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Recipients:
University of Cambridge
Award Year:
2016

Results

Regulatory T cell-neutrophil interaction in the development and maintenance of secondary pneumonia 06 Dec 2016

Secondary pneumonia following influenza infection is common, with considerable associated morbidity and mortality. Strikingly, secondary infections tend to arise from bacteria which live otherwise asymptomatically in the oropharynx. Based on existing data, I hypothesise that the development of secondary streptococcal pneumonia is dependent on a key immune-cell molecular pathway, namely Phosphoinsitol-3-Kinase delta (PI3Kdelta), and that inhibition PI3Kdelta will be protective via the following mechanisms. 1) Influenza-induced expansion of immunosuppressive regulatory T-cells (Treg) which depend on PI3Kdelta for suppressive functioning 2) Viral and Treg mediated suppression of neutrophil function 3) A change in the lung microbiome as a result of the effects 1 and 2, leading to established infection by Streptococcus pneumoniae. The goals are: 1) To determin whether PI3Kdelta-null animals are resistant to secondary streptococcal pneumonia. 2) To use tools including Treg depleted animals, conditional knockout animals and small molecule PI3Kdelta inhibitors to explore mechanisms of resistance. 3) To develop a more clinically relevant murine model secondary pneumonia, using a streptococcal colonisation model which when exposed to influenza will develop secondary pneumonia. 4) To characterise the respiratory microbiome of animals at various stages will be characterised, looking for factors that may facilitate or militate against development of secondary pneumonia.

Amount: £516,560
Funder: The Wellcome Trust
Recipient: University of Cambridge

Obesity: Exploiting Genomes for Novel Insights 06 Dec 2016

What are the mechanisms by which genes influence an individuals propensity to obesity. I study animal models to find answers to that question. I will study the link between genes and obesity in two complementary research streams. Firstly, I will build on my recent discovery of an obesity-associated POMC mutation in animal models which disrupts hypothalamic leptin-melanocortin signalling. Deep phenotyping of eating behaviour and physiology in the absence and presence of a synthetic MC4R agonist with the goal of defining the contribution of POMC-derived peptides to energy homeostasis. Secondly, I will use genome-wide association studies in animals to find further genetic determinants of obesity. Their relevance to humans will be tested in large patient cohorts with both rare, severe obesity and common obesity, and putative obesity loci studied in relevant cell models. Preliminary data has shown this approach is successful.

Amount: £415,141
Funder: The Wellcome Trust
Recipient: University of Cambridge

An advanced cryoEM instrument for the University of Cambridge 07 Dec 2016

We seek support to consolidate an advanced electron cryo-microscopy (cryo-EM) facility dedicated to structural studies of biological macromolecular assemblies. The facility would provide a revolutionary new tool to the large structural biology community in the University that would enable acquisition of critical data in support of a wide and diverse range of projects tackling fundamental problems in molecular biology relevant to human health. Currently, the named applicants primarily use X-ray crystallography to study large assemblies, but many of these samples cannot be readily crystallised. The recent development of a new generation of direct electron detectors, together with sophisticated data-processing software, has dramatically improved cryo-EM analysis, which now achieves routinely sub-nanometer resolution. Until recently, researchers in the university did not have access to cryoEM, but this has changed with the recent Wellcome Trust award to purchase a cryo-EM instrument for sample screening and intermediate resolution structure determination. We are building on this support, to develop the second phase of our strategy and seek funding for an advanced microscope capable of high resolution structure determination to complement and extend our existing instrumentations.

Amount: £3,000,000
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 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

Computational tools for analysing developmental morphogenesis at the tissue-scale 05 Dec 2016

Computational tools for analysing developmental morphogenesis at the tissue-scale

Amount: £47,159
Funder: The Wellcome Trust
Recipient: University of Cambridge

Adaptive decision templates in the human brain 30 Nov 2016

Interacting with the surrounding environment depends on our ability to extract meaningful patterns from incoming streams of sensory information. Learning and experience are known to facilitate this skill; yet, we know little about how the brain extracts structure and generalises this knowledge to novel settings. Here, I propose to test the brain mechanisms underlying structure learning using contrasting tasks that involve learning structure in space vs. time at different levels of complexity (simple vs. complex feature contingencies). I will use computational modelling to interrogate the processes involved in learning behaviourally-relevant structures (i.e. decision templates). I will relate this system-level insight to multimodal neuroimaging to provide converging evidence for brain mechanisms that mediate learning specialisation and generalisation. I will exploit high-field imaging to test fine-scale decision templates in the visual cortex. I will combine 7T imaging with human electrophysiology (MEG/EEG) and interventions (TMS) to test for local and larger-scale brain circuits that retune decision templates through feedback and inhibitory interactions. Finally, I will test whether these mechanisms support our ability to generalise previous experience to novel contexts and tasks. This integrated approach will advance our understanding of the brain’s capacity for adaptive and resilient behaviour with implications for promoting lifelong learning.

