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Recipients:
University of Cambridge
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Results

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

Investigating stiffness alterations in spinal cord injury 30 Sep 2018

Spinal cord injury is a devastating condition that may lead to loss of limb movement, sensation and bladder control. Despite intense research, treatment is still very limited. Most research to date has focused on biochemical signalling. However, some more recent studies have hinted that mechanics might play an important role in spinal cord regeneration. Using atomic force microscopy (AFM), a cutting-edge technique which allows us to very precisely measure stiffness maps of biological tissues, we will investigate the stiffness of spinal cord tissue at various time points after injury and compare this to the stiffness of healthy spinal cord. We will test whether artificially modifying the stiffness of the damaged spinal cord or modifying mechanosensing in spinal cord cells improves regeneration of neurons after spinal cord injury. Our studies will be carried out in a cervical contusion model in rats which closely mimics the pathology seen in the human spinal cord after injury, even though the behavioural impairments the animals show are markedly less grave.

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

Pregnancy testing over the counter, in activism, and at home: Britain, c.1970 2015. 12 Jan 2015

In 1971, Chefaro, a subsidiary of the Dutch firm Organon, launched Predictor, Britain's first HPT. This project will recover the history of HPTs from c.1970 to the present day, when their widespread visibility and availability is taken for granted. It will be divided into four parts. Part One examines how Predictor, a laboratory tool repackaged, but not redesigned, for domestic use, was produced and marketed, received by consumer watchdog organisations, and appropriated by women's liberation gro ups. Part Two examines the public debate over Schering's Primodos, a controversial pregnancy test drug that was taken off the market in 1978 amidst fears of a repeat of the Thalidomide tragedy. Part Three investigates how not only technological innovation and slick marketing, but also NHS cutbacks and the rise of IVF contributed to the runaway commercial success of Clearblue, launched by Unipath, a subsidiary of the multinational Unilever, in 1985-88. Part Four recovers the mainstreaming and aes theticization of pregnancy testing in fiction, cinema, television, comics, artworks, and new media to reexamine assumptions about the textual and visual politics of reproduction, currently strongly identified with highly charged images of the late-term human fetus and 'baby bump'.

Amount: £138,230
Funder: The Wellcome Trust
Recipient: University of Cambridge

A digital archive of William Bateson. 19 May 2015

Not available

Amount: £119,831
Funder: The Wellcome Trust
Recipient: University of Cambridge

Medical history of a WWII internment camp: creating online access to the voices of civilians interned by the Japanese on Singapore, 1942-1945. 19 Nov 2014

Cambridge University Library plans to conserve, digitise and share freely withresearchers worldwide the archives of two Second World War civilian internmentcamps on Singapore, Changi and Sime Road. Recently catalogued, these records have attracted the attention of both academics and members of the public, but due to their fragility their contents have remained hidden to all but those able to visit Cambridge. Few survivors of Japanese internment spoke of their traumatic experience, so the records are of immense interest to the friends and families of those interned in the Far East, as well as to the academic community, and particularly to those studying the effects of malnutrition and tropical diseases. In our archives, the internees meticulously documented their captivity - theiraccommodation, work for the Japanese, their recreation, diet and health, and repatriation at the end of the war. Nominal Rolls and the files of the Camp Commandant and Quartermaster are complemented by newspapers, written and circulated by the internees, diaries, letters, plays and memoirs. The records were created on very thin scraps of now brittle paper, and the paper in several folders is tipped-in, obscuring its full contents, so microfilms offer researchers an incomplete record. Our plan is to repair the paper, separating, cleaning and encapsulating leaves, to make it safe to digitise. Once digitised each record will be hosted on our Digital Library platform, http://cudl.lib.cam.ac.uk/, and we will also re-package the originalrecords so that they can be exhibited and handled safely by the families of internees.

