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Results

Microfluidic Platform for Investigating the Kinetics of Extracellular Vesicle Induced Metastatic Niche Formation 21 May 2018

Extracellular vesicles (EVs) are believed to be important messengers in the progression of metastatic cancer that prime distant organs for tumour cell colonisation. However, due to an inadequacy of relevant tools, we have a poor understanding of how EVs distribute to, diffuse into and remodel organs into metastatic niches. The goal of this project is to develop novel microfluidic platforms for performing real-time continuous quantification of EV kinetics over multiple days in physiologically-relevant microenvironments. Towards this end, I propose three aims: Develop Microfluidic Metastatic Niche Platforms to explore the interaction of extracellular vesicles with liver tissue and vasculature. Investigate the kinetics of EV distribution, uptake and diffusion in liver and vasculature compartments of Microfluidic Metastatic Niche Platforms. Explore the influence of EV kinetics (distribution, uptake and diffusion) on the ability of cancer cells to attach, invade and proliferate in Microfluidic Metastatic Niche Platforms. The results of this project will enhance our understanding of metastatic cancer progression and will contribute valuable data for numerous follow-up studies aiming to inhibit or even prevent the development of metastatic niches.

Amount: £99,951
Funder: The Wellcome Trust
Recipient: Imperial College London

Structure and mechanism of the Ino80 chromatin remodelling complex 28 Nov 2017

Compaction of the genome into chromatin helps to protect the genetic material but also causes problems in regard to access for essential processes such as transcription, replication and repair. Chromatin remodelling complexes alter the state of chromatin through a number of processes that includes chemical modifications of nucleosomes and sliding their position on DNA. Nucleosome sliding is catalysed by a number of protein complexes, one of which is the multi-subunit INO80 complex. INO80 contains an ATP-dependent translocase motor, that is common to all nucleosome sliders, but also a variety of other subunits, most of which have unknown roles. Furthermore, not only does it require two INO80 complexes interacting with a single nucleosome to promote sliding, but the complex also has an ability to "sense" the presence of other nucleosomes to space them evenly on DNA indicating interactions with multiple nucleosomes. The mechanism for this process is poorly understood, particularly at a molecular and structural level. INO80 is highly regulated in several distinct ways, including chemical modifications, small molecule effectors and subunit interactions but none of these are well understood. Finally, how the various subunits, many of which are ATPases in their own right, contribute to INO80 activities is also unclear.

Amount: £1,701,911
Funder: The Wellcome Trust
Recipient: Imperial College London

Suppression of adaptive immunity by Salmonella 28 Nov 2017

Dendritic cells (DCs) have a crucial role in the development of adaptive immunity to bacteria. DCs transport the intracellular pathogen Salmonella from intestinal Peyer’s Patches to mesenteric lymph nodes where they present bacterial antigens to CD4+ T cells using MHCII molecules. DCs also secrete cytokines that stimulate recruitment and activation of T and NK cells. Salmonella is a globally important intracellular pathogen that survives in DCs and interferes with the processes of DC migration, cytokine production/sensing and T cell activation. The overall goal of this application is to understand mechanisms by which Salmonella interferes with these processes. Recently we identified an effector of the SPI-2 type III secretion system (SteD) that reduces the number of mature MHCII molecules on the surface of DCs. A significant component of the planned work is to understand its mechanism of action in detail. We will use candidate-based and unbiased screens, along with molecular cell biological approaches to characterize mechanisms involved in suppressing DC migration, production of IL-12 and IFN-gamma-stimulated host cell signaling. Collectively, this research will advance the field by providing novel insights into different mechanisms by which a bacterial pathogen subverts the development of adaptive immunity.