Amount: £1,344,200
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

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

University of Cambridge PhD Programme for Clinicians 30 Nov 2016

This programme recruits clinicians of outstanding calibre nationwide. With the largest concentration of biomedical science in Europe in laboratories on the Campus or wider Cambridge, we offer research training of highest quality that spans the spectrum from basic science through experimental medicine to epidemiology and public health. Strong, ongoing, mentorship is central to our programme; this, coupled with carefully chosen placements in laboratories empowers fellows to make better-informed choices of research and supervisor, including interdisciplinary projects. During PhD training, we aim to maximise their potential to acquire research skills and achieve a doctorate linked to significant discoveries and publications. With continued, intensive, guidance postdoctorally via established mechanisms, we guide fellows into pathways (e.g. higher research fellowships, clinical lecturer posts) that are tailored to individual progress, balancing re-entry into clinical training with maintaining research momentum. Our vision is to strengthen and broaden this model to include fellowships at veterinary and MBPhD level; and, in partnership with the University of East Anglia, extend opportunities to trainees throughout the region and add research diversity with a new theme in Gastroenterology, Nutrition and Microbiology. The longterm aim of the programme is to produce the next generation of clinical academics.

Amount: £6,397,500
Funder: The Wellcome Trust
Recipient: University of Cambridge

Neuronal reward mechanisms 30 Nov 2016

We investigate neuronal reward and economic decision signals in behavioural tasks with designs from learning and economic decision theories, supplemented by selected, closely related neuroimaging experiments. We study the main components of the brain's reward system, including dopamine neurons (reward prediction error), orbitofrontal cortex (economic decision variables), striatum (so far insufficiently characterised reward signals) and amygdala (short- and long-term rewards). We search for reward and decision signals that provide explanations and hardware implementations for the constructs of reward and economic theories. We need to know these fundamental neuronal signals before focussing on cellular and molecular mechanisms, which differs from work on sensory and motor systems whose signals are better characterised.  We state three aims:  Aim 1: We characterise neuronal processing of skewness-risk, arguably the most frequent risk form.  Aim 2: We identify neuronal signals for utility and test formal axioms for utility maximisation, which is supposedly the goal of 'rational' agents. Utility is THE basic economic decision variable that explains most economic choices.  Aim 3: We assess neuronal representations of preferences, and bridge the gap between biologically necessary rewards and tradable economic goods, by testing basic assumptions of revealed preference theory.

Amount: £4,413,529
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

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

From habits to compulsions: the role of glutamate and serotonin in Obsessive-Compulsive Disorder 09 Nov 2016

This proposal aims to characterize the neural basis of compulsion development. This requires neurobehavioural investigation of the hypothetical transition between habits and compulsions. To achieve this, I will invent a new behavioural paradigm capable of assessing not only habit formation but also habit perseveration. Three specific aims are defined. Firstly, I will characterize the behavioural mechanisms through which both healthy humans and patients with Obsessive-Compulsive Disorder (OCD) arbitrate between intentional and automatic actions after habits have been established by measuring post-training human preferences for habitual versus goal-seeking actions. I will compare the influence of both appetitive and aversive instrumental learning in the shift between purposeful and automatic actions between groups. Secondly, using functional Magnetic Resonance Imaging (fMRI), I will characterise the neural mechanisms underlying the transition from habits to compulsions, by disentangling the neural contributions of the goal-directed and habit systems in their interaction to control behaviour. I will test whether perseveration results from impairment in the goal-directed system, or hyperactive habit circuitry, or perhaps both. Finally, I will use Magnetic Resonance Spectroscopy (MRS) and Positron emission tomography (PET) to measure dynamic changes in glutamate, GABA and serotonin availability to further elucidate the neurochemical abnormalities which may underlie OCD.