Amount: £99,103
Funder: The Wellcome Trust
Recipient: University of Cambridge

Molecular mechanisms controlling peptide selection for immune recognition. 03 Dec 2014

I have discovered that TAPBPR is a novel MHC class I specific component in the antigen processing and presentation pathway. This work represents a major advance in the field of MHC biology. It is now essential to investigate the specific function of TAPBPR in the immune system in order to understand its role in health and disease. My key research goals are to: 1)Determine the role of TAPBPR in MHC I peptide selection. Techniques used will include sequencing the peptide repertoire presented to the immune system by mass spectrometry in wild-type and TAPBPR depleted cells, in vitro peptide exchange assays for TAPBPR function on MHC molecules, and T cell assays to assess the consequence of TAPBPR depletion on recognition of MHC by T lymphocytes. 2)Characterise the molecular mechanisms underpinning TAPBPR function. Experimental methods used will include affinity chromatography with mass spectrometry to identify other TAPBPR binding partners, solving a crystal structure of TAPBPR b oth alone and with MHC class I, and assessing functionality of mutated TAPBPR molecules. 3)Investigate the contribution of TAPBPR in infection control and autoimmunity. The role of TAPBPR in infection control will be determined by investigating the susceptibility of TAPBPR knockout mice to viral and bacterial infections. The contribution of TAPBPR in the pathogenesis of the spondyloarthropathies, the strongest autoimmune disease associated with MHC class I, will be determined by comparing t he functionality of TAPBPR variants found in patients to controls on HLA-B27 peptide presentation and immune recognition.

Amount: £1,000,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Regulatory signalling networks between stem and niche cells in lung regeneration. 27 May 2015

For multipotent stem cells to properly orchestrate injury repair, it is necessary for signals to instruct stem cells to produce specialised cells that replace injured epithelia. The precise signals from the stromal/niche cells that can stimulate differentiation for lung injury repair are under-investigated. In this proposal, I will directly address gaps in the understanding of the regulation of stem cell lineage differentiation by characterising novel stromal cell populations expressing Lgr6 in the murine distal lung and their functional interactions with region-specific stem cells during injury repair. Aim 1 will define dynamics of Lgr6-expressing cells by tracking them in homeostasis and during injury repair. In vitro organoid co-culture of regional epithelial stem/progenitor cells with Lgr6+ cells will address functional interactions between epithelia and Lgr6+ stromal cells. I will also determine if Lgr6+ cells are essential for stem cell lineage differentiation in vivo. Aim 2 will further dissect regulatory signalling molecules derived from Lgr6+ cells. Gene expression profiling of Lgr6+ cells with regional epithelial cells will describe key signalling pathways that will be evaluated by in vitro organoid co-culture assay and by in vivo mouse genetics. This work will enhance our understanding of regulatory networks between stem-niche interactions in lung regeneration.

Amount: £1,226,049
Funder: The Wellcome Trust
Recipient: University of Cambridge

Hedgehog signalling in T cell effector and memory function in vivo. 27 May 2015

The aim of my research is to characterize the role of Hedgehog (Hh) signalling - known as a key determinant of tissue differentiation and development - in regulating CD8 effector and memory formation and function in vivo. I will utilize Hh reporter mice to determine the level of Hh signalling in effector and memory subsets during the course of the CD8 response to infection and tumour challenge. By comparing Hh-deficient and wildtype, antigen-specific CD8 T cells, I will interrogate the functiona l relevance and clinical importance of Hh signalling. RNASeq analysis on CD8 subsets and single cells will be carried out to reveal the Hh-specific CD8 target gene signature responsible for the observed effects in the different CD8 subsets. Novel Hh target genes identified in this analysis will be functionally characterized. In parallel I investigate the effects of Hh pathway manipulation on the CD8 anti-tumour response using live-imaging approaches of whole animals and tumour slices. The prop osed study will not only reveal the spatio-temporal activation and functional relevance of Hh signalling during the CD8 immune response in vivo but will also identify the underlying molecular mechanisms and determine the effects of Hh inhibitors and agonists on this response.