Amount: £2,170,670
Funder: The Wellcome Trust
Recipient: Imperial College London

Mechanisms of how endocrine hormones regulate appetite 31 May 2018

The aim of this project is to investigate whether specific metabolites produced in the duodenum during digestion and correlated with the release of the gastrointestinal hormone glucagon-like peptide-1 (GLP-1) actually drive this release of GLP-1 to regulate energy and glucose homeostasis. We will use gut organoids as a model of enteroendocrine cell function to study the effects of the metabolites tyrosine, taurine and acetone, alone and in combination, and with or without glucose present. Hypothesis: Tyrosine, taurine and acetone will stimulate GLP-1 release from duodenal organoids Aim: To investigate the effects of tyrosine, taurine and acetone on GLP-1 release Objective: To establish whether tyrosine, taurine and acetone alone or in combination with each other or glucose stimulate GLP-1 release from duodenal organoids This work will establish the possible role of these metabolites in driving GLP-1 release, and thus whether using them as dietary supplements may represent a potential therapeutic approach to obesity and metabolic disease.

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

Modelling the feasibility of achieving 70% target vaccination coverages for rabies elimination in free-ranging dog populations in India 30 Sep 2018

Rabies kills over 20000 people every year, predominantly in India, where it is spread by the bite of infected free-ranging dogs. The WHO recommends that canine rabies can be controlled and eventually eliminated by consistently vaccinating at least 70% of the dog population in a region. However, there is little information on dog populations in India and what proportion are truly free-ranging. This influences the feasibility of conducting mass rabies vaccination campaigns and achieving the target of 70% vaccination coverage. This study will look at dog populations at selected sites in India to estimate population size and structure such as proportion of males and females, young and adult animals and the occurrence of rabies. The study will assess ownership patterns to determine what proportion of dogs are truly free-ranging. Rabies vaccination campaigns will be conducted at these study sites to determine the feasibility of achieving 70% vaccination coverage. The data on dog population and vaccination coverage will be used to mathematically model the effects of this kind of intervention, and determine the best way to implement it at these sites. The results of this study will directly inform rabies prevention and control strategies at the regional levels and in India.

Amount: £0
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

Pathways to Equitable Healthy Cities (London Hub for Urban Health) 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 PEHC project focuses on how policy scenarios that involve changes to key urban sectors and services impact population health and health inequality in Accra, Beijing, Dhaka, London, Tehran and Vancouver.

Amount: £5,154,996
Funder: The Wellcome Trust
Recipient: Imperial College London

Statistical Analysis of the Type 6 Secretion System in Pseudomonas Aeruginosa 30 Sep 2018

Pseudomonas aeruginosa is a Gram-negative bacterium that is a leading cause of many hospital borne infections. In particular recent research has identified the Type 6 Secretion System (T6SS) present in P. aeruginosa and has focused on the structure and mechanism of the system. This highly complex system allows P. aeruginosa to accurately penetrate adjacent cells and thus insert an array of toxins which can cause cell death or disrupt cellular pathways. Building on this work we would like to understand the T6SS from a statistical perspective. Understanding the spatial distribution and dynamics of the T6SS along the cell membrane of P. aeruginosa are amongst a number of different questions we hope to explore in this project. To achieve these targets we will use fluorescently tagged components of the T6SS mechanism as well as confocal microscopy of living P. aeruginosa, thus allowing for 3-dimensional reconstruction. These biological questions will be answered using a variaty of quantitative approaches. To extract important information from the image data a number of imaging and video preprocessing methods will need to be applied. After preprocessing the this data will be analysed using a variaty of statistical methdologies in order to provide a quantitative description.

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

The role of the factor H-related proteins in kidney disease 17 Jul 2018

The complement factor H-related (FHR) proteins influence susceptibility to kidney and eye (age-related macular degeneration) disease, and to meningococcal infection. The FHR proteins are related to complement factor H (FH), the major negative regulator of complement C3 activation. Unlike FH the biological roles of the FHR proteins remain unclear. Understanding how FHR proteins damage the kidney is very important because they are associated with both rare (C3 glomerulopathy) and common (IgA nephropathy) kidney diseases that lack effective treatments. My key goals are to determine how FHR proteins mediate renal injury and if modulating FHR activity can reduce complement-mediated kidney injury. My experimental program will utilise novel mouse strains, developed during my current fellowship, to determine if absence of FHR proteins reduces kidney injury in experimental nephritis, including IgA nephropathy. I will characterise the mechanisms through which mutant FHR proteins cause C3 glomerulopathy by detailed phenotyping of the first model of FHR-associated C3 glomerulopathy. I will elucidate the mechanism through which accumulation of glomerular C3 causes kidney injury. My program will help us to understand how to manipulate these proteins therapeutically which I predict will reveal a means of modulating complement that is safe and amenable to long-term therapy.

