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Recipients:
University of Cambridge
Currency:
GBP
Funders:
The Wellcome Trust

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

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

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

Visualizing Citizen Voice in a Moment of 'Big Data' 30 May 2017

Visualizing Citizen Voice in a Moment of 'Big Data'

Amount: £21,350
Funder: The Wellcome Trust
Recipient: University of Cambridge

Embryo architecture, potency and tissue interactions during mouse and human development 11 Jul 2017

Mammalian embryogenesis entails close partnership between embryonic and extra-embryonic tissues to regulate changes in embryo architecture and developmental potency. We aim for an integrated view of how these events progress hand in hand during key stages of mouse and human embryogenesis. The first architectural changes of the embryo are polarisation and compaction that trigger the separation of embryonic and extra-embryonic lineages. Yet their own trigger remains unknown. We will dissect potential triggering pathways and through genetic manipulations determine their importance for cell fate. Embryo remodelling at implantation is intimately associated with pluripotent-state transitions. We will harness our novel techniques for embryo culture throughout implantation to uncover mechanisms behind these events in relation to signalling partnerships between embryonic and extra-embryonic tissues. By arranging partnership between embryonic and extra-embryonic stem cells in 3D-culture we have recapitulated embryo-like morphogenesis and spatio-temporal gene-expression. We will characterise tissue interactions in such stem cell-derived embryos to understand principles of self-organisation. Our work established an unprecedented opportunity to study human early post-implantation embryogenesis in-vitro. We will build the first morphological and transcriptional atlas of human development beyond implantation. This will bring understanding of normal development and shed light upon why many pregnancies fail at early stages.

Amount: £2,135,983
Funder: The Wellcome Trust
Recipient: University of Cambridge

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity 22 Feb 2017

Intestinal infections affect billions of people worldwide, resulting in nearly 1.4 million deaths each year. The commensal microbiota can prevent pathogenic infection, as demonstrated by increased susceptibility to infection upon antibiotic use; however, the precise mechanisms of microbiota-mediated protection are not well-characterized. I have recently discovered that colonization of mice with commensal Enterococcus faecium leads to improved intestinal barrier function and decreased Salmonella and Clostridium difficile pathogenesis. I went on to uncover a mechanism by which a unique enzyme, SagA, from these bacteria activates intestinal epithelial cells (IECs) to increase anti-microbial peptide (AMP) expression and mucin distribution. These studies revealed several host and microbiota factors involved in pathogen tolerance. My proposed independent research will identify the mechanisms by which commensal bacteria modulate IECs and intestinal immunity. Utilizing advance microscopy, proteomics and sequencing approaches, I will characterize the effects of E. faecium, SagA and other microbiota metabolites on IEC gene expression and function and subsequent pathogen resistance. Using proteomics-based bioorthogonal reporters and intersectional genetics, I will then dissect how microbial modulation of IECs affects the differentiation and function of intraepithelial lymphocytes. Elucidating the IEC programs triggered by commensal bacteria will enable better strategies to prevent and treat intestinal infections.

Amount: £1,212,214
Funder: The Wellcome Trust
Recipient: University of Cambridge

Regulation of nuclear envelope function and links with disease 22 Feb 2017

The nuclear envelope (NE) lies at the interface between the nucleus and the cytoskeleton. It forms a complex structure controlling cell compartmentalization and regulates many processes including nucleo-cytoplasmic transport of proteins and RNA, chromatin organization, DNA replication and DNA repair. Hence, defects in NE integrity and nuclear architecture cause drastic changes in cell homeostasis and are associated with a broad range of diseases including cancer, premature ageing syndromes, neurodegenerative diseases or muscular dystrophies, but also with physiological ageing. One of the main challenges is to understand how NE defects lead to so many types of diseases. Previous theories include changes in gene expression and mechanical weakness. My previous work has shown that subcellular processes including microtubule or chromatin organization can modulate NE function, and has identified the acetyltransferase NAT10 as a key regulatory node for control of nuclear architecture. My goal is to now investigate how NAT10 and other factors regulate the NE. I will thereby gain new understanding of how of nuclear architecture is orchestrated and how this is disrupted in age-related diseases including HGPS. This research will not only contribute to our fundamental understanding of nuclear architecture but will also potentially identify new therapeutic strategies for NE-associated syndromes.

