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Results

Role of the haematopoietic stem cell niche in pre-leukemic clonal haematopoiesis and myelodysplatic syndromes 21 Feb 2018

Myelodysplastic syndromes (MDS) are prototype pre-leukemic conditions that initiate in haematopoietic stem cells (HSC). These are characterized by clonal HSC expansion, inefficient production of mature blood cells and a higher propensity to progress to acute myelogenous leukaemia. Multiple studies suggest that MDS-HSCs are highly dependent on the bone marrow niche. It is possible that leukemic stem cells exploit the normal remodelling capacity of the niche to create a self-reinforcing leukemic environment, thereby favouring leukaemia development. However the molecular mechanisms involved in this process are still largely unknown. This project aims at identifying the signalling networks involved in the bidirectional crosstalk between MDS-HSCs and specific niche cells, and how this contributes to MDS pathogenesis in both mouse and human. A multidisciplinary approach will be used, combining transcriptomic analysis of niche cells and HSCs, 3D-imaging of the bone marrow and computational modelling. I will investigate which essential interactions between MDS-HSCs and their niches are responsible for their competitive advantage over normal HSCs. These studies have the goal of ultimately disrupting these interactions as a novel therapeutic avenue for MDS, a disease that currently has very few treatment options.

Amount: £1,374,297
Funder: The Wellcome Trust
Recipient: Imperial College London

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £272,325
Funder: The Wellcome Trust
Recipient: Imperial College London

Molecular mechanisms mediating immune evasion in African trypanosomes 17 Jul 2018

The African trypanosome Trypanosoma brucei is an extraordinarily effective extracellular pathogen. Key for its survival is a protective Variant Surface Glycoprotein (VSG) coat, which is expressed at an extraordinarily high level from a VSG gene located in an RNA polymerase I transcribed VSG expression site. Although an individual trypanosome has multiple bloodstream form expression sites, stringent mono-allelic exclusion ensures that only one is transcribed at a time. We would like to understand how this mono-allelic exclusion operates. We have generated T. brucei strains with disrupted mono-allelic exclusion, which dynamically switch between two different expression sites. What restriction has disappeared? T. brucei additionally contains metacyclic expression sites, which are mono-allelically expressed in the relevant life-cycle stage. How are these different types of expression sites controlled? We have recently made the striking discovery that blocking trans-splicing leads to an abrupt halt in transcription of the active VSG expression site. How does RNA processing feed back to control this unusual RNA polymerase I transcription unit? Last, we have discovered that VSG synthesis is sensed during the cell cycle, and blocking its synthesis triggers a precise pre-cytokinesis cell cycle arrest. How does this happen, and what stress responses are triggered?

Amount: £1,695,299
Funder: The Wellcome Trust
Recipient: Imperial College London

Structures, Recruitment and Regulation of Key Components in DNA Damage Response 10 Apr 2018

Genome stability and integrity are extremely important for proper cellular functions. However, each cell suffers from tens of thousands of DNA damage daily. Cells have thus evolved a myriad of ways to deal with these damages. A double-strand break (DSB) is the most severe form of damage and cells have developed multiple pathways to ensure efficient repairs are carried out. Homologous recombination is a faithful repair process and a large number of proteins are involved in this pathway. We aim to characterize some of the key proteins in homologous recombination including the master signaling kinases ATR/ATM (Mec1/Tel1 in yeast), the chromatin remodeler INO80 and the tumour suppressors BRCA2, PALB2 and BRCA1. We have obtained significant breakthrough in some of the areas in the last five years funded by a Wellcome Trust Investigator award. In this current proposal, we will continue to investigate their structures and core mechanism of actions. More importantly, we now want to investigate how these key players are recruited and how they are regulated. The knowledge obtained will help us understand the causes of cancer and aging and can also provide new avenues for therapeutic development.

Amount: £1,999,970
Funder: The Wellcome Trust
Recipient: Imperial College London

Data Worlds and Futures: Archives, Bioinformation and Evidence 27 Jun 2018

As body fragments, tissue samples and DNA sequences are progressively transformed into highly mobile and replicable data, bioinformation raises urgent questions about the entanglement of (life and) death with the materialities and mechanisms of data worlds. This project explores the relation between bioinformation, infrastructures and evidence in relation to forensic archival practices and data processing. It examines the social lives of data through practitioners’ day-to-day activities, social practices of collection, storage and use through associations that privilege particular data types and configurations. An integrated programme of activities will: 1) establish a research network of bioinformation scholars; 2) engage forensic specialists and data scientists in two collaborative workshops to explore the digitisation and storage of biomaterials and the algorithmic applications used to interpret data and produce evidence; 3) produce exploratory empirical research at a forensic services provider and repository, as a background case study to analyse digitisation and data processing in forensic research and forensic service provision. This project will open up major areas of enquiry that will improve public understandings of evidence intersecting forensic science, genetic profiling, and algorithmic processing. It will foster new avenues in bioinformation research, data policy and algorithmic governance in the field of health and wellbeing.

