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Recipients:
University of Cambridge
University of Oxford
Currency:
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Results

The cognitive neuroscience of over-eating: normative and clinical studies of goal-driven and stimulus-driven responses 05 Apr 2017

There is a pressing need to understand the phenotypic variations of obesity in order to elucidate the diverse pathways and mechanisms by which it arises and, ultimately, to offer suitably tailored interventions. My proposed work aims to provide insights into the cognitive neuroscience of health-harming over-consumption. Its ultimate goals are to characterise cognitive mechanisms underlying eating behaviours, exploring how these are selected and deployed in ways that are shaped by both internal and environmental signals. The work is based on the view that obesity is ultimately driven by a complex integration of environmental and bodily signals and that a comprehensive approach must characterise this integration in order to determine how it may be altered in over-eating. My proposal has the following goals: To understand how stimulus-driven (automatic) and goal-directed (reflective) reward behaviours are balanced in relation to eating choices and to explore how this balance may differ across hungry and sated, lean and obese people. To relate these underlying processes to hormonal/metabolic signals as well and to real-world eating choices. To characterise the effects of three specific perturbations to this integrated system: (i) elective gastrectomy, (ii) single gene mutations affecting hypothalamic circuitry and (iii) psychopharmacological manipulations

Amount: £1,500,053
Funder: The Wellcome Trust
Recipient: University of Cambridge

Master's Award in Humanities and Social Science 30 Jul 2017

In my three essays, I will explore case studies of British biotechnology and bioethics since the 1960s. My first essay will investigate the history of organ donation regulation in the UK by focusing on two pieces of legislation: the Human Tissue Act of 1961 and the Human Organ Transplants Act of 1989, which aimed to regulate the procurement of cadaveric and live organ donors, respectively. Next, I will examine the British Biotech controversy of the 1990s. After exaggerating their production of marimastat for cancer treatment, the company lost accreditation and eventually dissolved. I will explore this public controversy using as a key source the episode in BBC2’s series Blood on the Carpet that recorded the politics behind the company’s downfall as a key source. Finally, I will examine the use of Foucauldian ideas in the rise of British bioethics in the 1960s. Focusing specifically on the emergence of what, following Ludwik Fleck, I call the bioethical thought collective, I hope to expand on Daniel Wilson’s work by analyzing how the collective’s philosophical ideals deployed and engaged with Foucault’s concept of biopower. Pursuing these research topics will expand my understanding of current British bioethical debates and American-British policy differences.

Amount: £28,440
Funder: The Wellcome Trust
Recipient: University of Cambridge

Future of Animal-sourced Foods (FOAF) 06 Oct 2016

Changes in the amount and type of animal-sourced food (ASF) we consume, and in the way they are produced, are critical drivers of global human health and environmental quality. The project will develop novel policy tools and interventions to allow more informed and effective action to be taken to maximise the health and environmental co-benefits of changes in ASF consumption. We shall build a quantitative food system model incorporating economic, health and environmental modules that will allow the effects of existing drivers and novel policy interventions to be assessed. We shall exploit unique epidemiological resources to provide new evidence about how different types of ASF affect health, and conduct experiments to develop new interventions to influence the consumption of ASFs and ASF substitutes. A social-science component will research how social norms and political economic factors affect the practicality and acceptability of interventions, and how this may be changed. The effects of different types of ASF production on climate change, water use and quality, and ecosystem functions will be measured and brought together for the first time. The project will develop a distinct work stream in China and engagement with multiple audiences will be integral to all its activities.

Amount: £947,700
Funder: The Wellcome Trust
Recipient: University of Oxford

Metabolic and Cardiovascular Disease. 30 Sep 2017

Not available

Amount: £2,352,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of genomic markers of ageing for the risk of metabolic disease 31 Jan 2017

Background: The risk for many common complex diseases, including type 2 diabetes, increases with age. Technological advances have recently enabled large-scale investigation of genomic markers of ageing in population-based studies. Whether genomic ageing contributes to the age-related rise of diabetes and related metabolic disorders is unknown. Aim: To systematically identify and study genomic markers of ageing, including telomere length, DNA methylation, and chromosome loss, and investigate their causal roles for morbidity and mortality from type 2 diabetes and other common complex diseases. My overall aim will be achieved by addressing the following specific objectives: Objectives: 1. To perform a systematic literature review of genomic markers of ageing to identify determinants and consequences and assess methods for their characterisation in epidemiological studies. 2. To identify and characterise genetic and modifiable behavioural and environmental risk factors of genomic ageing in large-scale population-based studies. 3. To investigate causal roles of genomic markers of ageing for morbidity and mortality from ageing-related diseases using Mendelian randomization methods, and conduct exploratory studies of the underlying pathways through detailed metabolomic characterisation.

