- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 30 Sep 2017
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Myc is a key oncogene in many cancers occurring across a diverse range of tissues. tn order to better understand and trea t such cancers, it is vital that we understand how the opposing functions of Myc, proliferation and apoptosis, are balanced and regulated in healthy ti'ssue, and how this goes wrong in cancer. The aim of this research project is to build a comprehensive executable model of the Myc tra nscri ptiona I program in fibroblasts. Analysis of this executable netv;ork model could help identify unknown interactions between genes in the network.Furthermore, it may help find key regulators of Myc function, which could act as potential drug targets. Predictions gained from the modelling work will be validated experimentally in collaboration with the Evan lab at the Department of Biochemistry.
Haematopoiesis occurs in two distinct waves during development, namely transient primitive haematopoiesis and definitive haematopoiesis that persists into adulthood. Many important questions remain unanswered about the earliest stages of blood development. For example, there are debates on the identity of the ini tial early mesodermal cells that give rise to the H SCs, as well as the factors that regu late the cell fate decisions in these cells. In this project, t seek to provide answers to these questions by utilising recently devel.oped techniques (i.e. single-cell RNAseq [scRNAseq] and single-molecule RNA in situ hybridisation(smRNAISH]) to study haematopoiesis in mouse embryos. Analysis at single cell resolution has the potential to resolve many of the current con troversies on the nature of early blood development. Firstly, I propose to identify subpopulations present in wild type early mesodermal cells using scRNAseq data. Once the sub populations are identified, their spatiotemporal trajectories will be analysed using smRNA ISH . Both scRNAseq and smRNA ISH will then be performed on mutant mice with key transcription factor knockout to observe how the knockouts affect normal haematopoiesis. Finally, I propose to synthesise a transcriptional regulatory network by incorporating all the information obtained from scRNAseq and smRNA ISH .
Investigation of the mechanisms used by Vaccinia virus protein C6 to modulate the host immune response and contribute to virus virulence. 18 Dec 2012
This project aims to understand the mechanisms used by Vaccinia virus (VACV) protein C6 to modulate the host immune response. Specifically, how C6 inhibits type I interferon (IFN)- induced gene expression, the function of the interaction between C6 and the cellular protein SMARCc1, and the contribution of different C6 interactions to virulence in vivo. The subset of IFN-induced genes whose expression is altered by C6 will firstlybe determined. Key events in the signalling pathway required for the IFN-dependent induction of gene expression will be analysed in the presence of C6 to determine where inhibition by C6 occurs. SMARCc1 is a component of the mammalian SWI/SNF complex involved in chromatin
The recent discovery of brown adipose tissue (BAT) in adult humans makes possible a new therapeutic approach to treat obesity, by activating endogenous BAT or making white adipose tissue more like BAT. To understand how to achieve these aims, physiological activation of BAT must be understood. Whiles much is known about thermoregulatory thermogenesis, the neuronal networks regulating metabregulatory thermogenesis (thermogenesis to counteract increased calorie intake) are not well understood. The central and peripheral mechanisms of metaboregulatory thermogenesis will be examined unsing three approaches in mice. Firstly, to determine whether the neuronal pathways regulating thermoregulatory and metaboregulatory thermogenesis are distinct, candidate hypothalamic nuclei that respond to a HFD will be identified by measuring c-Fos activation. Secondly, control of sympathetic tone to BAT by orexin neurons will be evaluated by ablating orexin neurons in adult mice and determining the effect on thermoregulatory and metaboregulatory thermogenesis. Finally, the molecular mechanisms by which Bmp8b increases sensitivity to adrenergic stimulation and thermogenesis in BAT will be investigated. Candidates signalling pathways and molecules will be identified by transcriptomic and proteomic approaches, and characterised in vitro. These experiments will help to eradicate the mechanisms of metaboregulatory thermogenesis, from central to peripheral regulation.
Characterisation of 18F-NaF as a novel marker for vascular calcification, and development of new treatment strategies for soft tissue mineralisation 18 Jan 2013
Arterial calcification is a process that involves calcium deposition in vessel walls. Mineralization is often found in human atherosclerosis, and a recent report suggests that coronary artery calcium scoring serves as a superior predictor of cardiovascular events. 18F-NaF has been proposed as a reliable marker of vascular calcification. However, it is currently unclear which molecular mechanism are detected using this molecule, which biological processes are involved, and how this informs on plaque rupture risk. To address these issues, we have proposed three aims: Aim 1 is to evaluate the ability of 18F-NaF to quantify calcification in human ex vivo plaque; Aim 2 is to study animal models that can recapitulate the process of calcification using PET imaging for the assessment of calcification and Aim 3 isto examine whether animal models provide a mechanism to test the ability of drugs to alter the calcification process. Together the fulfilment of these aims will allow us to assess 18F-NaF as a novel marker for vascular calicifcation and cardiovascular risk, and test pharmacological treatments with this model. These findings could have important implications to decrease mortality worldwide.