Amount: £29,084
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Developing public and professional engagement to promote global policy and a new research vision to improve the health of labour migrants 04 Dec 2017

Population mobility within and across borders is becoming increasingly complex, yet there has been little synthesis of evidence or expert consultation on the wide-ranging health implications of migration. Indeed, the largest migrant group – labour migrants - have been excluded from the research agenda to date, with little known about the health consequences for the families they leave behind. The UCL-Lancet Commission on Migration and Health aims to consolidate evidence and generate new insights into the interactions between migration and health. The proposed project aims to support the work of the Commission by: a) identifying and synthesising data through two systematic reviews and meta-analyses on labour migrants and left-behind children; b) gaining expert insights, including convening a stakeholder meeting to assess evidence and generate innovative solutions and evidence-based recommendations; c) develop a public engagement strategy to foster shared expertise in this area; and d) define first steps towards establishing a new Global Observatory on Migration and Health that will seek to promote knowledge generation, translation, and monitoring of global and regional standards to improve health outcomes related to migration.

Amount: £40,272
Funder: The Wellcome Trust
Recipient: Imperial College London

Promoting awareness of perinatal depression in Nigeria; 30 Apr 2018

Perinatal depression is a major cause of disability in women, and often has adverse consequences for cognitive, emotional and behavioural development in the child. It is estimated that 90% of people with a mental illness in Nigeria go untreated. Dr Kike Olajide recently completed a Wellcome funded fellowship to develop a peer-delivered psychosocial intervention for perinatal depression in Nigeria. During a ‘Theory of Change’ workshop, increased community awareness about perinatal depression was identified as a necessary prerequisite for successful intervention. We therefore now intend to promote conversations and increase awareness about what scientific research has shown about the nature of perinatal depression. We will first stage a play. This will be led by Dr Olajide in Nigeria together with local workers. We will then create a documentary of the performance and use this both online and in further meetings in different areas in Nigeria to encourage families, practitioners and policymakers to reflect on what research has shown about causes, effects and treatment. The play will combine techniques from a traditional Yoruba "Alaarinjo" and the "Theatre of the Oppressed". The aim is to improve mental health literacy and aid the future recognition, management and prevention of perinatal depression in Nigeria.

Amount: £25,000
Funder: The Wellcome Trust
Recipient: Imperial College London

Integrating Ethics and Equity into Priority Setting for Universal Health Coverage: A Proof-of-Concept Study in South Africa 25 Jul 2017

Priority-setting for health is morally complex with unavoidable trade-offs. Policymakers face ethical dilemmas in healthcare coverage decisions. With many countries pursuing Universal Health Coverage, health technology assessment (HTA) has become a popular approach to health decision-making. HTA evaluates the value-for-money of different health interventions while providing a mechanism to facilitate transparent and inclusive decision-making. Although ethics is stated as a core component of HTA, and theoretical HTA ethics frameworks exist, the uptake of ethics analysis in HTA is limited. Few studies have explored practical implementation and impacts of systematic ethics analysis in HTA. This "proof-of concept" study in South Africa will generate evidence on how a context-specified ethics framework for health priority-setting can be developed and the influence its application may have on HTA recommendations – with the potential to impact near-term decisions for the National Health Insurance (NHI) policy rollout and longer-term approaches to HTA in South Africa and beyond. With key stakeholders, we will co-produce an ethics framework to guide NHI decision-making, then evaluate how applying the framework influences HTA recommendations. Findings will be widely disseminated, presenting impacts on coverage recommendations, resources required to develop and apply the framework, and implementation considerations for systematic ethics analysis in HTA.

