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Results

Impact of Rapid Expansion of the Estratégia de Saúde da Familia in Rio de Janeiro: Mixed Methods Evaluation 26 Oct 2016

Our project aims to influence the development of PHC in Rio de Janeiro, other large cities in Brazil, and internationally by generating and actively disseminating timely evidence to policy-makers especially in a period of economical crisis. We will achieve this by including policy-makers and programme implementers from Rio de Janeiro in our research team. We will jointly host dissemination events with the Pan American Health Association in Rio de Janeiro and Brasilia with policy makers from cities across Brazil to share the findings in order to inform policy development in the country and internationally. Our evaluation will provide important information to other countries seeking to achieve UHC in major urban areas and large cities, such as Colombia and India. By fostering links between academics and policy makers from Brazil, UK, and USA with extensive experience in analysing linked datasets, microsimulation modelling and qualitative research, we will build research skills and research translation capacity among all team members.

Amount: £159,936
Funder: The Wellcome Trust
Recipient: Imperial College London

HIV prevention among young women in eastern Zimbabwe: Developing HIV prevention cascades and interventions to improve uptake and adherence 31 Jan 2017

In southern Africa, nearly 30% of new HIV infection occur among young women (15-24). While treatment as prevention may have impacts on HIV transmission, the implementation of efficacious HIV prevention interventions is critical for achieving the goal of ending the AIDS epidemic by 2030. Analogous to HIV treatment cascades, HIV prevention cascades (HPCs) have the potential to support the evaluation and implementation of HIV prevention efforts. However, there is a lack of scientifically robust methods to measure and interpret HPCs. Similarly, behavioural economic theory has been shown to provide fruitful insights for improving ART uptake and adherence but its application to HIV prevention is limited. Focusing on HIV prevention among young women (15-24), this projects aims at filling these gaps in HIV prevention research. The objectives are: Develop multi-level theoretical frameworks of factors influencing HIV prevention uptake and adherence among young women. Define each step of HPCs in relation to HIV prevention among young women and develop questions for measuring these. Develop questions for interpreting these HPCs. Test these methods in a high HIV prevalence sub-Saharan African setting. Develop interventions to improve HIV prevention uptake and adherence based on behavioural economic theory.

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 05 Dec 2016

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 Wellcome Seeding Drug Discovery Award involves the innovative use of human cardiac muscle grown from stem cells to pinpoint the molecules responsible for cardiac injury and will take his programme of research the essential steps further, towards the development of MAP4K4 inhibitors as clinically workable compounds.

Amount: £4,499,155
Funder: The Wellcome Trust
Recipient: Imperial College London

Understanding signal integration in eukaryotic cell growth 22 Feb 2017

The aim of the project would be to understand signal integration in the TOR (Target of Rapamycin) growth signaling pathway. TOR growth signaling is mediated by the kinase activity of TOR complex 1. This is contingent on concurrent activation of two sets of small GTPases, the Rags and Rheb, which recruit TORC1 to lysosomes and activate it there. Both GTPases are regulated by GTPase activating proteins, the GATOR complex(es) in the case of the Rag GTPases, and the TSC (tuberous sclerosis complex) in the case of Rheb. We would attempt to recombinantly express, purify and reconstitute these complexes, in order to interrogate their activity in response to known signals using biochemical and biophysical assays. We would also attempt to obtain their structures, using x-ray crystallography and electron cryo-microscopy, leading to a molecular understanding of their regulation. The results would be beneficial both academically, given the key position of TOR signaling in eukaryotic cell growth, and medically, as TOR is a known to be a key target in immuno-repression, cancer and tumour syndromes. Any new information on the regulation of the tuberous sclerosis complex would almost certainly be directly applicable to this, and related, hereditary condition(s).

