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Recipients:
University of Cambridge

Results

The biology of acute myeloid leukaemia 30 Sep 2016

Mutations in epigenetic regulators play a pivotal role in leukaemia initiation. We propose to study the most commonly mutated epigenetic regulator in AML: the de novo DNA methyltransferase DNMT3a (25%). It is unclear how DNMT3a mutations subvert HSC, surprisingly in bulk studies differences in methylation do not correlate with differences in gene expression, but somehow DNMT3a mutated HSC have an advantage in xenografts and survive apparently successful chemotherapy in 80% of patients. Even if a persistent clone does not predict relapse rate these patients tend to have a poorer prognosis. DNMT3a mutations are also the most prevalent in individuals with "clonal haematopoiesis". To study DNMT3a mutated preleukaemia we will use a mouse model where the most common DNMT3a mutation (R882H) and an RFP are under the control of the Mx1-cre promoter. By titrating the dose of pIpC we will generate a chimeric mouse where only ~ 20% of cells express the mutant allele. We will study clonal dynamics after challenging HSC homeostasis (through lineage tracing of the RFP) and document alterations in gene expression at the single cell level at baseline and after perturbing HSC using state-of-the-art technology (Polaris system). We will then corroborate our findings in human DNMT3aR882 preleukaemia.

Amount: £252,167
Funder: The Wellcome Trust
Recipient: University of Cambridge
Amount: £244,848
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the phenotype, function and interactions of tissue-resident B cells 30 Sep 2016

Tissue-specific immunity is shaped by the local milieu. In organ systems that interface with the environment (e.g. skin, gastrointestinal tract), exogenous signals generated by commensals or diet can profoundly influence resident immune cells. In non-interfacing tissues (e.g. kidney), endogenous signals such as interstitial osmolality may also influence the immune landscape. Tissue epithelial cells play an important role as environmental sensors and may instruct local immune responses. In addition, environmental cues may be directly detected by resident immune cells. To date, studies of tissue sentinels have focused on innate immune cells and on T cells with limited data on B cells. We have preliminary data from human and murine kidneys, and from human liver tissue and murine bladder tissue demonstrating the presence of tissue-resident B cells. In humans, they are predominantly of a memory phenotype. We hypothesize that tissue-resident B cells make an important contribution to local immune responses and that their localization and function will be determined by tissue-specific environmental cues. This project aims to investigate the phenotype of these tissue resident B cells (both in mouse and human), their antigenic specificity, origin, function and interaction with other cells.

Amount: £235,304
Funder: The Wellcome Trust
Recipient: University of Cambridge

Infectious disease engagement activities in Sierra Leone during the post-Ebola recovery period 24 Feb 2016

We aim to understand the mechanistic basis for why GII.4 noroviruses have dominated for the past 15 years as well as identifying new mechanisms of controlling and preventing norovirus infection. One goal of the project will determine the contribution of the viral RNA polymerase fidelity and activity to norovirus pathogenesis as the enzyme from pandemic noroviruses is more error prone and has higher activity than non-pandemic noroviruses. We will use cutting edge sequencing methods to characteris e norovirus evolution in the human population, identifying possible pandemic signature mutations in the viral RNA polymerase. We will then characterise the effects of these mutations on RNA polymerase activity, virus replication and virus pathogenesis, identifying new vaccine strategies. State of the art quantitative proteomics will be used to determine the effect of the norovirus replication on the host cell and the role of these pathways examined in more detail. We will then identify small mol ecule inhibitors of these pathways and examine if they have anti-norovirus activity. We will also consider the role of the host cell RNA quality control pathway in the norovirus life cycle as our preliminary data indicates that this pathway provides an attractive therapeutic target

Amount: £59,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Does Epicardium promote Cardiomyocyte Maturation & Cardiac Regeneration? 29 Jun 2016