Amount: £250,000
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

Gurdon Institute Centre Renewal 30 Oct 2016

The Gurdon Institute focuses on several related topics at the interface between developmental biology and cancer: Cell division, proliferation and genome maintenance; Function and regulation of the genome and epigenome; Mechanisms of cell fate determination, multipotency and plasticity; The cell biology of organ development and function. We investigate these areas in both normal development and cancer using several model systems, with an increasing emphasis on organoids. Our five-year vision is to expand our research in two strategic directions: Human development and disease We will study the development and homeostasis of tissues and organs using human organoid systems. We will also develop new models of human diseases, including cancer, using organoids and patient-derived stem cells. Quantitative analysis of cellular dynamics We will analyse developmental and disease processes quantitatively at the molecular, cellular and tissue scales, using next generation sequencing and imaging approaches. We will also increase our collaborations with physical scientists expert in analysing the complex datasets generated by these approaches. We plan to continue to translate our research into new therapies. This will be enhanced by the establishment of the Milner Institute, which will provide a platform for collaborations with pharmaceutical companies on disease models emerging from our research.

Amount: £13,247,091
Funder: The Wellcome Trust
Recipient: University of Cambridge

After the plague: health and history in medieval Cambridge 26 Jan 2016

This collaborative project explores the historical effects of major health events such as epidemics. It combines multiple methods (archaeology, history, osteoarchaeology, isotopic and genetic studies of both human and pathogen aDNA) to study the people of medieval Cambridge. It uses the recently excavated large sample of urban poor people from the Hospital of St. John (AD 1200-1500), complemented by comparative samples from other medieval social contexts and other historical periods. The results will be analysed both statistically and biographically. A proximate goal is to build a nuanced picture of health, lifestyle and activity in medieval England, one grounded in direct examination of human bodies themselves. The overall goal, however, is to understand the biosocial effects of the Black Death of 1348-1350, an epidemic of bubonic plague which decimated Europe. By comparing samples from before and after the epidemic for a wide range of social and biological indicators, this research will reveal how the plague changed human well-being, activity, mobility, health and the genetic constitution of Europe.

Amount: £1,263,262
Funder: The Wellcome Trust
Recipient: University of Cambridge

Determination of the prevalence breast cancer predisposition genes in South East Asian women and development of an Asian polygenic risk assessment tool 05 Jul 2016

Breast cancer is rising rapidly in Asia and is the most common cause of cancer related deaths in Malaysia. Notably, whereas 80% of breast cancer in the UK occurs in post-menopausal women, only 40% occurs in post-menopausal women in Malaysia, and the proportion of risk attributable to genetic factors is likely to be correspondingly higher. In the absence of population-based screening, targeted screening provides a cost-effective alternative to reducing breast cancer mortality. Unfortunately, there remains a significant gap in knowledge and access to counseling and testing of BRCA1, BRCA2 and other cancer predisposition genes in most of Asia. With the decreasing cost of genetic testing, there is an opportunity to bridge that gap. We plan to: (1) characterise the prevalence of genetic susceptibility to breast cancer in the South East Asian population in Malaysia and Singapore; (2) provide risk estimates for BRCA1 and BRCA2 in our population; and (3) calibrate risk assessment models to accurately predict an individual’s risk of carrying germline alterations and their risk of cancer. The findings of this research will enable shared decision making and inform the development of appropriate management to ensure that healthcare resources can be used efficiently for targeted screening and prevention.

Amount: £555,752
Funder: The Wellcome Trust
Recipient: University of Cambridge

A Cluster for the Development of Dynamic 3D Nanoscopy 05 Jul 2016

Imagine if we could watch multiple molecules in living cells as they move and interact. This dream may seem years away, but it is now realistic to achieve real-time dynamic super-resolution imaging of multiple tagged proteins in three dimensions (3D) in cells and in tissues. This will allow biologists to discover large-scale patterns involving diverse structures including transport vesicles, ribosomes, and chromatin domains, all previously inaccessible because they lie in the gap between the resolution of electron (1- 2 nm) and light microscopy (200-300 nm). The "big picture" of cellular organization/information processing would emerge, with advances in understanding cell function in health and disease. While we can now do this in 2D, 3D imaging is needed to follow objects as they move out of the plane. Achieving 3D imaging is a major challenge and will require two orders of magnitude more information per cellular volume, and novel algorithms to classify, analyze, and visualize patterns from massive datasets. We propose specific innovations (Table 1) that, should allow us to achieve this over the next five years, given our team’s proven track record of success.

Amount: £660,923
Funder: The Wellcome Trust
Recipient: University of Cambridge