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Award Year:
2016
Recipients:
University of Cambridge

Results

A new biology of clinical outcome in immune-mediated disease 05 Apr 2016

Western medicine has developed by classifying disease into defined diagnostic categories. It is disease course after diagnosis, however, that determines a patient’s outcome, and the factors driving this variable prognosis have been largely ignored. We have focused on uncovering the biology underlying clinical outcome in immune-mediated disease. We have identified two CD8 T-cell transcription signatures that are associated with outcome but not diagnosis in four important immune-mediated diseases (Nat Med 2010, JCI 2011), and found that the signature associated with poor outcome is characterized by CD8 T cell "exhaustion" (Nature 2015). Genetic studies confirmed that pathways underlying prognosis are distinct from those underlying disease susceptibility (Cell 2013). We will explore this "biology of prognosis". Our goals are to: 1) understand the biological basis of the CD8 T-cell transcription signature that determines prognosis. This will use in vitro and human in vivo studies, alongside genetic and epigenetic analyses informing our understanding of the mechanisms of prognosis in immune-mediated disease, and allowing the refinement of biomarkers now entering the clinic. 2) develop approaches to modulate CD8 T-cell exhaustion to treat disease, by re-purposing existing drugs, defining their mechanisms of action, and testing key candidates drugs in vitro and in animal models.

Amount: £1,528,893
Funder: The Wellcome Trust
Recipient: University of Cambridge

Repurposing AMPAkines for enhancing myelin regeneration in multiple sclerosis 01 Sep 2016

Multiple sclerosis (MS) affects around 2.5 million worldwide, and there are no fully effective treatments currently available. Myelin regeneration can occur spontaneously in demyelinating diseases such as MS, and is essential for functional recovery. However, it often fails, leading to sustained clinical disability. Thus, promoting myelin regeneration is an important therapeutic aim. The recent research of Dr Káradóttir and colleagues has revealed an important regulatory mechanism of how the brain can repair itself. The team identified novel communication between stem cells, which are capable of repairing myelin damage, and nerve fibres that have lost myelin (as occurs in MS). When we deliver a drug that increases the ‘sensitivity’ of the stem cells to these signals from nerve fibres, we augment the capability of the stem cells to repair myelin damage. The aim of this pathfinder award is to further validate this as a therapeutic strategy and provide clear proof of concept evidence for the use of drugs that augment the stem cells sensitivity to electrical signals from nerve fibres, to promote myelin regeneration in MS. The future impact of identifying a pharmacological agent that is effective in augmenting myelin regeneration is immense; potentially revolutionising treatments for a number of white matter diseases in addition to MS.

Amount: £130,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Stem Cell Biology and Medicine 30 Sep 2016

Not available

Amount: £133,023
Funder: The Wellcome Trust
Recipient: University of Cambridge

University of Cambridge - Metabolic and Cardiovascular Disease 30 Sep 2016

University of Cambridge - Metabolic and Cardiovascular Disease

Amount: £133,023
Funder: The Wellcome Trust
Recipient: University of Cambridge

Stem Cell Biology and Medicine 30 Sep 2016

Not available

Amount: £133,023
Funder: The Wellcome Trust
Recipient: University of Cambridge

University of Cambridge - Developmental Mechanisms 30 Sep 2016

University of Cambridge 4 year PhD Programme - Developmental Mechanisms

Amount: £133,023
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the endocrine and paracrine roles of the imprinted Igf2 gene in growth, development and metabolism 30 Sep 2016

Insulin-like growth factor 2 is major regulator of growth in mammals. It is produced at high levels inside cells and rapidly secreted into the extracellular milieu and circulatory system, thus acting as paracrine and endocrine signals for cellular proliferation, organ and whole body growth. The mechanisms which govern these multiple actions are poorly understood. We recently found that the pancreatic connective tissue (or mesenchyme) is a reservoir of Igf2 that regulates both exocrine and endocrine growth during early development. The major goals of my project are to elucidate how mesenchymal Igf2 promotes growth of the whole pancreas and to contribute to our understanding of Igf2 as an endocrine signal. Specifically, I will test the hypotheses that Igf2 binding to Igf1r in pancreatic mesenchyme is required for paracrine growth signalling, and that fetal mesenchyme is a major source of circulating Igf2. My project takes advantage of precision genetics facilitated by access to unique conditional mouse models of loss and gain of function for Igf2, allied to cell-type specific transcriptomic analysis and whole-body physiologicalphenotyping. Investigations into cross-talk mechanisms between cell types that drive systemic growth are likely to provide novel insights about growth regulatory pathways and metabolic diseases such as diabetes.