Human embryonic stem cells (hESC)-derived cardiomyocytes have great potential for cardiac repair and regeneration following myocardial infarction but remain significantly challenged by graft cell survival, maturation and vascularisation. The epicardium is essential for cardiac development as it forms cardiac fibroblasts, coronary smooth muscle cells, and controversially, cardiomyocytes and endothelial cells. The epicardium has emerged as a potential cardiovascular progenitor source for vascularization and cardiomyocyte support. Signalling pathways underpinning epicardial-myocardial cross-talk are postulated to be key in cardiomyocyte maturation and regeneration. Studies based on mouse models have identified several epicardium-derived paracrine factors that increase the number of cardiomyocytes and contribute to angiogenesis, although their role in cardiac maturation is unclear. This project aims to definitively characterize the role of epicardium in promoting cardiomyocyte maturation and regeneration. Key goals are: 1) To investigate the role of hESC-derived epicardial cells in the promotion of functional integration and maturation of cardiomyocytes in an in vitro tissue-engineered cardiac construct. 2) To interrogate the role of paracrine mediators including MDK and/or FSTL1 in promoting cardiomyocyte maturation and regeneration. 3) To investigate the function of hESC-derived EPDCs in promoting the survival, maturation, electrical connectivity and function of stem cell-derived cardiomyocytes in the mammalian myocardial infarct.

Amount: £270,886
Funder: The Wellcome Trust
Recipient: University of Cambridge

Characterisation of novel mutations in Steroid Receptor Coactivator 1 29 Jun 2016

Steroid Receptor Coactivator-1 (SRC-1) is coactivator for various transcription factors (TFs) and nuclear hormone receptors (NRs). In rodents, SRC-1 plays a role in the regulation of energy balance and glucose homeostasis by activating ligand-bound nrs and TFs. We have recently identified 15 novel mutations in this molecule using whole exome sequencing and targeted resequencing of 2548 patients with severe early onset obesity (Genetics of Obesity Study: GOOS). In addition to obesity, these patients have other symptoms, including disproportionate insulin resistance and chronic diarrhoea. We hypothesise that human SRC-1 mutations directly impair the interaction with pSTAT3 to cause severe obesity, and impair NR-mediated gene expression, to cause insulin resistance and intestinal dysfunction. I propose to undertake the detailed functional and clinical characterisation of SRC-1 mutations. I will use HEK-293 cells to characterise the functional consequences of SRC-1 mutations, particularly focusing on their interaction with STAT3 and NRs. Patients will be invited to take part in clinical studies in which we will assess energy and glucose homeostasis, body composition and the circulation of bile salts. This work will improve our understanding of obesity, and shed light on mechanisms underlying patients’ symptoms to inform further work including interventional studies.

Amount: £185,660
Funder: The Wellcome Trust
Recipient: University of Cambridge

Regulation of HSV-1 infection by the non-homologous end joining machinery 08 Apr 2016

DNA viruses, such as Herpes Simplex Virus 1 (HSV-1), exploit specific host DNA repair mechanisms to assist their replication. More recently, the DNA repair machinery that senses damaged self-DNA was shown to function in the innate immune sensing of viral DNA during infection. We aim to understand how a specific DNA repair pathway, non-homologous end joining, affects HSV-1 infection and how this virus exploits or evades these host responses. This work will further our knowledge of cell-intrisic immunity and DNA repair as well as leading to the rational design of improved vaccines and oncolytic viruses. Our preliminary data indicate that two NHEJ proteins, DNA-PKcs and PAXX act to restrict HSV-1 in different ways, via activation of innate immune responses or by directly affecting virus replication. This study will provide the mechanistic basis of these observations and compare these data with the other components of the NHEJ machinery and how they regulate HSV-1 infection. This work will therefore explore two hypotheses: NHEJ proteins regulate innate immune sensing of HSV-1 DNA NHEJ proteins restrict HSV-1 replication in the nucleus

Amount: £99,981
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding the translation landscape at the host pathogen interface 01 Jun 2016

Viral infection triggers the expression of hundreds of interferon-stimulated genes (ISGs) that serve to restrict viral replication and spread. The function of one of the most highly upregulated ISGs, the IFN-induced protein with tetratricopeptide repeats (IFIT)1 is still not clear. Most cellular mRNAs have a 5´-N7-methylguanosine (m7G) cap and are also methlylated on the first base (cap1-RNA). I recently showed that IFIT1 bound tightly to mRNAs that had an m7G cap but lacked 2´-O-methylation of the first base (cap0-RNA) and inhibited their translation. To date, the only viruses restricted by this cap0 binding activity are mutants encoding inactive 2´-O-methyltransferases. My hypothesis is that IFIT1 influences the anti-viral response via interactions with host proteins and RNAs, modifying the translational landscape of the infected cell, while imposing a strong evolutionary pressure on viruses to maintain a cap1-RNA structure. I will determine how and which cellular RNAs IFIT1 and the related IFIT1B (that can also bind cap1-RNA) bind in the cell, the fate of these bound RNAs and the impact RNA binding has on IFIT1 protein-protein interactions and the cellular translation profile. By understanding the impact of IFIT1 on the cell we will gain insight into its role in the host antiviral response.