Novel strategies using 'biased'agonists at the apelin receptor for the treatment of cardiovascular disease 18 Jan 2013
Pulmonary arterial hypertension (PAH) is a fatal disease caused by genetic mutations in BMPR-II, or drugs and toxins such as monocrotaline (MCT). We hypothesize this combination of afterload reduction and positive inotropy caused by apelin, the endogenous ligand of the APJ receptor, may be beneficial to PAH. MM07, a synthetic apelin analogue and a biased agonist of APJ, is highly potent in functional assays and less likely to desensitize APJ. Preliminary results indicate that MM07 is stable in vitro and safe in vivo. Our main objective is to study the effects of apelin in animal models of PAH, and in cultured cells. Using the MCT-treated rat meodel, the ability of MM07 to prevent and reverse PAH will be tested. Then the effects of APJ agonism will be confirmed using a competitive antagonist. Additionally, MM07 will be tested in another animal model with a BMPR-II mutation. A non-peptide APJ agonist may also be used to prevent PAH. Furthermore, alteration of the apelin/APJ system will be investigated in vitro in cells from PAH patients. The consequences of these changes and connections with the BMPR-II pathway will be explored. Our findings may support the use of APJ agonists in cardiovascular diseases like PAH.
Wellcome Trust PhD Programme for Clinicians at the University of Cambridge: 'The prevalence and significance of clonal selection in healthy haematopoietic stem cells and its relationship to myeloid leukaemogenesis'. 16 Sep 2013
Cancer is known to result through a gradual process of mutation accumulation. Haematopoietic stem cells (HSCs) do not escape such mutational accrual. We postulate that mutations that confer a survival advantage to an HSC will lead to the generation of a small pool of clonal cells, in affected individuals. We intend to develop protocols for accurate detection of such clones at their early stages, study the prevalence of clonal expansions in asymptomatic individuals and search for correlations between commonly acquired mutations and HSC advantage. We believe that this is a stochastic process that may belie the development of pre-leukaemic clones. In defining the clonal landscape of the myeloid compartment we will search for mutations implicated in AML in normal individuals using cRNA baits and deep sequencing. Aims 1. To investigate the prevalence, stability and natural history of myeloid cell clones in haematologically normal individuals and determine the types & order of acquisition of somatic mutations driving these clones. 2. To determine to what extent such clones share mutational profiles with myeloid malignancies thus providing evidence that myeloid leukaemogenesis is a stochastic process. 3. To delineate the processes underlying the phenomenon of skewed X-chromosome inactivation profiles in haemopoiesis in females: Is this a clonal process driven by somatic mutations or does it represent, at least in some cases, stem cell selection based on advantageous X-linked polymorphisms?
PhD Programme for Clinicians at the University of Cambridge: 'Developmental studies of murine and human lung development towards differentiation of human induced pluripotent stem cell to lung epithelial progenitors'. 16 Sep 2013
Respiratory diseases are associated with a high and increasing global incidence of mortality and morbidity which is related to the inability to meet the demands for lung transplantation. Human induced pluripotent stem cells (hiPSCs) might enable the differentiation of patient-specific iPSCs into any relevant cell type to be used for disease modelling and drug screening and could also bring us a step closer to cell-based therapies, including personalised organogenesis. For disease modelling, generating disease-specific lung epithelial cells from hiPSCs is particularly important because murine models often do not phenocopy human lung disease. Published differentiation protocols are based on the assumption that to produce fully mature epithelial cells, progression through a progenitor stage is necessary. The inability to efficiently produce fully mature epithelial cells might be due to an inability to produce bona fide lung progenitors. I aim to ascertain optimal conditions for the generation of human lung progenitors from hiPSCs using the naïve pluripotent stem cell platform of the Smith laboratory. To achieve this, I will also characterise both early human and murine lung development. Intensive study of those should provide me with a road map to recapitulate the milestones of early development in order to efficiently drive iPSCs toward mature lung epithelial cells.