Amount: £43,786
Funder: The Wellcome Trust
Recipient: University of Cambridge

Engaging the public in health services research 15 Sep 2016

Engaging the public in health services research Engaging the public in health services research

Amount: £100,000
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 complete synaptic-level connectome of a nervous system and experimental connectomics 30 Nov 2016

Animals sense the local environment, learn and remember past events, predict future ones, and combine current and past information to choose appropriate motor responses. Underlying these capabilities is the nervous system, which continuously integrates multiple sources of information and chooses one response in exclusion to all others. Our vision is to study neural circuit function on the basis of known synaptic-level wiring diagrams. In Aim #1, we propose to map the complete wiring diagram of an insect, the Drosophila larval central nervous system, using serial electron microscopy. With the knowledge of the circuits formed by the identified and genetically accessible larval neurons we can study how circuits change either by experience or in disease. In Aim #2 we propose to read out the engrams, the persistent yet reversible structural circuit patterns that form in response to learning and that underlie long-term memories, using associative memory in the larval mushroom bodies as the model system. For circuits to assemble correctly while remaining plastic, hundreds of genes need to work in concert. In Aim #3, we will study the effects of mutations in select genes associated with neural diseases on the synaptic-level circuit structure, causing the disease phenotype.

Amount: £1,763,361
Funder: The Wellcome Trust
Recipient: University of Cambridge

Genetics and causality: towards more accessible and more reliable Mendelian randomization investigations 26 Oct 2016

I propose to advance methods for Mendelian randomization to make investigations more reliable and more accessible, and to build a team to develop and apply these state-of-the-art methods. I will continue with the development of robust methods that give consistent estimates even when the stringent instrumental variable assumptions are not fully satisfied, and compare how these methods perform with real data. I will extend existing methods, considering estimates of non-linear causal relationships, and approaches for variable selection with heterogeneous genetic variants in different gene regions, and with highly-correlated variants from the same gene region. I will develop novel approaches for using covariate matching and matching by design (such as the analysis of sibling pairs). I will disseminate these methods in explanatory papers aimed at applied researches, and in a software package. I will partner with leading epidemiological and clinical researchers to apply these methods to scientific questions of interest, and feedback difficulties from these analyses into further methods development. I will develop pipelines for the prioritization of biomarkers as targets for pharmaceutical or clinical intervention from high-dimensional datasets, where thousands of candidate risk factors have been measured and detailed analysis of each risk factor in turn is impractical.

Amount: £724,155
Funder: The Wellcome Trust
Recipient: University of Cambridge

Immune-regulatory functions of Group 2 Innate Lymphoid cells in cancer 26 Oct 2016

Anti-tumour 'type-1' immunity is driven by NK cells and cytotoxic CD8 T cells, while T helper type-2 (Th2) cells are associated with a pro-tumourigenic phenotype. Group 2 innate lymphoid cells (ILC2) are the innate counterpart of Th2 cells, and are locally activated by epithelial derived alarmins. While recognised as central orchestrators of 'type-2' inflammation in allergies, there is no evidence for their importance in shaping a pro-tumourigenic environment, despite the known roles of alarmins in tumourigenesis. My preliminary data reports the presence and profound enrichment of ILC2 in pancreatic intraepithelial neoplasias (PanIN) as they progress to pancreatic ductal adenocarinoma in P48-Cre LSL-KrasG12D (KC) mice. I will resolve the role of ILC2 in pancreatic carcinogenesis using an orthotopic implantation model in conjunction with next-generation ILC2-targeted reagents and intravital imaging. Secondly, I present preliminary data that suggests a negative-feedback mechanism by which lung ILC2 dampen the anti-tumour immune function of NK cells. I will use exclusive ILC2-targeted reagents to resolve this mechanism, and its effect on lung metastasis formation. As tissue resident immune-modulators, ILC2 may provide a critical new target in cancer therapy.

Amount: £1,316,243
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge Stem Cell Institute 30 Oct 2016

Stem and progenitor cells are essential for the maintenance of metazoan tissues. Their dysfunction underlies diverse human diseases and their manipulation provides enormous therapeutic possibilities. The Cambridge Stem Cell Institute (CSCI) is a world-leading centre for stem cell research. Its mission is to transform the prevention, diagnosis and treatment of disease through a deep understanding of the mechanisms regulating stem and progenitor cells, both normal and pathological. In 2018 CSCI investigators will come together in a new purpose-built building on the Cambridge Biomedical Campus adjacent to Addenbrookes Hospital. A key strategy is to embed biological, clinical and physical scientists operating across disparate tissues and at multiple scales, thus allowing commonalities and differences to be explored in an cohesive and inter-disciplinary manner. A network of affiliated PIs will provide bridges to basic and disease-focused institutes throughout Cambridge and will ensure that CSCI represents the heart of a vibrant stem cell community. Importantly a critical mass of clinician scientists will create synergistic interactions between basic scientists and those driven by disease-focused questions, thus ensuring that CSCI is fully integrated with its clinical environment and empowered to pursue its translational goals.