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

Developmental Programming of Cardiovascular Dysfunction by Chronic Intermittent Hypoxia 31 Jan 2017

Cardiovascular disease remains the greatest killer in the world. The environment encountered in fetal life can exert a profound influence on an individual’s risk of cardiovascular disease; what is known as developmental programming. Understanding the mechanisms via which programming occurs may lead to preventative therapy. One common outcomes of complicated pregnancy is fetal exposure to chronic intermittent hypoxia (CIH). However, the mechanisms underlying fetal programming by CIH are not known. One potential mechanism is increased oxidative stress in the fetal cardiovascular system, established through reverse electron transport (RET) following re-oxygenation secondary to hypoxic succinate accumulation. The aim of this project is to isolate the effects of CIH with or without RET inhibition on programming of cardiovascular disease. Using an integrative approach, combining studies in vivo with those at the isolated organ, cellular, mitochondrial, molecular and metabolomic levels, this work will be carried out in the chicken. The chick embryo is the ideal species of choice, as it allows the direct effects of CIH to be isolated on the developing cardiovascular system while negating additional confounding effects of the challenge in decreasing maternal food intake and triggering changes in lactation, as it occurs in mammals.

Amount: £60,318
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the regulation and function of gap and Hox genes during segmentation in a short germ insect 31 Jan 2017

Three of the most abundant and diverse animal phyla - the Arthropoda, Annelida, and Chordata - are segmented along their anterior-posterior axis. Embryos of the fruit fly Drosophila form all of their segments simultaneously. In contrast, most arthropods, and all vertebrates and annelids, produce the majority of their segments sequentially. Although the molecular and genetic mechanisms regulating simultaneous segmentation have been well-characterised, our understanding of the mechanisms regulating sequential segmentation, especially in arthropods, remains poor. Gap genes are among the best-characterised components of the segmentation cascade in Drosophila. They are also expressed during segmentation of sequentially-segmenting arthropods. In Drosophila, gap genes define broad regions of the embryo; however, in sequentially-segmenting arthropods, they appear to have a different role, possibly mediated via Hox genes. Determining their function in sequential segmentation may shed light on how this developmental process is regulated, and how it was modified to give rise to simultaneous segmentation. For my PhD, I therefore propose to investigate the expression patterns, interactions and functions of gap and Hox genes in a simultaneously-segmenting arthropod, Tribolium castaneum. To accomplish these goals, I will analyse gene expression, cell behaviours and embryonic development in wild type and genetically manipulated Tribolium embryos.

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

Development and leptin signalling in human stem cell-derived POMC neurons 31 Jan 2017

Energy homeostasis in mammals is tightly controlled by a distinct neural circuit in the hypothalamus and its dysfunction leads to obesity. Pro-opiomelanocortin (POMC) neurons are a central component of this circuit. While obesity research has been largely limited to studies in rodents in the past decades, recently published protocols now allow the in vitro generation of human POMC neurons from human pluripotent stem cells (hPSCs). This enables us to study disease-associated mechanisms directly in the human cell type relevant to obesity. In my PhD I will contribute to a thorough characterisation and optimisation of this in vitro system. I will study when human POMC neurons are born in culture, assess their responsiveness to metabolic cues that regulate their activity and test different means of enhancing this responsiveness. This in vitro characterisation of POMC neuronal activity will be complemented by transplantation studies, in which I will test whether hPSC-derived POMC neurons possess all the features of functional maturity required to reinstall energy homeostasis in obese mice. I will finally use this novel tool to study the molecular mechanisms of certain signalling pathways in human POMC neurons, which might lead to the identification of potential targets for therapeutic intervention in human obesity.