Amount: £1,084,517
Funder: The Wellcome Trust
Recipient: University of Cambridge

ISA-InterMine: accelerating and rewarding data sharing 06 Jul 2017

There is a growing recognition that research should be carried out in an open fashion, making data available early and in a reusable form to maximise worldwide research output. However, fulfilling this promise requires front-line researchers to comply with current data management standards as required by the data policies of funders and journals. These are additional burdens to research that will give them little immediate return. Thus we propose to create a cloud-based, open-source, extensible data collection and presentation platform that will provide scientists with: (1) immediate reward for their annotation efforts through sharable data visualisation, integration outputs and exploration tools; (2) standardised web services to facilitate script-based data manipulation and analysis; (3) an easy-to-use pipeline for preparing their data for publication; (4) incentives to improve data quality, accessibility, and machine-actionability at the appropriate level of granularity; and (5) allow institutions and other parties to host the platform to ensure its availability and reliability. We will do this by building on the success and complementarity of the ISA tools suite (Oxford) and the InterMine platform (Cambridge) to make it quicker and easier to generate rich integrated dynamic web sites at single paper/lab scale up to consortium scale.

Amount: £670,410
Funder: The Wellcome Trust
Recipient: University of Cambridge

Diagnosing Diagnosis: a multidisciplinary perspective 17 Jul 2017

Diagnosis is at the heart of the medical encounter, but many features of making, communicating and recording a diagnosis remain poorly understood and little researched. Without greater understanding, we cannot provide adequate guidance to clinicians about what information to share with patients or adequate advice to patients about what questions to ask, and policy incentives to address problems with ‘overdiagnosis’ or ‘misdiagnosis’ are at risk of unintended consequences. Key goals: To examine the process of making, communicating and recording a medical (differential) diagnosis in the acute care setting; To examine institutional influences on the diagnostic process; To examine ethical and philosophical influences on making and communicating diagnoses; To establish an empirically based, ethically grounded framework for making, communicating and recording a diagnosis to improve patient outcomes on both individual and societal levels. Methodology: Qualitative methods including ethnography and interviews will be combined with medical records analysis and quantification of the reach and permanence of diagnostic labelling between health care settings. Integrated with this empirical work, ethical analysis will explore how the interplay between responsibility, uncertainty and trust affects the process and communication of making a medical diagnosis. This is emphatically multidisciplinary research which benefits from combining different perspectives and methodologies.

Amount: £647,257
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the role of R2B receptor tyrosine phosphatases in developmental signalling pathways 27 Apr 2017

Tyrosine phosphorylation is a key post translational modification that is often dysregulated in disease. The balanced actions of kinases and phosphatases are required for cellular homeostasis. However, the substrates and functions of phosphatases are poorly understood. The receptor tyrosine phosphatase PTPRK was identified as a recurrent fusion partner of the oncogene RSPO3 – an amplifier of the Wnt pathway. Additionally, PTPRK was identified in a forward genetic screen for modulators of APC min driven intestinal tumorigenesis. Given these genetic links, and hints in the literature that PTPRK can dephosphorylate beta catenin, a Wnt transcriptional activator, we plan to investigate the signalling cross-talk between PTPRK and Wnt signaling. First, this project aims to discover whether Wnt signalling influences the regulation of PTPRK at the messenger RNA and protein level. Second, we plan to test how depletion of PTPRK affects Wnt signaling output using luciferase reporter assays and western blotting. The outcome of this project will be a comprehensive assessment of the interplay between PTPRK and Wnt signalling, with important implications for the role of PTPRK in colorectal cancer, which is one of the current focusses of the Sharpe Lab.