Amount: £128,944
Funder: The Wellcome Trust
Recipient: Imperial College London

‘People like you’: contemporary figures of personalisation 01 Feb 2017

We aim to contribute to critical medical humanities by investigating an emergent culture of personalisation in the UK, associated concepts of the person and health. We expect to stimulate debate on personalised medicine by showing how it can be understood more fully in relation to other personalising practices and how features shared across this broad field are consequential for our wellbeing. Our innovative figural approach will be applied to case studies of both top-down and open-ended practices of personalisation in medicine, data science and digital culture. In collaboration with creative consultants, we will conduct practice-led research to produce additional insight into the role of participation in, and the sense made of, personalisation. Our aim is to put the ‘person’ back into personalisation, and relate such persons to the data collected from them and on their behalf. This approach will allow us to investigate individuals’ sense of self, agency and identification with others. It will allow us to consider the implications of new techniques for stratifying ‘persons’ precisely in shaping health outcomes and healthcare priorities. In sum, we will assess whether personalising practices, considered together, are influencing taken-for-granted concepts of the person with consequences for individual and collective health.

Amount: £396,385
Funder: The Wellcome Trust
Recipient: Imperial College London

SouthEast Asian Research Collaboration in Hepatitis (SEARCH) 05 Apr 2017

New direct acting antivirals (DAAs) to treat hepatitis C (HCV) have the potential to overcome many current barriers to curative treatment throughout the world. However, licensed durations of therapy will overtreat many individuals with unnecessary costs and inconvenience to patients who often have to pay for (at least part) of their treatment. The central work within this collaborative will be a large randomised trial with an innovative design to evaluate different treatment strategies suitable for scale up in low income countries. Two different treatments will be evaluated, strategies being dropped early if not demonstrating high enough cure rates. The trial will be based in Vietnam, home to an estimated 1 million HCV-infected individuals with a high proportion of genotype 6 HCV infections (relatively neglected by clinical studies to date). As a low/middle-income country, Vietnam can access more affordable generic therapies allowing studies to be done that would be prohibitively expensive in wealthier countries. The collaborative encompasses wider expertise to inform the use and scale up of DAAs (i) Whole genome sequencing to understand the impact of viral resistance mutations, particularly in G6 (ii) Pharmacokinetic/pharmacodynamics modeling (iii) Health economic analysis to evaluate cost/benefits of different treatments and treatment strategies

Amount: £3,350,722
Funder: The Wellcome Trust
Recipient: Imperial College London

Integrative Transport Phenomena in Chemokine Gradient Establishment 05 Apr 2017

A functioning immune system relies on carefully tuned fluid, cellular and molecular transport processes. Chemokines are secreted chemoattractants that orchestrate the migration and positioning of leukocytes, and are indispensable components of all protective and pathogenic immune and inflammatory responses. Lymphatic endothelial cells (LECs) play a prime role in chemokine production and exchange with the surrounding tissues, where a combination of diffusion, advection, binding kinetics and cellular uptake result in the generation of spatial chemokine gradients that govern leukocyte migration. If chemokine gradients are not appropriately tuned, leukocytes fail to respond and immune responses are compromised. While previous research has revealed much about chemokine function at the sub-cellular level, there is little quantitative knowledge of how physical and biological mechanisms interact to produce functional chemokine gradients in vivo, or of how the specific characteristics of those gradients affect leukocyte behaviour. We aim to develop a comprehensive quantitative knowledge base of chemokine gradient formation and regulation using integrated experimental and modelling approaches. This will provide unprecedented insight into this complex, dynamic and critically important process, and has potential impact on vaccination and on the treatment of diseases with key immune cell contributions, such as allergy, autoimmunity, cardiovascular disease, and cancer.

Amount: £1,927,134
Funder: The Wellcome Trust
Recipient: Imperial College London

A London consortium to establish a high resolution cryo-electron microscopy facility for research and training 07 Dec 2016

With the recent revolutionary advances in electron cryo-microscopy (cryo-EM), made possible largely by state-of-the-art microscopes (the Titan Krios), direct electron detectors and data processing, it is becoming realistic to determine atomic resolution structures of macromolecules using cryo-EM. Indeed, cryo-EM is the only method available for structural determinations of many large proteins and complexes that are difficult to produce or of transient, dynamic nature. Recent examples demonstrate that cryo-EM can be used to study proteins as small as 150 kDa and achieve resolution better than 2 Å, making cryo-EM potentially the leading methodology for most structural biology projects. London has the highest concentration of structural biologists in the UK, but to date the only Krios instruments are due to be installed at the Francis Crick institute for the sole usage of the large number of Crick-affiliated researchers. Consequently, the majority of London researchers have no rapid or local access to a Krios setup, significantly affecting our international competitiveness. The London consortium for cryo-EM (LonCEM) brings together researchers from Imperial College London, Institute of Cancer Research, Kings College London and Queen Mary University London and proposes to establish a high-resolution cryo-EM facility to enable excellent research, collaborations and training.

