pros/prox1, the regulator of NSC proliferation and differentiation and myc, the proto-oncogene regulator of stem cell size. We will characterise the mechanism of post-transcriptional regulation of pros, myc and 21 additional functionally important examples we have discovered, all of which have extremely long 3’UTRs that are bound and regulated by the same conserved RNA binding proteins, Syp and Imp. We will also measure, genome-wide, mRNA stability and characterise the trans-acting factors and cis-acting signals regulating stability and translation. The proposed programme will characterise a hitherto under-studied layer of regulation acting in addition to transcription in complex tissues, providing major new mechanistic insights into how the brain develops in health and disease.
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.
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.
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.
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.
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)