Amount: £1,129,760
Funder: The Wellcome Trust
Recipient: Imperial College London

Identification of immune mechanisms and genes associated with the high rate of relapse in patient with visceral leishmaniasis and HIV co-infections 22 Nov 2016

Visceral leishmaniasis (VL), a neglected tropical disease caused by Leishmania parasites, has emerged as an opportunistic infection in HIV patients. In Ethiopia, over a third of VL patients are co-infected with HIV. In contrast to VL patients, VL/HIV co-infected patients have a high rate of VL relapse after successful treatment. The mechanisms accounting for this increased relapse rate are poorly characterised. In the present study, I propose to identify immunological mechanisms and actively expressed genes that can be associated with frequent relapse in VL/HIV patients. To do this, I will recruit VL and VL/HIV patients from the Leishmaniasis Research and Treatment Center at the University of Gondar Hospital. Blood samples will be collected at time of diagnosis, at the end of anti-leishmanial treatment, and up to 12 months following cessation of treatment, in patients who relapse and those who don’t. I will measure neutrophil, monocyte and T-cell effector functions; furthermore, genome-wide transcript analysis from VL and VL/HIV patients will be used to identify transcripts of immune response pathways and functions that are differentially expressed in patients who relapse. The results of my work will contribute to a better understanding of the immunological mechanisms accounting for VL relapse in HIV/VL patients.

Amount: £211,404
Funder: The Wellcome Trust
Recipient: Imperial College London

Vacation Scholarships 2017 - Imperial College London 16 Jun 2017

Vacation Scholarship Institutional Award

Amount: £15,500
Funder: The Wellcome Trust
Recipient: Imperial College London

The mechanism of preferential uptake of Haemophilus influenzae bacteria in human bronchial cell lines and the role of this pathway in COPD exacerbations 27 Apr 2017

Chronic obstructive pulmonary disease (COPD) exacerbations severely impair quality of life and are the most frequent reason for UK hospital admissions in the winter months. The exact causes of exacerbations are unknown, but are closely associated with Haemophilus influenzae. This bacteria often arises as a secondary infection following viral exacerbations - however, it is unclear how these secondary bacterial infections occur. A proposed theory is that upon entering human bronchial epithelial cells, bacteria survive and evade the immune system until a viral infection releases them. Preliminary studies have shown H. influenzae uptake is increased in COPD patients than healthy controls. The mechanism of uptake appears to act via macropinocytic pathway, requiring cytoskeletal reorganisation and phosphatidylinositol-4,5-bisphosphate (PI)3-kinase activation. This is mediated by P5 and hap proteins on the surface of H. influenzae, although epithelial targets remain unclear. This project aims to develop models of uptake of various bacteria in a range of human bronchial cell lines and to study the role of pathways in this process. Understanding the reason behind preferential H. influenzae uptake and the targets of inhibition provide novel therapies to prevent bacterial colonisation and prolonged exacerbations, relieving the strain that COPD exacerbations have on the NHS.

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

Dissecting the role of aryl hydrocarbon receptor in thermogenic adipose tissue 06 Jun 2018

The obesity crisis has reached epidemic proportions and represents one of the most significant global public health challenges. The recent discovery of energy dissipating brown adipose tissue (BAT) in adult humans has raised the possibility of targeting BAT for the treatment of obesity. Indeed, studies in humans and mice have demonstrated an inverse relationship of BAT activity with obesity and metabolic syndrome. I propose to explore the potential of natural dietary compounds that are sensed by the aryl hydrocarbon receptor (AHR) as novel inducers of BAT activity. I will identify the physiological role of AHR in thermogenesis and utilize conditional gene-targeting approaches to define cell-autonomous functions of AHR in specific cell-types within BAT. Importantly, I will determine whether dietary AHR ligands, such as phytochemicals and microbiota metabolites, can induce the thermogenic activity of BAT, promote energy expenditure and improve metabolic disease in the context of obesity. To elucidate the mechanisms by which AHR modulates thermogenic programs, I will identify its direct transcriptional targets in specific cell-types using ChIP-seq and RNA-seq. Together, these studies will provide important insights into the regulation of thermogenesis by specific dietary factors and may facilitate the use of natural AHR ligands for the treatment of obesity.