Amount: £3,000,000
Funder: The Wellcome Trust
Recipient: Imperial College London

Sexual Violence, Medicine, and Psychiatry 01 Feb 2017

Medical professionals play central roles in examining, treating, and counselling victims of sexual violence. Their scrutiny of the complainant’s body is decisive in determining whether or not the police take the assault seriously and whether legal proceedings are instigated. Women, men, and children who are sexually abused depend on the medical and psychiatric professionals for physical and emotional care. Physicians play significant roles in determining whether an accused person is subsequently convicted, punished, or treated. The research focuses on the constituent parts of the UK, US, Australia, and New Zealand between the first decade of the nineteenth century and the present. It sets out to promote human health through providing unprecedented insights into the role of medicine and psychiatry in understanding, interpreting, treating, prosecuting, and preventing sexual violence in the context of four Research Streams: 1) Medicine and Law; 2) GPs, Police Surgeons and Forensic Medical Examiners; 3) From Psychopathia Sexualis to the DSM/ICD; 4) Psychiatric Aftermaths. There will also be a research theme on child sexual abuse, attached to one or more of the Research Streams. The project will be a powerful example of how historical scholarship can inform contemporary crises and debates.

Amount: £1,237,585
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Connecting causes and immune consequences of infection-induced metabolic change 11 Jul 2017

This research proposal focuses on metabolic changes driven by the immune response to bacterial infection in the model system Drosophila melanogaster. We will use in vivo genetic manipulations, experimental and computational analysis of gene expression, and experimental metabolomics to address two overarching biological questions. First, how does immune activation drive metabolic change? Second, how do these metabolic changes aid or impede the realised immune response and host survival? The proposal contains three aims directed at these questions. In the first aim, we use whole-animal metabolomics to identify metabolite level changes driven by different infections. In the second aim, we identify signals and transcriptional regulators responsible for the concerted regulation of metabolic enzymes during infection, and connect these signals and regulators with their downstream immunometabolic consequences. In the third aim, we target specific metabolites for analysis, using in vivo genetics to determine which immune-driven metabolic changes have important effects on realised immunity and tolerance of infection. Key goals: we will - identify the metabolite changes resulting from different bacterial infections - establish how these changes are driven by innate immune detection and signalling - connect specific metabolite changes with their effects on infection tolerance and immune function in vivo.

Amount: £1,103,343
Funder: The Wellcome Trust
Recipient: Imperial College London

Characterizing transcriptional transition states in cell differentiation 30 Sep 2018

As stem cells differentiate, their transcription profiles change over time. These complex dynamics are essential for generating specialised cell types and facilitating normal development. I aim to characterise the movement of these differentiating cells through gene expression space using a multidisciplinary approach. I will use stochastic models to simulate stem cell dynamics over developmental time, and fit these models to transcriptomic data using Bayesian methods (Approximate Bayesian Computation and Particle Markov Chain Monte Carlo). My approach also aims to incorporate structural information from Genome Architecture Mapping experiments, to further improve these models. This work will improve the characterisation of key transition states within stem cell dynamics, and lead to more informative models of cell differentiation.

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

Causal mechanisms in stroke subtypes 30 Sep 2018

Stroke describes an insult to the brain that is caused by a disruption of blood flow. There are different subtypes of stroke, which may be subdivided by the cause of the disruption to blood flow. The mechanisms underlying different stroke subtypes vary, and therefore so do optimal treatment strategies for each subtype. Individuals vary in their genetic make up. Genetic variants that are strongly associated with a particular trait can be used to investigate the effect of that trait on the risk of different stroke subtypes. For examples, if individuals with genetic variants that are strongly associated high blood pressure also more often suffer a particular stroke subtype, it would suggest that higher blood pressure causes that subtype of stroke. This technique is called Mendelian randomization, and has the advantage that genetic variants are randomly allocated, and so the genetic variants that any individual gets are not affected by their lifestyle or environment, preventing these factors from biasing the associations observed. During my fellowship, I will be using the Mendelian randomization technique to unravel the mechanisms that cause different subtypes of stroke.