My project deals with the role of the state in the early modern drugs trade, which I approach through the study of Russia from 1550 to 1750, a country rarely dealt with in histories of early modern medicine. In much of the early modern world, the drug trade was dominated by merchants and medical practitioners; in contrast, the trade in Russia was controlled by central government. Recent research focuses on the former, private, trade. I will address the question of how and with what effect did th e Russian state control the drugs trade, through a study focusing on the interactions between trade, ideas, and medical practice. This study will examine the transnational networks Russia relied upon for sourcing and selling drugs, and how they evolved; the commodities being traded, and the changing supply and demand of certain items; ideas about medicines and prescribing present in Russian medical texts; and how the actual practice of prescribing related to those ideas. Consideration of these i ssues will help build a view of Russia's place in the global drugs trade, and so allow analysis of the role of the state in a vital part of early modern medical care.
The alloimmune response to human induced pluripotent stem cells and their differentiated progeny in a humanised mouse model. 20 Nov 2012
Human induced pluripotent stem cells (hiPSCs) generated from adult cells such as skin fibroblast have the ability to differentiate into many cell types including pancreatic progenitor cells. Humanised mice reconstituted with a human immune compartment are an invaluable tool in the study of the humoral alloimmune response to hiPSCs and their differentiated progeny. This alloimmune response is, however, not yet characterized but is likely to be determined in large part by HLA expression. My projec t aims to first characterize the immune response to human adult or hiPSC-derived cells in a humanised mouse model by addressing the hypothesis that optimal humoral alloimmunity requires positive thymic selection of CD4 T cells on human MHC. Next, hiPSCs will be derived from skin fibroblasts and differentiated into pancreatic progenitors. The humoral immune response to autologous or allogeneic hiPSC-derived pancreatic progenitor cells will be compared in humanised mice with the response against a dult islets, to test the hypothesis that HLA class I expression by hiPSCs increases after differentiation but that the humoral alloimmune response is nonetheless dampened compared to the response against adult cells.
Fragment-based lead discovery against the protein-protein interaction between Aurora A and TPX2 for the treatment of cancer 23 May 2013
The Wellcome Trust has awarded over £2.3 million to Chris Abell, John Skidmore and co-workers at the University of Cambridge to use fragment-based approaches for the generation of molecules which disrupt the interaction between the kinase Aurora A and the regulatory protein TPX2. Such compounds are expected to have utility in the treatment of a number of solid and haematological cancers, with one particular focus being reversal of taxane resistance in solid tumours. The project will generate lead compounds suitable for screening in cancer cell-lines and animal models to further validate the target and will also provide leads for future optimisation towards a drug. This funding follows on directly from an ongoing Strategic Award pioneering the use of fragment-based approaches against protein-protein interactions, which used biophysical screening and X-ray crystallography to generate the fragment leads for the planned project.
Discovery and development of novel small molecule inhibitors of the human Hyperpolarization activated Cyclic Nucleotide-gated 2 (HCN2) ion channel for the treatment of inflammatory and neuropathic pain 15 Jul 2013
Treatments for inflammatory pain (IP) and neuropathic pain (NP) are frequently ineffective and have many side effects. Scientists in Professor Peter McNaughton's laboratory at the University of Cambridge have discovered that both IP and NP are abolished in mice when an ion channel is genetically deleted. This suggests that drugs blocking this ion channel will have value as novel analgesics. IP is associated with injury, infection or chronic conditions such as arthritis; and NP is caused by nerve damage in conditions such as post-herpetic neuralgia and diabetic neuropathy. Both IP and NP can impose major limitations on lifestyle and working patterns and currently available treatments have major drawbacks. For example, non-steroidal anti-inflammatories cause gastric and renal damage; and opioids cause constipation and problems with tolerance and addiction. The team aims to develop selective ion channel blockers, which avoid those that play essential roles in the heart and brain, and test them in animal models of IP and NP. In separate parallel studies they will use a known non-selective blocker to carry out proof-of-principle studies in human NP.