Amount: £1,917,963
Funder: The Wellcome Trust
Recipient: Imperial College London

The role of leukotriene A4 hydrolase in dictating inflammation and remodelling in chronic lung diseases 28 Nov 2017

Whilst inflammation and ensuing repair are critical to the body’s response to infection/injury, aberrant inflammatory and reparative processes and subsequent pathological remodelling are cardinal features of chronic lung diseases (CLDs). I believe the enzyme leukotriene A4 hydrolase (LTA4H) critically regulates inflammation/repair processes through dual activities that generate lipid mediator leukotriene B4 (LTB4) but degrade matrikine Pro-Gly-Pro (PGP). PGP is a neutrophil chemoattractant whilst LTB4 drives the recruitment/activation of numerous immune cells. Additionally, I now demonstrate that PGP regulates epithelial and fibroblast functions critical to repair/remodelling. I hypothesise that intrinsic and extrinsic perturbation of the LTA4H axis drives distinct pathological inflammatory and remodelling phenotypes in CLDs. The key goals of this proposal are: Dissect how the dual functions of LTA4H regulate pathological inflammatory and remodelling features of CLDs, and infer if novel LTA4H modulators show therapeutic potential. Understand how LTA4H is perturbed by genetic influences and environmental insults resulting persistent inflammation and pathological remodelling. Evaluate the LTA4H axis in CLD patients to ascertain why it is aberrant and how it correlates with pathological and clinical endpoints. These studies examine biological pathways that define the balance between health and disease, and will facilitate the endotyping of patients for therapeutic intervention.

Amount: £1,798,687
Funder: The Wellcome Trust
Recipient: Imperial College London

Understanding how Gram-positive pathogens sense and respond to daptomycin 30 Sep 2018

Antibiotic resistance is a growing threat to human health as it results in infections which are difficult to treat and are associated with high rates of mortality. Daptomycin is a last-resort antibiotic used to treat infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. However, daptomycin fails to cure approximately 20 % of infections. Bacteria can protect themselves from daptomycin by releasing lipids from their cell membranes which prevent the antibiotic from reaching and killing its target. Understanding more about this bacterial defence mechanism is important as it will allow development of novel approaches to improve the effectiveness of daptomycin therapy. Therefore, the aim of this project is to understand how S. aureus senses the presence of daptomycin and how this leads to the production of lipids. I will determine which proteins are necessary for this defence mechanism and whether other Gram-positive pathogens also sense daptomycin and induce the release of lipids in a similar way to S. aureus. These studies will lead to a greater understanding of this novel resistance mechanism and may lead to the identification of factors which could be targeted therapeutically to reduce the pathogen’s defences and therefore improve rates of daptomycin treatment success.

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

Oestrogens and beta adrenoceptors in the heart 31 May 2018

The actions of oestrogen on the heart are poorly understood. The preliminary findings of the lab group (Prof K MacLeod) I am hoping to join suggest long-term absence of ovarian hormones lead to potentially detrimental changes in Ca2+ handling mechanisms in the heart that may cause the formation of a more pro-arrhythmic substrate. Oestradiol replacement prevented these adverse effects. The work I hope to be involved in will investigate if lack of oestrogens alters Ca2+ regulation by changing the number or function of beta adrenoceptors (beta-ARs) thus altering the efficacy of cardiac excitation contraction coupling and cellular Ca2+ regulation.