Amount: £1,019,562
Funder: The Wellcome Trust
Recipient: University of Cambridge

Diabetes and Inflammation Laboratory. 21 Apr 2015

Our goal is to identify clinical interventions in patients recently diagnosed with, or children at high risk of developing, type 1 diabetes (T1D), thereby maximising the health benefits of genetics and genomics in this common immune disorder. Our studies in T1D serve as a model for the investigation of other diseases and their treatment. We will take specific steps towards achieving this goal during the next five year programme: (1) Genetics. Define the genetic basis of T1D by fine-mapping di sease-associated causal variants and haplotypes, identify their target genes, and investigate the regulation of these genes before and after cell activation/differentiation. (2) Phenotypes and mechanisms. Identify aberrant cellular interactions and pathways caused by susceptibility genes that mediate a loss of immune tolerance to insulin-producing beta cells culminating in their destruction. These will provide potential targets for therapeutic intervention, as demonstrated by our work in the I L-2 pathway. (3) Experimental medicine. Complete our mechanistic investigations of the effects of IL-2 administration in patients, as a prelude to testing the efficacy of ultra-low dose IL-2 in the preservation of C-peptide and beta-cell function. Investigate, using the same mechanistic approach and depending on our emerging knowledge, another potential therapeutic.

Amount: £8,289,795
Funder: The Wellcome Trust
Recipient: University of Cambridge

A high resolution platform to capture the dynamic spatial proteome. 11 Jun 2015

This proposal aims to create a platform for mapping the subcellular location of a substantial proportion of the proteome in a single experiment with high resolution. It is based on preliminary work carried out by the Lilley group in collaboration with Thermo, giving tantalising insight into what this technology could deliver if developed further into a fit-for-purpose spatial proteomics platform. The key objectives are: 1. Expand the sampling of subcellular proteome to locate proteins to multi ple compartments. 2. Capture information of the effect of post-transcriptional and post-translational modification on spatial location. 3. Develop approaches to enable the mapping of the dynamic subcellular redistribution of proteins upon biological perturbation. 4. Incorporate work-flows that will deliver spatial information about targeted sub-sets of proteins and integration with whole cell maps. 5. Develop cross-linking strategies to preserve interactions of peripheral membrane proteins and between components of multi-protein complexes. 6. Develop a set of bespoke informatics tools facilitating the application of pattern recognition for robust analysis. 7. Create a GUI to facilitate community-wide interrogation of cellular maps. 8. Develop on-line protocols. 9. Apply the technology to the co-applicants and collaborators research, adding value to projects already funded by the Wellcome Trust.

Amount: £200,788
Funder: The Wellcome Trust
Recipient: University of Cambridge

Construction and testing of a whole-cell arsenic biosensor with a simple visual readout for field use 29 May 2015

Arsenicosis from chronic consumption of contaminated ground water affects virtually all organs and tissues where skin lesions, bronchitis, gastroenteritis and ultimately a range of cancers are typical pathologies. Although arsenic contamination of drinking water is a global problem, it most seriously affects on the order of 100 million people in some of the poorest regions on earth including India/West Bengal, Bangladesh and Nepal. Prof James Ajioka's team at Cambridge University and Prof French at Edinburgh University are aiming to construct an inexpensive and reliable kit to assess arsenic contamination in drinking water in rural villages. Based on the observation that some bacteria detect arsenic, they will engineer an arsenic sensing device based on the Bacillus subtilis arsenic operon. This biosensor will be combined with a reporter system based on the violacein operon, resulting in bacteria that would turn green when it detects very low, safe levels of arsenic in the drinking water, but if the arsenic contamination is at a dangerous level, it will turn violet. The transcriptional signal to drive the pigment device in the bacteria can be tuned to respond to arsenic levels within definition of WHO safe or dangerous levels. The kit will be based on a weakened strain of the harmless soil dwelling bacteria, B. subtilis, housed in a robust plastic container to further reduce any risk and for easy, environmentally friendly deactivation/disposal.