The overarching goal of my research program is to gain a mechanistic understanding at the molecular level of how important pathogens interact with their host cells during infection. We seek to understand: How do enveloped viruses assemble and recognize host cells? How do enveloped viruses deliver their genome into the cytoplasm? How are innate immune responses to viral nucleic acids generated, amplified and regulated? We employ a diverse set of complementary approaches including X-ray crystallog raphy, electron microscopy, solution biophysics, fluorescence microscopy and cell biological approaches to understand the mechanisms that underlie these processes in molecular-level detail. Our projects have important potential applications in global health. We will develop two specific projects: 1--Enveloped viruses deliver their genome into the cell by fusing the viral and cellular membranes. The molecular steps required for membrane fusion are still poorly understood. We propose a comprehens ive analysis of the mechanism and kinetics of membrane fusion of various enveloped viruses using biophysical and cell biological approaches. 2--The mechanism of viral RNA recognition by the innate immune system remains poorly understood. We have shown that MDA5 coats viral RNA, forming filaments that nucleate the assembly of multimeric signaling platforms. We will determine the structures and kinetic assembly parameters of MDA5 filaments, and their relationship to signaling activity.
Defining the mechanisms of induced pluripotency. 10 Jul 2013
My research has centred on nuclear reprogramming since my PhD. As an independent Principal Investigator I have developed unique systems to better investigate the process of induced pluripotency. This resulted in the identification of Nanog and culture environment as key players and has helped re-define our understanding of the biological roles of Oct4. As a senior principal investigator I want to build on this platform and on exciting new findings from my lab. Specifically, I will focus on mecha nisms of induced pluripotency and on parallels with in vivo phenomena. 1-Define mechanistically the cell state transition leading to the acquisition of a naive pluripotent cell state. New data from our lab shows that Nanog and culture environment work synergistically on reprogramming mechanisms. We also found that depending on the culture environment, defined ES-level of Oct4 expression instructs either a naive pluripotent cell state or cell differentiation. My aim is to further explore t he relationships between key players and understand how the observed reprogramming mechanisms are regulated. I also want to fully define the direct molecular reprogramming mechanism of Nanog by investigating how its interactions with co-factors, mostly epigenetic regulators, affect its capacity to reprogram. 2-Investigate parallels between mechanisms of reprogramming and analogous biological processes. We were the first to draw a parallel between induced pluripotency and embryonic developm ent. Our future aim is to investigate how general is this concept by assessing if identified nuclear reprogramming mechanisms are recapitulated during the acquisition of the naive epiblast in the early embryo.
My laboratory investigates the molecular mechanisms that control the 24 hour (circadian) clock. This fundamental process is integral to the function of all cells. Our recent work has highlighted a critical role for a family of proteins called peroxiredoxins in the clockwork, and has shown that redox oscillations in mammalian cells contribute significantly to a cell's rhythmic properties. A Senior Fellowship would allow me to examine how the clockwork functions in 'real-time', using a variety of novel tools that we are developing to do this. We will also perturb redox pathways (that normally get rid of harmful oxidants produced because of respiration) and investigate the effect of this on the clockwork using these tools. A final goal will be to integrate redox oscillations with existing components of the clockwork, which rely on the process of gene transcription to work. The goal is therefore to fully characterise the mechanism of how a cell keeps time, particularly with respect to redox metabolism, which is a new and exciting area of study within the field.
Multi-locus models of pathogen evolution. 29 May 2013
Time-resolved genetic data offers a new and exciting opportunity to study pathogen evolution. Sequencing a population at multiple time points reveals genetic changes as they occur. Mathematical models based upon the dynamics of evolutionary systems allow for more accurate identification of alleles under selection, and better measurements of the magnitude of selection, than have previously been achieved. I will develop models to interpret time-resolved genetic data, so as to better understand the evolution of pathogens. Unified by the theme of modelling rapid evolutionary dynamics, this work will make progress in understanding multiple pathogenic organisms. Specifically, this project will use high-coverage sequence data to quantify the role of selection in the intra-patient evolution of influenza, relevant to the emergence of new pandemics. It will examine how immune and drug pressure, acting upon the HIV virus, affect viral diversity in the early stages of an infection. The project will develop methods to better interpret genetic data from drug resistance experiments, in order to identify genomic factors leading to drug resistance in malaria parasite, helminthes, and leishmania. Finally, I will investigate the potential of multi-locus genetic models of evolution to understand, and to predict, the evolution of seasonal influenza.