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

The role of seasonal population movements in malaria transmission and control 30 Sep 2018

Increasing control efforts have produced important declines in malaria prevalence over the past 15 years. As more and more regions approach elimination, the role of human mobility patterns becomes increasingly relevant. Containment efforts in regions with no or low prevalence are hindered by parasite importation through movement of infected people. I aim to understand the role of migration in malaria spread, looking in particular at seasonal flows. I will review and analyse available data on human migration in sub-Saharan Africa and then use this data to extend a pre-existing large-scale malaria simulation model to include seasonal migration. This will allow me to examine the impact of migration on malaria transmission and persistence. The results of this work will likely have important implications for malaria elimination and help formulate future control policies.

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

The role of Fubp3 in the pathogenesis of osteoporosis 30 Sep 2018

Osteoporosis is the commonest disease of bone. Affected individuals have an increased risk of fracture as bone is of reduced strength and quality. Fractures can cause significant pain and disability as well as costs to the health service. The number of people with osteoporosis is increasing as the population gets older. Currently treatments are limited, but understanding the genetics of bone disease has already led to promising new treatment ideas. Genetic studies of large numbers of people have associated variants in Fubp3 with both osteoporosis and fractures. However, FUBP3 is not currently known to have a function in bone. We hypothesise that it may be required for normal bone growth and maintenance of normal bone mineralisation and strength. We will study mice lacking the Fubp3 gene in order to understand the function of FUBP3 in bone. With this knowledge we hope to identify new signalling pathways involved in osteoporosis which can be targeted by new treatments.

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

Novel inhibitors of MAP4K4 (HGK), an acute therapy to prevent cardiac muscle cell death following myocardial infarction 01 Oct 2017

Heart disease is the most frequent source of death and disability worldwide, most especially as heart attacks (cardiac muscle cell death from obstructed blood flow to the heart). Its severity is due in part to heart muscle's inability to rebuild itself as most other tissues can. One potential strategy, to enhance standard therapies like “clot-busting” drugs and stents, is to suppress cell death directly by protecting the injured, jeopardized muscle cells. Professor Michael Schneider at Imperial College London has identified the enzyme MAP4K4 as a key regulator of cardiac cell death and has devised novel, potent, selective drug-like inhibitors to protect human cardiac muscle grown in the laboratory. This Seeding Drug Discovery Award will enable the innovative use of human cardiac muscle grown from stem cells to pinpoint the molecules responsible for cardiac injury and will take the programme of research the essential steps further, towards the development of MAP4K4 inhibitors as clinically workable compounds.

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

Unraveling novel molecular mechanisms of iron-sensing in African trypanosomes 18 Oct 2017

This proposal aims to understand intracellular iron homeostasis in Trypanosoma brucei, a parasitic pathogen that causes African Sleeping Sickness in humans and nagana in animals. Iron is an essential micronutrient for all organisms and serves as a regulatory signal for virulence factors in prokaryotic and eukaryotic systems. Its homeostasis is tightly regulated and extensively studied in these systems revealing specific mechanisms in each domain. However, it remains relatively understudied in T. brucei despite its crucial role in pathogenesis. Using a genome-wide transcriptome profiling pilot study of T. brucei under transferrin/iron-starvation conditions, I identified novel parasite-specific iron-deficiency responsive genes. Based on these findings, I hypothesize that novel intracellular iron-dependent regulatory and signaling processes exist in T. brucei that control expression of iron-responsive genes. I will investigate this hypothesis in-depth by: characterizing the function of these novel iron-responsive genes, probing global proteomic changes under transferrin/iron-starvation, and systematically mapping the post-transcriptional iron-sensing regulatory network using genetic and biochemical approaches. Functional characterization of these regulators/effectors will reveal how an iron-stress signal is converted into a biological response, how this process in T. brucei is distinct from those of mammalian hosts, and will potentially provide new insights for development of novel therapeutic targets

Amount: £975,800
Funder: The Wellcome Trust
Recipient: Imperial College London