Amount: £46,168
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the role of Kv1.6 in pain pathways 31 Jan 2017

Kv1.6 is a member of the Shaker-like Kv1 potassium channel protein family. Widely expressed in the nervous system, these channels have delayed outward rectifier properties and evidence indicates that they act to suppress action potential firing. In the field of neuropathic pain, of which neuronal hyperexcitabilty is a common hallmark, these channels are of interest as their malfunction or downregulation may contribute to the disease pathophysiology. While less is known of Kv1.6 than other subunits of the same family, it has recently been reported that this channel is upregulated following nerve injury, signifying some role for Kv1.6 during the time after injury. Pharmacological inhibition at this stage indicates a functional role for Kv1.6 in restoring hypersensitive pain thresholds somewhat towards more normal values. Having already conducted some preliminary research on the Kv1.6 knock-out mouse, I will employ various in vivo, ex vivo and in vitro techniques from behavioural chronic pain models to electrophysiology, calcium signalling and gene/protein expression analysis in order to further probe the importance of this channel in health and disease, and to determine its sites of action amongst the various neuronal populations along somatosensory/pain pathways in the peripheral and/or central nervous system.

Amount: £29,760
Funder: The Wellcome Trust
Recipient: University of Oxford

Chemogenetic silencing of nociceptor populations 31 Jan 2017

Nociceptors are heterogeneous sensory neurons and due to single cell sequencing, our understanding of their diversity is expanding. To understand which nociceptor populations are responsible for different pain-related behavioural phenotypes, we aim to employ a chemogenetic silencing tool to allow reversible inhibition of selected cells in vivo. Our chemogenetic tool of choice is the mutated glutamate-gated chloride channel (GluCl). Initially, we expressed the channel in cultured DRG neurons and using patch-clamp recordings observed dose dependent silencing upon application of the agonist ivermectin (IVM). We have optimised the channel and assessed channel functionality in vitro and in vivo following AAV-mediated delivery. Behavioural assays suggest IVM treated animals had significantly elevated pain thresholds compared to vehicle treated mice. Using rodent pain models (SNI, CCI) in conjunction with conditioned place preference tasks, we aim to further establish this method of nociceptor silencing as a potential therapeutic. Furthermore, to understand nociceptor heterogeneity our first target population will be the A-delta nociceptors. Using transgenic strategies we hope to selectively express GluCl in A-delta nociceptors and perform electrophysiological and sensitive behavioural assays pre and post IVM treatment. Ultimately this project aims to facilitate the discovery of novel nociceptor populations, their roles and their therapeutic potential.

Amount: £31,040
Funder: The Wellcome Trust
Recipient: University of Oxford

Statistical models of gene-environment interactions 31 Jan 2017

This PhD focuses on developing statistical methods to discover gene – environment (G-E) interactions. To date there has been some interest in testing for G-E interactions in animal models, but limited success in uncovering examples of G-E interactions in humans. This is in part due to the problem of exposure assessment, or rather, because representative data on the environment of a number of individuals over a lifetime has been hard to acquire. However the data recently made available by the UK BioBank, on over 500000 individuals and a wide array of environmental covariates, may now make it possible to detect these interactions. We aim to use a Bayesian methodology to first test a number of known models, such as a random effects model, against the dataset. We will then attempt to use a Gaussian Process Regression model to identify covariates involved in G-E interactions. This approach is advantageous as GPR is non-parametric, thus avoiding the curse of dimensionality, and places no assumptions on the order of interactions. However as this method currently scales in a cubic manner following the number of samples, significant computational challenges remain.

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

Early lineage decisions during mouse gastrulation 31 Jan 2017

Diversification of mesoderm and endoderm subtypes occurs at the outset of mouse gastrulation as epiblast cells migrate through the primitive streak (PS). The underlying inductive signals, gene-regulatory networks, and epigenetic modifications that direct lineage diversification at this early stage remains ill-defined. The aim of this project is to dissect the molecular mechanisms that underpin cell fate diversification, as cells egress the PS, by investigating the function of T-box transcription factors (TF), Eomesodermin (Eomes) and Brachyury (T). Eomes and T are expressed in the PS and Eomes is required for specification of cardiac mesoderm (CM) and definitive endoderm (DE). Single cell lineage tracing and RNA-seq experiments will be completed to define the potency and heterogeneity of Eomes and T expressing progenitors. The functional role Eomes plays in haematopoiesis will also be investigated using multiple gain and loss of function experiments. Finally, we will investigate context dependent Eomes binding sites and interacting partners. Eomes tagged mouse embryonic stem cells (mESC) will be differentiated into CM or DE progenitors and with them we will perform ChIP-Seq, RNA-Seq and immunoprecipitation-mass spectrometry(IP-MS). The experiments proposed will help resolve the functional and molecular roles T and Eomes play during early stages of lineage diversification.