This proposal has three aims. Firstly, I will characterise the neural computations underlying model-based and model-free avoidance using fMRI in healthy subjects. To do so, I will adapt an existing appetitive paradigm to test if the existing framework can capture human avoidance behaviour. I will seek convergent evidence by comparing a standard version to a version designed to shift individuals towards model-free behaviour, e.g. using outcome volatility. Secondly, I will delineate the nature of the interplay between individual differences in Pavlovian fear conditioning and model-based vs. model-free avoidance by using interleaved Pavlovian conditioning trials. I will then use experimental manipulations to move our understanding of this interaction beyond correlation. I will test if increasing the strength of conditioned Pavlovian fear causes subjects to rely more heavily on model-free avoidance and if biasing individuals towards model-free learning reciprocally increases the strength o f Pavlovian conditioned fear and resistance to extinction. Finally, I will use the models developed at NYU to test causal predictions regarding the role of Pavlovian-instrumental interactions in patients with generalised anxiety disorder and obsessive-compulsive disorder diagnoses. In doing so, I hope to formalise dimensions with well-characterised neurocomputational bases that may explain the familiality and co-morbidity across anxiety disorder diagnoses.
Institute of Metabolic Science. 12 Oct 2012
With support from the Wellcome Trust and MRC, we have established an internationally leading Institute for Metabolic Science (IMS) in Cambridge. The world-class investigators we have assembled, combined with the excellent facilities we have established, have brought us within sight of our goal to translate advances in the understanding of basic mechanisms involved in obesity, diabetes and related metabolic diseases into benefits for health. In this proposal, we seek support for: 1. The co nstruction of a dedicated Metabolic Clinical Research Facility (MCRF) and Eating Behaviour Unit (EBU) to support the expansion of translational research programmes and capitalise on local strengths in the basic and clinical neuroscience of appetitive behaviour. 2. A collaborative programme with the Wellcome Trust Sanger Institute in the generation and phenotyping of murine models of metabolic disease. 3. Improved cell imaging and proteomic facilities in collaboration with the Cambridge Ins titute for Medical Research (CIMR). 4. Equipment to update our core Genomics/Transcriptomics laboratory We have been encouraged to submit a complementary bid to the MRC and further support is being provided by the University of Cambridge. If awarded, these additional resources will significantly enhance our abilities to conduct the highest level basic and translational science in metabolism.
Nanoscopy of dynamics in the living cell 16 Sep 2013
Dramatic advances in several physics-driven laboratories have established the principle of super-resolution optical imaging. Major improvements in spatial and temporal resolution are sorely needed for the technology to be useful to answer major biological questions. We propose a bold multi-disciplinary program to drive the technology forward with biological applications that demand dynamic visualization on the nanoscale in the belief that step-change technology development cannot effectively e volve without motivation and pull from those who need the applications the most. Leveraging major investments made by Yale, we have assembled a multi-disciplinary team of engineers, physicists, and cell biologists from the Gurdon Institute, the Cell Biology Department at Yale, the LMB at Cambridge, and Oxford University which over five years will develop a new generation of microscopes and probes capable of multi-color dynamic imaging deep in live cells with spatial resolution <50 nm in all d imensions which are to be sited in Cambridge and New Haven and made broadly available. The biological test bed to lead the technology is the dynamics of the secretory pathway, chosen because this difficult problem has resisted conventional optical solutions due to the close proximity of the substituent membranes. Optical nanoscopy impacts four of the Trust s major challenges.
Characterisation of the role of perilipin in the molecular regulation of triglyceride hydrolysis 06 Sep 2012
My project has four themes: 1) Characterising the phenotype and molecular properties of two novel forms of lipodystrophy due to mutations in two lipid droplet proteins, perilipin and CIDEC. Perilipin s biological role is well documented so I will define the human phenotype associated with the mutations and characterise the biological properties of the mutants. The biological function of CIDEC is poorly understood, so I will characterise the mutant and explore the protein s biology including d etermining its precise localisation, its structure and identifying interacting proteins. 2) To use patients with genetically defined forms of lipodystrophy to explore questions relating to more common diseases - a) To understand the mechanisms of adaptive thermogenesis in lipodystrophy using humans and animal models. b) To identify the major sources of fatty acids responsible for fatty liver and dyslipidaemia? c) To establish if mitochondrial dysfunction, a feature of T2DM, is a cause or conseq uence of insulin resistance? 3) To identify novel genetic causes of lipodystrophy using next generation sequencing platforms. 4) To establish protocols for adipocyte differentiation of induced pluripotent stem cells. These cells will be invaluable tools for characterising the consequences of novel and unidentified forms of lipodystrophy and, ultimately for therapeutic replacement strategies.