Amount: £33,171
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge Stem Cell Institute Four year PhD studentships - Stem Cell Biology- Samuel Myers 30 Jan 2015

This proposal is to facilitate creation of a world-leading centre for fundamental and translational stem cell research. The Cambridge Stem Cell Institute (SCI) will build upon previous Wellcome Trust and Medical Research Council funding by drawing together 30 research teams into a cohesive centre. These groups will ultimately be co-located in a purpose-designed 8000m2 facility to be constructed on the Cambridge Biomedical Research Campus. Platform technologies supported by a Centre grant will en able SCI to recruit and retain the most talented investigators and empower them to make ground-breaking advances in understanding stem cells and their medical applications. Fundamental research will focus at the molecular level on mechanisms of self-renewal, commitment, differentiation and reprogramming. Functional studies will address the role of stem cells in development, repair, ageing, physiology and pathologies including cancer. Disease-specific induced pluripotent stem cells will be exploi ted to unravel mechanisms of cellular pathogenesis and define drug targets. Strategies to mobilise endogenous stem

Amount: £11,112
Funder: The Wellcome Trust
Recipient: University of Cambridge

Tired of relapsing: manipulating T cell exhaustion as a treatment for autoimmune disease. 14 May 2014

The clinical course of autoimmune and infectious disease varies greatly even between individuals with the same condition. Greater understanding of the molecular basis for this heterogeneity could lead to significant improvements in both monitoring and treatment. During chronic infection the process of T cell exhaustion inhibits the immune response, facilitating viral persistence. I have shown that a common transcriptional signature reflecting high levels of CD8 T cell exhaustion predicts poor cl earance of chronic virus (HIV) but conversely predicts better prognosis during responses to persistent self-antigen in multiple autoimmune diseases. In autoimmunity, I found that where CD8 T cell exhaustion was high a concurrent signature of CD4 T cell costimulation was low and used this signature to identify specific costimulatory signals preventing the development of T cell exhaustion during in vitro culture. As the balance of costimulatory and coinhibitory signals dictates the emergence of T cell exhaustion during chronic viral infection, I plan to test whether T cell exhaustion can be induced during in vitro and in vivo models. My ultimate goal is to exhaust an autoimmune response as a novel, targeted treatment strategy. I aim for this work to form the basis of a future translational research programme.

Amount: £1,056,174
Funder: The Wellcome Trust
Recipient: University of Cambridge
Amount: £2,000,004
Funder: The Wellcome Trust
Recipient: University of Cambridge

The connectome of olfactory memory circuits in the adult fly 05 Jul 2016

Connectomics, establishing comprehensive neuronal wiring diagrams at the resolution of single synaptic connections, is still in its infancy. Although most neuroscientists are confident that connectomics will eventually have a major impact, doubts remain about when this will happen. We propose a project that within 4 years could transform an important field of neuroscience – the circuit basis of learning and memory – by reconstructing the olfactory memory circuits of Drosophila. A consortium of laboratories at HHMI Janelia has generated a complete serial section transmission EM volume of an adult female Drosophila brain. This 106 TB volume (100x larger than any previously imaged whole brain) will have a major impact on over 200 laboratories working in Drosophila neurobiology. We will reconstruct input and output neurons of the primary associative learning centre, the mushroom body, along with selected upstream layers bringing teaching signals and downstream layers mediating descending control of behaviour. This will reveal the complete network and synaptic organisation of a memory centre, whose logical principles, including sparse coding, dopamine-dependent plasticity, valence segregated by neuronal population, and network recurrence, are all relevant to mammalian brains. This will enable a wealth of experimental circuit studies as well as piloting large-scale, geographically-distributed connectomics.

Amount: £3,250,123
Funder: The Wellcome Trust
Recipient: University of Cambridge

Regulatory potential of repeat elements in the evolution of tissue-specific transcription 05 Jul 2016

The human genome, like all mammalian genomes, is in large part composed of decayed--but once active--repeat elements, many of which carry tissue-specific regulatory information. We hypothesise that repurposing of repeats has been critical for creating tissue-specific transcriptional regulation. Our research plan is an integrated experimental and computational strategy to systematically explore how these repeat elements have shaped the regulatory genome across the recent placental mammalian radiation.