Amount: £9,793,833
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating WASp-Cdc42 interaction 01 Apr 2016

Rho proteins are involved in many cellular processes. Classically, Rho proteins such as Cdc42 are involved in activating proteins that regulate the actin cytoskeleton. Deregulated Rho proteins have been implicated in tumourigenesis, invasion and metastasis of many cancers types. Cdc42 binds its effector WASp with a tight Kd, therefore peptides that mimic the ability of WASp to bind Cdc42 could be the basis for a new generation of potential anti-cancer agents. The aim of the project is to use site-directed mutagenesis to mutagenise the unstructured Cdc42 binding region of the WASp protein and quantify the binding of each mutant WASp to Cdc42. The mutant proteins will be expressed and purified in E.coli as GST-fusion proteins. Mutants will be assayed for their dissociation constant using a scintillation proximity assay. This will identify key residues that contribute to the high affinity binding of WASp and Cdc42. The wider aim of this research is to gather the data needed as a starting point for the generation of therapeutic Cdc42 binding peptides using a biased peptide library-based selection and screening experiment.

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

Ear Pieces: Listening, Diagnosing, Writing - 1815-2015 31 Jan 2016

Ear Pieces is a collaborative venture, and its purpose is to identify the changing forms and effects of listening in the period 1815-2015. Building on research in the field of sound studies, and drawing on archival resources in the UK and the US, it will be the first project of its kind to assess the mutual legibility of medical and literary records, and so to kindle a dialogue between specialists from the humanities, neuroscience, and clinical medicine. One aim of Ear Pieces is to document the definitional contours of harmful listening in the last 200 years, from colloquial strains of otitis – ‘glue ear’ and ‘swimmer’s ear’ – to peripheral kinds of hearing loss, impairment and excess, such as otosis, sound-blindness, melomania, and Involuntary Musical Imagery. How have such complaints been understood historically? Whose vocabulary are we drawing on when we speak of neurotological trauma? In bringing historians, musicologists, neuroscientists, and literary scholars together – in a series of seminars, a conference, and an essay collection – the aim is to excavate the parallel histories of otology and literature, to evaluate their intersections and points of resistance, and to gauge their present affinities, in public policy and the popular imagination.

Amount: £5,400
Funder: The Wellcome Trust
Recipient: University of Cambridge

Circuit principles of memory-based behavioral choice 30 Nov 2016

We aim to elucidate the circuit mechanisms underlying three key computations essential for memory-based behavioral choice: 1) updating valences attached to sensory cues, when actual and expected outcomes differ; 2) computing the “value” for each action, based on multiple, conflicting cues; and 3) selecting one action and suppressing other physically incompatible competing actions. One obstacle to progress in this field has been the problem of identifying underlying circuits with synaptic resolution, and causally relating structural motifs to their proposed function. Both insects and vertebrates have evolved cerebellar-like higher-order parallel-fiber systems specialized in forming large numbers of associative memories and in guiding memory-behavioral choice. However, no synapse-resolution wiring diagram of any such system has been available to guide analysis and inspire understanding.    We have recently mapped the synaptic-resolution wiring diagram of one such system, the insect mushroom body, in Drosophila larva, which reveals multiple novel circuit motifs and provides clues about learning and decision-making models and their neuronal implementation. An exquisite genetic toolkit available in this model system allows selective manipulation of individual neuron types to establish causal relationships between their activity and behavior. We are now in a unique position to causally relate the identified structural motifs to their function.

Amount: £1,737,376
Funder: The Wellcome Trust
Recipient: University of Cambridge

Characterization of the human extra-embryonic macrophage population, Hofbauer cells, phenotype and function 26 Oct 2016

Macrophages are among the first immune cells to seed embryonic tissues. They play important roles in early fetal development including tissue modeling and maintaining healthy tissue homeostasis. In humans, macrophages are present in the villous core of the placenta before a vascular connection with the embryo and these extra-embryonic macrophages, termed Hofbauer cells (HBC) are readily available for study. Developing our understanding of HBC and the role they play throughout gestation is important as they lie at the interface between the mother and fetus. HBC are likely to regulate placenta development, in particular the trophoblast cells that are the ultimate barrier between mother and fetus. HBC are also an important fetal defense against transplacental infections and in utero fetal infections are associated with pathogens that can survive in macrophages. However, the functions of HBC are poorly understood. Through this proposal, using some of the most advanced tools available today including multi-parameter flow cytometry, mass cytometry, RNA sequencing and organoid cultures, I will provide the first in-depth characterization of the human placenta extra-embryonic macrophages, HBC. I aim to describe the phenotype of HBC, their transcriptomic profile and functional properties. Keywords: Human extra-embryonic macrophages, Hofbauer cells, placenta, vertical-transmission, fetus, immunity.

Amount: £1,066,164
Funder: The Wellcome Trust
Recipient: University of Cambridge