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

Coarse-grained modelling to guide an understanding of eukaryotic cell physiology 30 Sep 2018

Unicellular organisms resemble factories that produce copies of themselves. In order to optimise growth, they adjust their relative allocation of resources to the various subprocesses that construct all necessary components of a new cell. In bacteria, these optimisations have been observed in many conditions. Generally, the fraction of ribosomal proteins scales linearly with the cellular growth rate. This suggests that bacteria are highly optimised for fast growth under many conditions. In a preliminary analysis, we have observed the same linear relation between growth rate and ribosomal protein allocation in yeast cells, grown using various sources of nitrogen. The shift towards expressing more growth-related ribosomal proteins occurs together with the cells needing fewer resources to utilise their nitrogen source. In the project, we will extend this analysis and use the results to inform a coarse-grained cell model. Our model should allow us to understand the principles of growth and biomass production. Because the eukaryote from this study is more closely related to human cells than bacteria, our results provide a stepping stone in developing anti-cancer treatments. In both synthetic biology and anti-cancer research, understanding the balance between growth and protein production is crucial towards obtaining good yields and/or controlling runaway growth.

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

A bacterial c-di-GMP responsive enzyme modulates LPS structure and triggers immune evasion 30 Sep 2018

Pseudomonas aerigunosa is a bacterial pathogen associated with acute and chronic infections in humans. The mode of infection by P. aeruginosa has been shown to depend on a small intracellular molecule produced by the bacterium, c-di-GMP, which is made by an enzyme called diguanylate cyclase (DGC). How c-di-GMP contributes to bacterial cell behaviour is not understood, but it is believed that a DGC transfers c-di-GMP to a receptor protein, thereby modulating its activity and capacitating the bacterium to develop a virulence trait. The Filloux lab has identified a DGC, SadC, which hands in c-di-GMP to a partner protein, called WarA. WarA shapes the surface of the bacterium, decorating it with a component called LPS. In absence of SadC and WarA, the surface is changed and the bacterium is quickly recognized by the immune system and eliminated. I aim to elucidate the WarA network and how it contributes to bacterial immune evasion in molecular details. I will use biochemical, genetic and genomic approaches or in vivo infection. Our understanding of the cascade of molecular events that lead to immune escape will then be used to screen for inhibitors that block the network and make P. aeruginosa susceptible to our immune system.

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

In vivo function of the activating NK cell receptors in intestinal inflammation 30 Sep 2018

Chronic inflammation of the intestine leads to mucosal damage and manifests in inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn’s disease. Sustained inflammation can lead to transformation of cells, making IBD a major risk factor for colorectal cancer (CRC). The mechanisms involved in disease development and progression are still poorly understood. We study the interaction between immune cells, the gut microbiota and cells lining the inside of the intestine to understand the link between the immune system and the environment in the gut. Specifically, we focus on natural killer (NK) cells, which can recognise and kill malignant or infected cells that express certain stress signals. We hypothesise that under certain circumstances, this system is out of balance, leading to mucosal damage and chronic inflammation. We aim to dissect the mechanisms underlying the contribution of activating NK receptors in chronic inflammation of the gut epithelium and subsequent tumour development. To that end, we will investigate the interplay between the NK receptor expressing immune cells, inflammatory local responses and the gut microbiota using mice that lack certain NK cell receptors.

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

Holographic Induction of Neural Circuit Plasticity 08 Apr 2016

Key words: Plasticity, Optogenetics, Neocortex, Neural Microcircuits, Functional Connectomics, Computer-generated Holography, Two-photon Microscopy Neocortical circuits modify both structure and function in order to learn, remember, refine task performance, and recover from injury. Electrical patch-clamp methods have identified several plasticity mechanisms on the single-cell level. The number of cells that can be simultaneously patched is however limited, hindering efforts to connect single-cell plasticity with circuit- and system-scale learning and memory. Computer-generated holography (CGH), combined with genetically encoded light-sensitive actuators ("optogenetics"), holds immense promise to overcome this limitation by targeting light to rapidly activate one or several neurons without physical electrode penetration. I will adapt two-photon CGH to: 1) rapidly map local inputs to a neuron in depth of neocortical brain slices; and, 2) manipulate the connection strengths between the neuron and its presynaptic inputs by holographically actuating spikes in the presynaptic neurons at short delays with respect to electically actuated post-synaptic spikes. CGH’s ability to rapidly solicited spikes in hundreds neurons will enable, for the first time, single-cell resolution plasticity interrogation in whole functioning microcircuits. The Wellcome Seed award will enable these critical first steps toward connecting synaptic plasticity with neural circuit emergent properties, learning, memory, and injury recovery.

Amount: £100,000
Funder: The Wellcome Trust
Recipient: Imperial College London