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Recipients:
University College London
University of Cambridge

Results

Metabolic and Cardiovascular Disease. 30 Sep 2017

Not available

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

Developmental mechanisms 30 Sep 2017

Not available

Amount: £2,750,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Mechanisms of transport of the leaderless protein galectin-3 to the cell surface 31 Jan 2017

Unconventional protein secretion is a poorly understood physiological process in which proteins without an N-terminal signal sequence exit the cell. There are currently four proposed pathways by which unconventionally secreted proteins are thought to exit the cell: by direct translocation across the membrane, via secretory lysosomes, by release from exosomes or multivesicular bodies, or through membrane blebbing. No complete mechanism has been described for any of these pathways, representing a significant gap in our knowledge of protein trafficking. Unconventionally secreted proteins play important extracellular roles physiologically, but abnormal levels are associated with several human diseases, including metabolic disease. As such, this mechanism is interesting to gain an insight into disease as well as to broaden our understanding of cell biology. I will investigate the unconventional transport of galectin-3 to the cell surface. Galectin-3 will here be used as a model to understand the mechanism of unconventional secretion. Data-driven and hypothesis-driven approaches will feed into each other to form a picture of how galectin-3 is secreted. A CRISPR-Cas9 screen has identified potential proteins that decrease cell surface galectin-3, providing the starting point for further investigation. Hypothesis-driven experiments will be used to investigate aspects of the models previously proposed.

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

The role and regulation of UHRF1 during epigenetic reprogramming 31 Jan 2017

During both mouse and human embryonic development there are two waves of global DNA demethylation associated with an increase in developmental potential: firstly during the development of the inner cell mass from the gametes, and secondly during the development of primordial germ cells. Although some of these changes in DNA methylation are correlated with gene expression, it is not understood why this epigenetic reprogramming is consistently so extensive. Until recently it was believed that most of this erasure of DNA methylation occurred actively. However, recent research has revealed that regulation of maintenance methylation accounts for the differing rates of demethylation in different reprogramming contexts. Across the majority of these different contexts, the activity of maintenance methylation is controlled by regulation of UHRF1 protein. This project aims to elucidate the mechanism by which UHRF1 protein is regulated during epigenetic reprogramming, then to use this knowledge to assess the importance of this regulation to the acquisition of pluripotency during mammalian embryonic development. This will improve our understanding of developmental and reproductive health and may even shed light on new or improved methods of reprogramming cells for therapeutic applications.

Amount: £26,820
Funder: The Wellcome Trust
Recipient: University of Cambridge

Machine Learning methods for microscopy image data in high-content screening 31 Jan 2017

An important area in drug development is understanding low-level molecular processes and pathways that cause diseases. These cellular phenotypes are high-dimensional and are increasingly being captured using single-cell assays and high-content imaging. In understanding natural cell trait variation and engineered variants, we can elucidate the cellular consequences of disease mutations. In my project, I will exploit cellular images in a range of contexts to investigate the link between genetic variation and cell trait variability using both natural genetic variation and engineered variants. To do so, I will develop machine learning methods to extract features from high throughput microscopy data, and to accurately account for genetic, environmental, and experimental sources of variability in them. Furthermore, I will work on integrative approaches using public genomic data to bring in other omics modalities, thereby tackling key challenges in the larger aim of deciphering disease and fostering drug development. I will use existing data from the HipSci project, high throughput drug screens from AstraZeneca, and, in addition, will design and oversee the generation of datasets through high-throughput CRISPR knockouts as part of Leopold Parts’ group at the Wellcome Trust Sanger Institute and Oliver Stegle’s group at the European Bioinformatics Institute.

Amount: £0
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

Functional proteomic analysis of novel antiviral restriction factors in primary leukocytes 31 Jan 2017

This project aims to identify and characterise novel antiviral restriction factors (ARFs) that play key roles in preventing infection of primary leukocytes. ARFs may function by preventing viral entry or exit at the cell surface, or replication at various intracellular stages. I will focus on the subset of plasma membrane (PM) ARFs, which will be identified by two properties: interferon (IFN) induction and virally-induced downregulation. For this I will employ tandem mass tag-based MS3 mass spectrometry, enabling quantitation of PM proteins in primary leukocytes. Key Goals: 1. Use IFNs and infection with two important human pathogens, human cytomegalovirus and HIV as a functional screen to identify novel cell surface ARFs 2. Investigate how these ARFs inhibit viral infection, and how are they targeted for destruction by viruses. The use of IFN as part of the functional screen will additionally enable exploration of the difference in effects between IFNalpha, beta and lambda at the PM, a subject which is currently surprisingly poorly understood. This will provide important insights into human immunity in its own right. Understanding how viruses interacts with and targets ARFs for destruction will have important implications for therapy.