Amount: £45,812
Funder: The Wellcome Trust
Recipient: University of Oxford

Systematic Identification of Lineage Specification in Murine Gastrulation 31 Jan 2017

Single-cell genomics is a fantastic tool for studying developmental biology: it allows unbiased and large-scale study of gene expression at the correct resolution for cell fate decision making. New fluidics systems provide the capability to study tens of thousands of cells simultaneously - as many as there are in the young embryo. For my PhD, I will analyse scRNA-seq data generated on this platform, studying mouse gastrulation between E6.5 and E8. I will be able to study this process at both an exceptional cell-level resolution (thanks to the fluidics) and at an unprecedented time resolution, at 0.1 day intervals. My focus will be on identification of lineage specification, and how cells make their fate choices. I will need to develop new methods to account for the large numbers of cells assayed, the numerous lineage decisions made, and heterogeneity of speeds of development across and between embryos. I hope to produce a map of lineage specification from epiblast (E6.5) cells through to every cell type present at E8. This work will provide a developmental atlas through gastrulation, and general inferences on cell fate decisions may provide insight for cellular reprogramming and regenerative medicine.

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

Understanding the Pathogenesis of Inflammatory Bowel Disease via Whole-genome Sequencing 31 Jan 2017

We will use a new whole-genome deep-coverage IBD dataset (15x+ coverage, 20 000 cases, 50 000 controls) to conduct genetic association studies. Several analyses are currently planned. The first study will use the data from >1000 IBD patients, who are part of a deep clinical phenotyping experiment, on their response to treatment with anti-TNF medication. We are hoping to determine specific genetic variants associated with successful treatment, non-response, loss of response, and unfavourable drug reactions. Once more samples are sequenced, we will attempt to discover novel low-frequency, rare, and very rare genetic variants associated with IBD. A recent low-coverage sequencing study has identified a rare missense variant in ADCY7 that doubles the risk of ulcerative colitis. In addition, a burden of very rare, damaging missense variants in genes associated with Crohn's disease was detected. The increased coverage and the size of the dataset may confirm the significance of such variants. Discovery of novel rare variants brings important insights into IBD biology, and improves the overall understanding of the genetic landscape of complex diseases.

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

The role of intra-area and inter-area neuronal interactions in the formation of perceptual decisions 31 Jan 2017

Humans and animals have to make decisions based on the integration of sensory information in order to thrive. In primates, neuronal activity in sensori-motor parietal area LIP has been proposed to reflect the accumulation of sensory information from a range of areas to make a perceptual decision. The change in firing rates has been described as an integration process with a diffusion-to-bound model or alternatively as step-like changes. This project aims to gain a better understanding of the neuronal processes underpinning perceptual decision-making and to test the universality of the proposed models. Simultaneous recordings with multiple probes from cortical areas LIP and V5/MT while animals solve a stereo-motion task will measure neuronal interactions (i) within LIP and (ii) with V5/MT. Extrastriate visual area V5/MT is important for the perception of motion as well as stereovision and has anatomical connections with LIP. Combined electrical stimulation and recording will establish the interaction of signals between these areas. I will also incorporate contextual effects into task and model to develop a realistic network model of how decision signals arise and shape cognitive function. This model can be applied to and tested with other brain areas and cognitive tasks.

Amount: £118,930
Funder: The Wellcome Trust
Recipient: University of Oxford

Defining how different types of midbrain dopamine neuron mediate behaviour in the contexts of reward and aversion 31 Jan 2017

Learning the value of actions based on prior experience is critical for adaptive behaviour. Rewarding and aversive stimuli have opposite motivational valence, with evidence suggesting that the phasic firing of distinct groups of midbrain dopamine neurons differentially encodes reward and aversion as a function of their projection target. My first research aim is to elucidate the molecular signatures of subpopulations of dopamine neurons innervating the nucleus accumbens or prefrontal cortex. To achieve this, I will combine injections of retrograde tracers with immunofluorescence revelation of molecular markers in mice. My second aim is to determine how distinct types of dopamine neuron, as defined by their specialised molecular profiles and projection targets, encode behaviour. To achieve this, I will carry out recordings of individual molecularly-identified neurons in head-fixed mice as they perform a classical conditioning task incorporating rewarding and aversive events. My third aim it to elucidate a causative role for a specific subpopulation of dopamine neurons in behaviour. To achieve this, I will use an optogenetics-based approach to inhibit these neurons in behaving mice. Overall, this research project is predicted to advance understanding of how different subpopulations of midbrain dopamine neuron subserve behaviour in the context of reward and aversion.