Amount: £901,216
Funder: The Wellcome Trust
Recipient: University of Cambridge

Role of epigenetic mechanisms in random X chromosome inactivation ex vivo and in vivo. 19 Apr 2016

Developmental progression is linked to accumulation of epigenetic information mainly in the form of chemical modifications of the chromatin. One of the most striking examples of that is random X chromosome inactivation (XCI) in female mammalian embryos. This process is dependent on coating of one X chromosome by a long non-coding RNA, Xist. This in turn promotes rapid and dramatic remodelling of the chromatin. The functional relevance and exact spatio-temporal dynamics of this process remains elusive. Here I propose to address these questions by using an integrated approach. Firstly I will use an ex vivo embryo culture system to monitor the dynamics of XCI. I will further integrate that information with single cell and population based epigenomic to generate in vivo and in vitro datasets accounting to a roadmap for XCI. I aim at identifying the initial stages of epigenetic programming leading to transcriptional repression as well as genomic loci involved in nucleating these changes. I will finally address the functional relevance of X chromosome epigenetic programming by using gene knockout models and genome-wide single cell transcriptomics approach. Such work will have wide-raging implications beyond the field of XCI and can be extrapolated into other epigenetic regulatory mechanisms.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

The modularity of action control in the nervous system. 11 Nov 2015

The first phase of the proposed research is to establish the principles by which control structures are represented in the nervous system in motor control and sequential decision-making. The behavioural patterns revealed using well-established assays will be tested in order to provide evidence for an optimally efficient representation of the task structure as predicted by the common computational framework of Bayesian structure modeling. The second phase is to use neuroimaging techniques (fMR I) on humans in order to identify the neural substrates of a learning process which efficiently encodes the task structure. Parallel analyses will be performed on a rich, and already acquired, dataset composed of electrophysiological recordings from rodents. This will test whether the same model applies across species, and critically, relate the model to previously established neural phenomenon. The results of these two phases will be integrated into a novel neuro-computational model of the a cquisition of control representations in corticostriatal circuits and their use in decision-making. Based on the hyperactivity of the dopaminergic system, the resulting model will be probed for predictions of behavioural deficits which will then be tested in patients suffering from schizophrenia.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Ischia Summer School on the History of the Life Sciences 31 Aug 2016

The Ischia Summer School on the History of the Life Sciences provides advanced training in history of biology and medicine in a historically rich and naturally beautiful setting for 26 PhD students and postdoctoral fellows, with strong UK representation. Lectures and seminars at the Ischia branch of the Naples Zoological Station by nine distinguished international faculty, with student presentations and discussions, encourage exchange of ideas across academic cultures. The 15th school, scheduled for 24 June – 1 July 2017, is on ‘Cycles of Life’, which we understand to range from ancient cycles of generation and corruption, the seasons and the weather cycle to modern reproductive, metabolic and ‘biogeochemical’ cycles, as well as contraceptive interventions in menstrual cycles and strategies to disrupt pest and pathogen life cycles. We will trace connections and identify patterns of continuity and change, explore shared properties of cycles and the differences and relations between disciplines and research programmes. The Naples Station will grant use of facilities, NSF will cover the costs of American participation and students will each pay €300. We are very grateful to Dan O'Connor for inviting an application and would be thrilled if the Trust could provide the balance of the funds.