Amount: £1,286,093
Funder: The Wellcome Trust
Recipient: Imperial College London

Novel role of SXL in chromatin association 31 May 2018

Sex Lethal (Sxl) is a gene which acts as a gender-switch in flies. In females, a full-length form of Sxl (SxlF) is present which initiates the start of female-specific development. In males however, a shorter form of Sxl (SxlM) is made which is unable to fulfil this function. Recently however, much research has highlighted the potential importance of similarly short proteins, termed micropeptides, in regulating pathways and protein function. As previous research has escaped SxlM due to its tiny size, it’s possible that SxlM fulfils some important role within male development which has yet to be determined. This project will investigate the importance of SxlM in the development of male physiology and behaviour, and attempt to understand how it may fulfil these roles through a novel molecular profiling technique termed Targeted DamiD, TaDa.

Amount: £0
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

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

Human retroviral latency: regulation and dynamics at the single-cell level 11 Jul 2017

Latent persistence of retroviruses, including HIV-1 and the human leukaemia virus HTLV-1, remains a major barrier to their eradication from the host. HTLV-1 appears to be latent in circulating lymphocytes, but the strong, persistently activated immune response indicates that the virus is not latent in vivo. We infer that HTLV-1 undergoes intermittent bursts of gene expression. We have now obtained direct evidence of HTLV-1 gene bursts in naturally-infected cells in vitro. The central question "What regulates HTLV-1 latency?" therefore becomes "What regulates the gene expression bursts of HTLV-1?" We have developed a powerful set of materials and techniques to identify the causes and quantify the kinetics of this gene bursting at the single-cell level. A major regulator of mammalian gene expression is the key chromatin architectural protein CTCF. We recently discovered that the HTLV-1 provirus binds CTCF and alters the higher-order structure of host chromatin. In this programme we will investigate the consequences for both the virus and the host cell of this remarkable experiment of nature. The results of this work will answer fundamental questions on the persistence and pathogenesis of HTLV-1, and contribute to the growing understanding of mammalian gene bursting.

Amount: £1,927,877
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

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

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

Empirical revision of biological networks using machine learning. 12 Jun 2006

Empirical Revision of Biological Networks using Machine Learning It is well known that existing public domain biological network descriptions contain topological errors of omission and commission. This PhD project aims to develop and evaluate methods to effectively and efficiently revise the knowledge deposited in public biological networks (like Kyoto Encyclopedia of Genes and Genomes) by using machine learning techniques. We plan to start the theory revision system by using facts and background knowledge from well characterised networks such as the aromatic amino acid pathways of yeast. We will gradually remove randomly selected information using existing theory revision systems to reconstruct the deleted portions of the system. At some point it is expected that the amount of information deleted will be so significant that full recovery is impossible. Doing this systematically for a different group of metabolic networks known organisms will allow us to characterise the limitations of the available techniques for biological data. Having assessed the limitations of existing techniques we will develop methods based on the new area of Statistical Relational Learning to overcome these limitations.

Amount: £141,262
Funder: The Wellcome Trust
Recipient: Imperial College London

Identification and characterisation of proteins responsible for oocyst development and evasion of mosquito immune responses. 08 Feb 2006

The malaria parasite Plasmodium is transmitted between its vertebrate hosts by a mosquito vector. Following uptake within the blood-meal, the parasite becomes motile and is known as the ookinete. The ookinete is capable of penetrating the epithelium of the mosquito midgut, and at the midgut basal lamina it differentiates into the oocyst. Maturation of the oocyst results in the release of thousands of invasive sporozoites, which can be transmitted to the next vertebrate host during subsequent bloodmeals. One strategy for the control of malaria is to target the parasite during its mosquito stages. However, to do so, the interactions between the parasite and the mosquito must be elucidated and Plasmodium secreted or surface proteins mediating these interactions must be identified. The aim of this PhD project is to identify genes that are specifically expressed during oocyst development, especially early stages, and to investigate the role of these gene products in oocyst development and their interaction with the mosquito immune system. The working hypothesis is that genes specifically up or down-regulated during Plasmodium oocyst development are likely to be important for oocyst differentiation and interaction with the mosquito immune responses, and that the levels of parasite gene expression may determine the outcome of the interaction with the mosquito immune system. Candidate genes identified through this type of transcriptional analysis then can be subjected to a detailed functional analysis. This research project would not only serve to increase our understanding of the molecular processes by which Plasmodium completes its life cycle in the mosquito vector, but might also identify novel targets towards malaria transmission blocking.

Amount: £6,177
Funder: The Wellcome Trust
Recipient: Imperial College London