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

Force Generation during Collective Chemotaxis in vivo 31 Jan 2017

Collective cell migration (CCM) plays an essential role in many developmental and physiological processes. However, much remains unknown about the mechanisms driving this CCM with a limited number of studies focusing on CCM, in absence of external cues, instead of the directional migration observed in vivo. Furthermore, studies have focused mainly on epithelial cells. Another issue relates to the forces involved in moving the cells as studies, to date, have produced contradictory results regarding whether leader or trailing cells generate propulsive forces. In this project, we will analyse the mechanical properties during the collective migration of Xenopus and zebrafish neural crest cells; a mesenchymal cell population which undergoes directional migration during development, giving rise to a range of cell types. Using traction force microscopy and FRET-tension sensors, we will identify which cells generate forces during CCM. Furthermore, we will address whether intercellular mechanocoupling is important for attaining coordination in CCM by measuring traction forces in cell cohorts with varying degrees of adhesion. Finally, we will elucidate the molecular mechanisms of CCM by disrupting proteins implicated in force generation and analysing the effect on generated forces. This study will thereby establish an understanding of the physical mechanisms driving CCM.

Amount: £14,399
Funder: The Wellcome Trust
Recipient: University College London

Investigating the role of RNA interference in retinal development and as an agent of degeneration 31 Jan 2017

Genetic diseases affecting the retina, are the leading cause of blindness in the developed world. Despite the wide knowledge of the genetic factors which result in retinal dystrophies, (more than 200 genes have been identified as playing a role) such conditions remain untreatable. In monogenic retinal dystrophies the age of onset of photoreceptor cell death and rate of sight loss varies, yet the pathogenic gene mutation is present throughout life. Why some cells die at a given point in time and others do not, is unknown. This project aims to investigate the role of endogenous micro RNAs (miRNA) in retinal development and the relationship between miRNA dysregulation and retinal dystrophy. Specific miRNAs will be inactivated using the CRISPR/Cas9 system and the effects on photoreceptor differentiation and optic cup lamination determined. Furthermore, retinal organoid cultures derived from Type I Usher (a syndromic retinopathy) patient induced-pluripotent stem cells (iPSC; derived by reprogramming skin fibroblasts), will be used to establish whether miRNA dysregulation is indicative of an early disease state and whether CRISPR/Cas9-based gene correction can return dysregulated miRNA levels to normal. Finally, the effects of delivering certain miRNAs to a mouse model of retinal dystrophy on early disease phenotype will be established.

Amount: £24,581
Funder: The Wellcome Trust
Recipient: University College London

Homeostatic gene networks in Drosophila models of epilepsy and dyskinesia 31 Jan 2017

Transcriptional and translation control in neurons is highly plastic, allowing firing frequency and synaptic output to be regulated with high temporal precision. Recent research has demonstrated that the complement of ion channels within a neuron can undergo homeostatic remodelling in response to altered neuronal excitability. However, the extent to which this occurs in neurological diseases is unknown, as are the alterations in ion channel expression that may buffer disease-linked mutations to the greatest degree. We aim to investigate these questions using the fruit fly, Drosophila melanogaster. Using homologous recombination, we will generate a novel knock-in fly model of Generalized Epilepsy and Paroxysmal Dyskinesia (GEPD). This disorder is caused by a gain-of-function mutation in the KCNMA1 BK potassium channel – the mammalian homologue of Drosophila slowpoke (slo). We will characterise changes in ion channel expression in GEPD slo knock-in flies through RNAseq, and using this data, perform a modifier screen to determine which alterations are compensatory or pathogenic. Genetic suppressors identified via this strategy will represent promising targets for future therapeutic interventions.