Amount: £19,960
Funder: The Wellcome Trust
Recipient: University of Cambridge

Evaluation of feasibility of assessing liver function during ex situ liver perfusion using microdialysis 01 Apr 2016

Each year 15% of patients on the UK liver transplant waiting list die awaiting a donor liver, while a significant proportion of livers go unused because clinicians are unsure that the liver would provide life sustaining function. We are now able to perfuse a liver ex situ with oxygenated blood while evaluating markers of damage and function, enabling better assessment of organ viability. Microdialysis is a method in routine use in neurosurgery to evaluate brain metabolism following trauma, and involves passing a fine dialysis catheter into the brain parenchyma and perfusing it with an isotonic perfusate and examining the dialysate for metabolic markers such as glucose, lactate, and pyruvate. It can also be used to interrogate metabolism by introducing labeled substrates. Microdialysis has been used to study liver transplants post transplant, but has not been used to evaluate function ex situ where its relatively rapid readout may facilitate early and accurate decision making.This project will examine the feasibility of using microdialysis in perfused livers. Human livers that have been declined for transplantation will be studied and the optimal technique developed. Microdialysis results will be correlated with perfusate chemistry (lactate fall, maintenance of pH, ALT, AST) and metabolomic profile.

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

WACCBIP-Wellcome Trust DELTAS Programme 05 May 2015

The proposed DELTAS Programme seeks to strengthen and extend the scope of the mission of the West African Centre for Cell Biology of Infectious Pathogens (WACCBIP: www.waccbip.org), which was established at the University of Ghana (UG) in 2013. We believe that the vision of the DELTAS initiative aligns perfectly with our own aspirations at WACCBIP, where our mission is to improve diagnosis, prevention and control of tropical diseases by providing advanced level training and research on the cell and molecular biology of infectious pathogens. WACCBIP faculty are drawn from the Department of Biochemistry, Cell and Molecular Biology (BCMB), and the Noguchi Memorial Institute for Medical Research (NMIMR) at UG as well as seven partnerinstitutions within Africa. International faculty include several leading scientists from UK institutions, and members of the American Society for Cell Biology. WACCBIP was selected by the World Bank as one of the African Centres of Excellence for Higher Education, and received funding to build capacity for training of PhD and Masters students in Biochemistry and Molecular Cell Biology. This application seeks support from the DELTAS scheme for increased impact and long-term sustainability in the following ways: 1. Develop the first graduate and professional Human Genetics programme in Ghana, which will complement our existing pathogen biology research training. This programme will provide a structured research training platform to synergize with existing genetics training programmes led by the H3Africa network. 2. Develop a post-doctoral programme to help keep newly qualified PhDs in Africa and attract African scientists who have completed their PhDs abroad to return home. These postdoctoral fellows will conduct supervised research at WACCBIP and its regional partner institutions. 3. Strengthen our co-supervisor system through a Student Visitor programme, sothat PhD students and postdocs will be funded for six-month visits to the laboratories of cosupervisors in the UK or USA to hone their research skills. 4. Strengthen the mentoring system so each postdoctoral and PhD trainee will have a local mentor and access to advice from a UK or US scientist. 5. Develop a short course in research ethics that will be run annually to train young African scientists on responsible conduct. The goal of the proposed programme is to provide advanced training of health professionals and increase research and innovation to guide development of new approaches to disease diagnosis, prevention, and control. Effective training programs must be anchored by a strong, well-structured, and focused research portfolio. Therefore, this application seeks to build on our strength in pathogen biology research by incorporating a genetics curriculum and research platform, which is critical for a complete understanding of disease mechanisms for both communicable and noncommunicable diseases. Thus, the proposed research training will incorporate genetics into the study of host-pathogen interactions, as well as in investigating the molecularmechanisms that predispose individuals to the development of non-communicable diseases. This application builds a coalition of local, regional and international partners who have advanced resources and expertise in human genetics and pathogen biology research to support the proposed training programmes.