Amount: £1,715,976
Funder: The Wellcome Trust
Recipient: University of Cambridge

Duplication and Cellular Functions of Drosophila Centrioles 05 Jul 2016

Centrioles, at the core of centrosomes, orchestrate structure and function in the interface and mitotic cell. Here we aim to understand how centriole duplication is controlled. This requires Plk4 kinase to phosphorylate Ana2 in part so it can bind Sas6. Here we address how phospho-Ana2 interacts with other core procentriole components, Dragon, Ana3 and Rcd4 and how these events are spatially regulated to achieve duplication. Second, we aim to characterize how centriole to centrosome conversion is regulated giving newly formed centrioles competence to duplicate and nucleate cellular microtubules. We will determine how Polo kinase regulates formation of the Cep135, Ana1, Asl network essential for centriole conversion. We will also assess roles of Polo and Plk4 in anchoring peri-centriolar material (PCM) to the centriole and Plk4’s role at the peri-centriolar satellites to mobilise centrosomal molecules. Thirdly, we address how centrosomes can organise membranous vesicles. We focus upon Dragon, a molecule present in the centriole and the Golgi apparatus, and Rosario, counterpart of lysozyme-like vesicle protein LYST, required to evenly distribute centrosomes in the syncytial embryo. We will characterize the process whereby primordial germ cells form in the syncytium, an event triggered by interactions of centrosomes with the embryo’s polar cytoplasm.

Amount: £1,543,160
Funder: The Wellcome Trust
Recipient: University of Cambridge

The molecular machinery of RNA metabolism and riboregulation in bacteria 05 Apr 2016

In response to stress conditions and environmental changes, bacteria generate scores of small RNAs that play key roles in reshaping the dynamic landscape of gene expression. This process involves chaperone proteins that facilitate the actions of such regulatory RNAs and enzymes that affect transcript lifetimes. We aim to understand the molecular basis of these processes. Trapped intermediates of the degradative machinery with bound regulatory RNAs and targeted substrates will be structurally characterised to visualize how transcripts are captured and channelled to active sites, where they meet a fate of rapid degradation or processing into matured forms. We will identify RNA targets of chaperones and the degradative machinery and explore whether the patterns change with physiological state or during the cell cycle, and why. We want to understand why the degradative machinery has a sub-cellular localization and the origins of its dynamic and cooperative interactions with substrates and the translational machinery. Our studies will help to explain how the use of RNA enables speed and accuracy to be attained in genetic regulation and enriches the capacity of even the simplest organisms to exhibit complex behaviour in homeostasis, development and pathogenesis. This knowledge could be exploited to treat threatening bacterial infections.

Amount: £1,630,519
Funder: The Wellcome Trust
Recipient: University of Cambridge

Maternal NK cell recognition of the placenta determines reproductive outcome 05 Apr 2016

Our aim is to understand how the uterine immune system regulates placentation and reproductive success in humans. We described a new mechanism of maternal allogeneic recognition that depends on KIR expressed by uterine NK (uNK) cells and their ligands, HLA-C, on fetal trophoblast. KIR and HLA-C genes are highly polymorphic and we find reproducible and specific KIR/HLA-C genetic combinations associated with reproductive disorders. We will: 1) use high throughput typing to allele level of KIR and HLA-C genes to describe how this variation affects pregnancy success. 2) translate these genetic findings into how NK cells affect trophoblast functions exploiting our new techniques, mass cytometry and long term trophoblast cell culture. 3) use transgenic mouse models to mimic the KIR/HLA-C combinations with poor outcome to study placentation in vivo and to test therapeutic anti-KIR mAbs. From a translational perspective we will: 4) investigate whether disorders such as pre-eclampsia that are common in women undergoing assisted reproductive technology with oocyte or sperm donation can be prevented by genotyping donors for KIR/HLA-C and 5) use the extraordinary variability of KIR genes in sub-Saharan Africa to study differences that can explain the increased frequency of pregnancy disorders in African women.

Amount: £2,140,661
Funder: The Wellcome Trust
Recipient: University of Cambridge