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

Attachment and the transgenerational effects of loss, abuse and trauma: Exploring and testing classic ideas through historical analysis and developmental science 02 May 2017

Since it was introduced by John Bowlby, attachment research has been among the most influential paradigms for understanding the social underpinnings of infant mental health and transgenerational mental health. However, an odd artefact of the way a major research instrument was constructed in the 1980s by Mary Main has meant that to date attachment research has largely treated loss, abuse, and trauma as essentially equivalent, despite their very different clinical implications. A multidisciplinary approach will be used to investigate these concepts and examine potential differences. Work Package 1 will comprise a critical re-examination of the concepts of loss, abuse and trauma in the published and unpublished works by John Bowlby and Mary Main, exploring their reflections on how these experiences might impact parenting. In Work Package 2, hypotheses elaborated in Work Package 1 will be tested using Individual Participant Data pooled from 59 attachment studies, representing 4,542 families. Work Package 3 tests explanations for differential effects of unresolved loss, abuse and trauma on parenting and child development using longitudinal data from 400 mothers and children. The study will shed new light on transgenerational mental health processes, and insights will be disseminated to professionals and families.

Amount: £97,935
Funder: The Wellcome Trust
Recipient: University of Cambridge

How do middle ear stem cells and the immune system interact in the pathogenesis of chronic otitis media? 30 Sep 2017

Chronic middle ear inflammation (otitis media) poses a significant global burden of disease in adults and children leading to permanent deafness. The middle ear mucosa maintains a well-ventilated middle ear but undergoes abnormal remodelling in disease. Similar to the adult upper airway, basal cells are hypothesised to be stem cells actively maintaining middle ear mucosa. Pathological remodelling via abnormal repair pathways may underlie chronic otitis media and studying these could help understand and treat the disease. Aim: To identify and characterise the stem cell population of the middle ear in health and how maintenance of middle ear mucosa is disrupted by the immune system leading to chronic inflammatory disease. Methods: Murine and human biopsies will be grown and characterised in vitro, in 3T3 co-culture, air-liquid interface and 3D spheroid models to study differentiation and proliferation mechanisms in health and confirm markers of stem cell and cell fate. These markers will be used to perform lineage tracing in mice in healthy mice and in crosses with Junbo mouse model of otitis media. Finally, the role of the immune system, specifically the aryl hydrocarbon receptor (AhR – responsible for detoxification of pollutants that are linked to otitis media) will be studied using AhR agonists/antagonists and Ahr deficient mice crossed with Junbo mice.

Amount: £309,724
Funder: The Wellcome Trust
Recipient: University College London

Fundamental mechanisms controlling human energy homeostasis 11 Jul 2017

Obesity and associated diseases such as type 2 diabetes, cardiovascular disease and some cancers represent a significant health burden. My overall aim is to identify new therapeutic strategies for severe obesity. Using extensive genetic and clinical data on unique cohorts of individuals at both extremes of the weight distribution (severe obesity and thinness), we will comprehensively map the molecular networks that maintain energy homeostasis and their disruption in disorders of weight regulation. Building on our previous work, we will focus on dissecting cellular mechanisms that converge on leptin-melanocortin signalling using human stem-cell derived hypothalamic neurons. In human studies, we will characterise the effects of specific pathways on eating behaviour, energy expenditure and substrate utilisation. By uncovering the fundamental mechanisms that control human energy homeostasis, our goal is to identify and validate control points that can be targeted to improve outcomes in obesity associated diseases.

Amount: £3,582,289
Funder: The Wellcome Trust
Recipient: University of Cambridge

Marriage, Health and Compatibility in Early Modern England 24 Jan 2017

This project will produce a history of marriage and health in early modern England. Marriage is generally understood as an institution governed by legal and religious regulations and social norms that have taken different forms throughout history. In post-Reformation England marriage was increasingly regulated and interrogated. Performing gendered spousal roles was part of religious practice, something perpetuated by the growing culture of conduct manuals. A central obligation of marriage was to care for one another in sickness. This has underpinned histories of domestic medicine that reveal that the early modern family was active in diagnosis and cure. The two major goals of this project are (1) To assess how good health defined a successful marriage in early modern England and (2) To investigate how the social norms and expectations of marriage changed over the course of a union. As part of this inquiry, subsidiary goals will be (3) To interrogate how marital compatibility was measured, (4) How poor health of one spouse affected the other, and (5) How illness impacted on the household as a whole. Finally, this project aims (6) To uncover how cultural expectations shaped the way early modern people wrote about marriage.