Amount: £132,017
Funder: The Wellcome Trust
Recipient: University of Cambridge

Putting genomic surveillance at the heart of viral epidemic response. 05 Apr 2017

This proposal is to develop an end-to-end system for processing samples from viral outbreaks to generate real-time epidemiological information that is interpretable and actionable by public health bodies. Fast evolving RNA viruses (such as Ebola, MERS, SARS, influenza etc) continually accumulate changes in their genomes that can be used to reconstruct the epidemiological processes that drive the epidemic. Based around a recently developed, single-molecule portable sequencing instrument, the MinION, we will create a 'lab-in-a-suitcase' that will be deployed to remote and resource-limited locations. These will be used to sequence viral genomes from infected patients which will then be uploaded to a central database for rapid analysis. We will develop methods for a wide-range of emerging viral diseases. Novel molecular biology methods will allow us to sequence individual viruses within a patient. Bioinformatics tools will be developed simple enough for non-bioinformaticians to use, without reliance on Internet connectivity. We will develop software to integrate these data and associated epidemiological knowledge to reveal the processes of transmission, virus evolution and epidemiological linkage. Finally we will develop a web-based visualization platform where the outputs of the statistical analyses can be interrogated for epidemiological insights within days of samples being taken from patients.

Amount: £482,639
Funder: The Wellcome Trust
Recipient: University of Cambridge

Transgenerational Epigenetic Inheritance - Cichlid as the New Model 05 Dec 2016

I aim to take advantage of the cichlid fish of Malawi to study the interaction between transposable elements, non-coding RNAs, epigenetics and heritability. This is in line with the overall goal of my Investigator Award. I believe this system to be superior to equivalent experiments we might conduct in mice. This is due largely to the high phenotypic diversity and low genomic diversity of these fishes. At the time of writing of my Wellcome Trust Investigator Award the cichlid model was too immature to proceed with an experimental plan. Now we have the required genomics, RNomics and epigenetics (DNA methylation) are all in place

Amount: £218,440
Funder: The Wellcome Trust
Recipient: University of Cambridge

The metabolic regulation of hypoxia inducible transcription factors. 05 Dec 2016

We have recently identified a novel pathway for metabolic regulation of HIF1 alpha by the OGDHC1. To continue this new area of research, it is essential that we have the necessary funds to maintian our competitive edge within the field, without diverting resources from our successful ubiquitin studies. The initial research on HIFs has been conducted by a talented graduate student, Stephen Burr. The timing of this funding request is particularly important, as it will allow Stephen to transfer his skills with a sufficient overlap for a new postdoctoral researcher to pursue this project.

Amount: £127,447
Funder: The Wellcome Trust
Recipient: University of Cambridge

Genetic and functional interactions in the mammalian DNA-damage response 05 Apr 2017

DNA in our cells is frequently subject to a wide array of molecularly-distinct forms of damage. To cope with this, life has evolved multiple DNA repair and associated processes, collectively termed the DNA-damage response (DDR). While considerable progress has been made in identifying DDR proteins and their regulators, much remains to be learned about how they operate and are controlled. Building on our successful proof-of-concept studies, we will carry out genome-wide and focused genetic screens via state-of-the-art CRISPR-Cas9 approaches and haploid-cell based chemical mutagenesis. Together with ensuing validation and mechanistic studies, the proposed research has the following interconnected goals: To identify novel genetic and functional relationships between DDR genes/proteins, and between these and other cellular components, thereby providing fundamental insights into how mammalian cells respond to DNA damage and defining how such responses are controlled and coordinated. To establish how defects and deregulation of certain DDR processes affect cellular sensitivity and resistance to established and emerging cancer therapies, and to explore the potential clinical relevance of these affects. To expand our knowledge of how DDR processes are affected by protein post-translational modifications, particularly ubiquitylation and phosphorylation.

Amount: £1,636,331
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

Activity and specificity of Notch regulated enhancers 31 Jan 2017

Signalling pathways are required iteratively during development, coordinating many different developmental processes. This diversity relies on them eliciting different qualitative and quantitative transcriptional responses depending on the context. The Notch pathway is one of the small set of core pathways and can promote distinct outcomes through different sets of target genes. How Notch responsive enhancers achieve this level of regulation is not understood. In this project, well characterized Notch responsive enhancers will be used to study how activity and specificity in response to Notch are encoded within the enhancer sequence and how different factors play a role in the control of these properties. 1. Activity: Characterize the transcriptional output of a Notch responsive enhancer and analyze how it is governed. 2. Specificity: Compare two enhancers that exhibit different response to Notch to determine how their response specificity is achieved. 3. Sufficiency: Assess if a defined enhancer is sufficient to confer a specific Notch response when introduced into a heterologous locus.

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