Amount: £31,243
Funder: The Wellcome Trust
Recipient: University of Oxford

Functional diversity and plasticity of mucosal-associated invariant T cells 31 Jan 2017

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that express a semi-invariant, MR1-restricted, T cell receptor (TCR). In humans, they comprise 1-10% of peripheral blood T cells and are enriched at mucosal sites. MAIT cells display characteristic expression of several surface molecules and transcription factors, and a typical cytokine response to stimulation. Therefore, they have been regarded as relatively homogeneous. However recent evidence indicates diversity in TCR expression and function that varies between tissues and individuals. Further investigation is required to understand the extent of MAIT cell heterogeneity and tissue-specific functionality. In several human autoimmune and inflammatory diseases, MAIT cells are activated or show phenotypic changes. How the altered cytokine environment in such diseases can modulate MAIT cell function remains to be determined. The key goals of my research are to provide a comprehensive assessment of diversity and plasticity in MAIT cell function, and to understand the factors that regulate this. To achieve this, I will use a combination of approaches including single-cell mRNA sequencing and epigenetic analysis, and will explore MAIT cells from varied settings encompassing resting and activated, tissue-localised, and disease-associated MAIT cells. This will provide important insights into their physiological role both in health and disease.

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

The evaluation of effective healthcare delivery in China using electronic medical records for 10 years in 0.5M participants in the China Kadoorie Biobank 02 May 2017

This DPhil project will assess the social determinants and equality in hospital care delivery and use, in 0.5 million participants who have been followed up for 10 years in the China Kadoorie Biobank. The first goal of this research is to evaluate differences in the annual rates of people hospitalised, the annual rates of hospital admissions per person, and the average length of stay (ALOS) overall and for 10 of the most frequent causes of hospitalisation (5 mostly unavoidable and 5 mostly avoidable causes) over the last 10 years and by region, hospital-tier, type of health insurance (HI) package and socioeconomic characteristics. Another goal is to study the variation in hospital care costs in China, considering LOS, and use of specialised procedures and major treatments, overall and for the 10 most frequent causes of hospitalisation over the last 10 years, by region, hospital-tier, HI package, and socioeconomic characteristics. Finally, the inequalities behind the variation in use and costs of hospital care will be investigated across regions, HI package and socioeconomic characteristics. This will provide the reliable quantitative evidence to evaluate operational defects and plan initiatives to improve healthcare delivery by individual hospitals, HI organisations and the wider community in China.

Amount: £95,184
Funder: The Wellcome Trust
Recipient: University of Oxford

Epidemiology and health burdens of antimicrobial resistant bacterial infection in Southeast Asia and impact of antibiotic use on patient survival 19 Jun 2017

Epidemiology of drug-resistant infection (DRI) and impact of antibiotic use on patient mortality remain largely unknown in Southeast Asia. Correction factors are crucial to estimate the total deaths attributable to DRI when only mortality of patients with bacteraemia is known. The correction factors are available for developed country and not for developing country. I aim to establish correction factors for developing country. I also aim to study the epidemiology of drug-resistance and estimate the number of excess deaths attributable to DRI in Southeast Asia. Most studies on the impact of inappropriate antibiotic use on mortality were conducted in high-income countries, and methods used were vulnerable to biases. Neglecting both the time-varying nature of contributing factors; including risk of DRI over time, and the effect of antibiotic overuse on risk of DRI in other patients could misestimate the impact of antibiotic use on patient mortality. I aim to use advanced statistical models to overcome the potential biases, and to estimate and compare the impact of appropriate and inappropriate antibiotic use in Thailand and Vietnam against that in the United Kingdom where antibiotic stewardship is well established. These are important to assist designing and assessing of antibiotic stewardship programme in developing countries.

Amount: £18,800
Funder: The Wellcome Trust
Recipient: University of Oxford