Amount: £151,620
Funder: The Wellcome Trust
Recipient: University of Cambridge

Genetic background effects in human iPSCs and iPSC-derived cell types 12 May 2017

Human induced pluripotent stem cells (iPSC) have emerged as a key model system to study the function of genetic variants, as they provide access to relevant cell types and developmental lineages through cellular differentiation. However, while it has been shown that the genetic background of the donor individual has an effect on molecular phenotypes measured from iPSCs, it is currently not known how much the genetic background influences studies that use iPSCs to model rare disease mutations, making interpretation of results challenging. In this project, I will use CRISPR-Cas9 technology to study specific rare disease mutations in different genetic backgrounds. Specifically, I will focus on loss-of-function mutations causing Kabuki syndrome, a disorder of the epigenetic machinery, and use patient-derived iPSCs together with engineered mutant and control lines to quantify the contribution of the genetic background on the transcriptome and epigenome of the iPSCs as well as neuronal precursor cells derived from them. This project will establish the value of using patient-derived iPSCs over generic iPSC lines with engineered mutations. This information is critical for the design of any subsequent studies in which iPSCs serve as the baseline, such as directed differentiation experiments and therapeutic targeting of the mutation.

Amount: £99,935
Funder: The Wellcome Trust
Recipient: University College London

Complex Urban Systems for Sustainability and Health (London Hub) 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 CUSSH project focuses on how to transform cities to address vital environmental and population health imperatives, and entails partnership with the cities of London, Beijing, Kisumu, Nairobi, Ningbo and Rennes.

Amount: £5,150,000
Funder: The Wellcome Trust
Recipient: University College London

Investigation into the role of RBM8A/Y14 in the development and function of megakaryocytes and platelets using a human pluripotent stem cell model of haematopoiesis 30 Sep 2018

Platelets are small blood cells, which cause blood to clot, preventing bleeding after injury. They are produced by megakaryocytes, large cells in the bone marrow. In people with low platelet counts (thrombocytopenia), life-threatening bleeding occurs spontaneously or after injury. Studying platelet and megakaryocyte development and function is important in understanding a) diseases causing thrombocytopenia, such as genetic disorders and other conditions, particularly cancer (and chemotherapy) and b) strokes and heart attacks, where platelets are excessively activated, forming clots that block vessels. Using stem cells (special cells capable of becoming any cell type) derived from adult skin or blood samples we grow & study megakaryocytes and platelets in the laboratory. We study a rare genetic disease, Thrombocytopenia with Absent Radii (TAR) syndrome, in which babies are born with very few platelets and abnormal bone formation (particularly the radius in the forearm). Our group discovered the cause of TAR, due to abnormalities in a gene called RBM8A, which helps cells control what proteins are produced; however precisely why this causes TAR is unclear. We believe our research will uncover the mechanism of this condition, helping to treat patients with TAR and improve wider understanding of how megakaryocytes & platelets develop and function.

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

Integrated interdisciplinary approaches to design new anti-bacterials with novel mechanisms of action to tackle antimicrobial resistance in Tuberculosis 30 Sep 2018

Tuberculosis (TB) remains a serious threat to global health. The World Health Organisation estimate that 10.4 million new cases were contracted in 2015, and that over 500,000 of those cases were resistant to at least one of the antibiotics currently used to treat this condition. The spread of such resistance is a serious concern and as a result there is a need for the development of new drugs to combat TB. Recent work has identified two classes of molecule which have promising anti-tubercular properties: tetrahydroisoquinolines and non-steroidal anti-inflammatory drugs. My project will focus on the development of new anti-bacterials from these classes of molecule while exploring the reasons behind their anti-tubercular properties. This will be achieved through a combination of chemistry and molecular microbiology, making use of both laboratory and computational techniques.

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

Co-evolution of tumour mutational and CD4 T-cell differentiation landscapes 30 Sep 2018

Lung cancer is the second most commonly diagnosed cancer in the UK and the greatest cause of cancer-related death. A type of this disease called non-small cell lung cancer (NSCLC) accounts for the majority (85%) of cases. T-lymphocyte cells (T-cells) of the immune system patrol the body and can recognise and destroy cancer cells by recognising mutated proteins (neoantigens) on them. Despite this, the majority of patients with advanced lung cancer die of the disease, indicating the ineffective function of the immune system. In particular, little is known about the role of a particular group of immune cells called T-helper cells that are thought to be important. In chronic infections where T-cells are constantly exposed to their targets, they become less responsive as younger cells are driven to turn into later ones more rapidly. As younger cells are lost, the body's ability to fight the infection reduces. In cancer, it is possible that mutations drive a similar problem. Using lung cancer specimens from patients on a clinical trial and animal models of cancer, we propose to study the question of whether and how mutations can paralyse the ability of T-helper cells to fight the disease.

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