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

Determining the Significance of Pathway Bias at the Calcitonin Gene-Related Peptide Receptor Family in Human Endothelial Cells 27 Apr 2017

Family B G protein coupled receptors (GPCRs), notably the calcitonin like receptor (CLR), have been implicated in cardioprotective functions. The functional GPCR is a heterodimer of CLR and one of three possible receptor activity-modifying proteins (RAMPs). There are 3 main agonists for this GPCR: calcitonin gene-related peptide (CGRP), adrenomedullin (AM), and adrenomedullin 2 (AM2). CLR is pleotropic, activating intracellular pathways through coupling to G proteins or beta-arrestins. Indeed, we recently showed, using both a heterologous yeast expression system and mammalian (HEK-293) cell lines, that the signalling bias of the CLR is dependent upon both the agonist and the RAMP. However, the cell environment of the receptor massively affects signalling bias. Therefore, to validate these results, investigation of the pharmacology of the CLR in endogenous cell lines is essential. The aim of this research is therefore to use two different human cell lines (HUVECs and HUAECs) to pharmacologically investigate CLR/RAMP2 (the adrenomedullin receptor) and CLR/RAMP1 (the CGRP receptor) when endogenously expressed. It is hoped that this will provide greater insight into the function of CLR signalling in the vascular endothelium. This information may then be used to help characterise the pathophysiology of common cardiovascular diseases such as hypertension and myocardial infarction.

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

Identification of the active eIF4E in trypanosomes 27 Apr 2017

A detailed understanding of the initiation of translation in kinetoplastid pathogens is still elusive. There is an innate complexity due to the number of isoforms of eIF4E and eIF4G, two of the three components of eIF4F. Second, there has been no simple way to rapidly ablate expression of a protein to render an immediate phenotype. RNAi is available but it takes 3 to 4 cell cycles to dilute the eIF4E sufficiently to detect a phenotype and then is difficult to distinguish primary and secondary phenomena. We have recently developed a system for the inducible ablation of a specific protein in less than 60 minutes. This summer studentship will exploit this method to ablate separately the two isoforms of eIF4E that probably are responsible for mRNA cap binding during translation initiation. An analysis of the qualitative and quantitative effect on protein synthesis after ablation will inform on whether the two eIF4E isoforms have different, overlapping or identical functions. The work builds on expertise in the lab and utilizes a new technique to answer a long standing question.

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

Gurdon Institute Centre Renewal 30 Oct 2016

The Gurdon Institute focuses on several related topics at the interface between developmental biology and cancer: Cell division, proliferation and genome maintenance; Function and regulation of the genome and epigenome; Mechanisms of cell fate determination, multipotency and plasticity; The cell biology of organ development and function. We investigate these areas in both normal development and cancer using several model systems, with an increasing emphasis on organoids. Our five-year vision is to expand our research in two strategic directions: Human development and disease We will study the development and homeostasis of tissues and organs using human organoid systems. We will also develop new models of human diseases, including cancer, using organoids and patient-derived stem cells. Quantitative analysis of cellular dynamics We will analyse developmental and disease processes quantitatively at the molecular, cellular and tissue scales, using next generation sequencing and imaging approaches. We will also increase our collaborations with physical scientists expert in analysing the complex datasets generated by these approaches. We plan to continue to translate our research into new therapies. This will be enhanced by the establishment of the Milner Institute, which will provide a platform for collaborations with pharmaceutical companies on disease models emerging from our research.

Amount: £13,247,091
Funder: The Wellcome Trust
Recipient: University of Cambridge

Amulets and the material culture of healing 25 May 2017

The goal of this project is to investigate how amulets represent varying forms of value and power across differing chronologies. The Science Museum's collection will allow me to comprehensively examine a diverse range of objects, and research different forms of medical, magical and scientific worth and potency unavailable by studying textual sources alone. This project will ask three questions: How do objects with both similar and antithetical social values–from the rare to the quotidian, the expensive to the ubiquitous–represent differing forms of remedial power? In which different ways do these amulets represent the patients' experience of illness and healing and how can we as historians and museum curators afford these objects ‘voices’ without being anachronistic and jeopardising their original power? Finally, what material features have led to certain objects being considered as curative, prophylactic or apotropaic, and to what extent do function and potency depend on manmade and natural materials? This project will use these amulets to help answer important questions about European healing practices from medieval period to present day. A direct, material analysis of the objects and collections will elucidate the historical importance of these objects, and what they can contribute to our knowledge of health and healing.

Amount: £15,523
Funder: The Wellcome Trust
Recipient: University of Cambridge