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Recipients:
University of Cambridge
Award Year:
2016

Results

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

<p>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.</p>

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

What determines the switch from glycolytic to oxidative metabolism in the developing germ line? 08 Jun 2016

<table> <tbody> <tr> <td>Mitochondrial&nbsp;disorders affect ~1 in 5000 of the population and cause progressive, incurable diseases which often result in premature death. The primary genetic &nbsp; defect affects either nuclear DNA or mitochondrial DNA (mtDNA), and &nbsp; ultimately leads to a biochemical defect of ATP synthesis. However, despite having the same basic biochemical basis, mitochondrial disorders have an enormously variable clinical presentation and disease course. I will test the &nbsp; hypothesis that nuclear and mitochondrial ge netic factors modulate the &nbsp; clinical expression of mitochondrial disorders, thus explaining the variable &nbsp; phenotype. Specifically, I will: (i) Define the sub-cellular mechanism &nbsp; responsible for the mtDNA genetic bottleneck during female germ cell &nbsp; development in a germ-line model in vitro, and validate these findings in &nbsp; vivo in both mice and humans, leading to the identification of compounds &nbsp; which influence transmission. (ii) Comprehensively characterise the nuclear &nbsp; gene defects in a natio nal cohort of patients with Mendelian mitochondrial &nbsp; disorders using whole-exome and restricted whole-genome sequencing. This will &nbsp; identify new mitochondrial disease genes that will undergo functional &nbsp; validation using tissue-specific cell lines differentiated from &nbsp; patient-derived induced pluripotent stem cells (iPSCs). (iii) Use &nbsp; state-of-the-art genomics to identify nuclear genetic factors that modulate &nbsp; the phenotype of the primary mitochondrial DNA disease, Leber hereditary &nbsp; optic neuropathy.&nbsp; Studying the &nbsp; functional consequences of the disrupted nuclear genes in tissue-specific &nbsp; lineages differentiated from patient-derived iPSCs will provide the first &nbsp; insight into the tissue-specificity of mitochondrial disorders.&nbsp; These three areas are inter-related in &nbsp; patients with mitochondrial diseases. By characterising the mechanisms, I aim &nbsp; to identify novel approaches to prevention and treatment.</td> </tr> </tbody> </table>

Amount: £197,877
Funder: The Wellcome Trust
Recipient: University of Cambridge

Circadian rhythms in the bacterium Escherichia coli 08 Apr 2016

<table> <tbody> <tr> <td>My&nbsp;laboratory investigates the molecular mechanisms that control the 24 hour (circadian) clock. This fundamental process is integral to the function of&nbsp;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&nbsp;oscillations in mammalian cells contribute significantly to a cell's rhythmic&nbsp;properties. A Senior Fellowship would allow me to examine how the clockwork&nbsp;functions in 'real-time', using a variety&nbsp; of novel tools that we are developing to do this. We will also perturb &nbsp; redox pathways (that normally get rid of harmful oxidants produced because of&nbsp;respiration) and investigate the effect of this on the clockwork using these&nbsp;tools. A final goal will be to integrate redox oscillations with existing&nbsp;components of the clockwork, which rely on the process of gene transcription &nbsp; to work. The goal is therefore to fully characterise the mechanism of how a cell keeps time, particularly with respect&nbsp;&nbsp;to redox metabolism, which is a new and exciting area of study within&nbsp;&nbsp;the field.</td> </tr> </tbody> </table>

Amount: £182,839
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

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

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

Engaging the public in health services research 15 Sep 2016

<p><span style="line-height: 16.2px; background-color: #e7e7e7;">Engaging the public in health services research</span></p> <table> <tbody> <tr> <td><span>Engaging the public in health services research</span></td> </tr> </tbody> </table>

Amount: £100,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Mechanisms of endogenous analgesia. 30 Sep 2016

The programme will address how two distinct mechanisms of endogenous analgesia control activity in the brainstem periaqueductal grey. I aim to provide an account in computational terms, in order to specify the precise decision algorithms (rules) by which they operate. First I address the mechanism by which predictions reduce pain, by exploring precisely what information within a prediction controls pain perception. Specifically, I will test Bayesian models against competing accounts. Brain i maging will be used to determine how this is implemented in forebrain structures, and if/how they modulate activity in the periaqueductal grey. Second, I address the mechanism by which escape under threat reduces pain. Here I propose a theoretical analysis of controllability in escape/avoidance learning, building on my existing Reinforcement Learning framework. I will implement evolutionary simulations designed to show whether pain modulation emerges as an intrinsic reward to guide escape. On the basis of this, I will test model predictions (behaviourally) and their implementation (using fMRI), using an active versus passive escape learning paradigm. Finally, I will use deep brain stimulation to provide convergent evidence of how these mechanisms depend on the periaqueductal grey, looking for a statistical interaction between stimulation and endogenous analgesia.

Amount: £175,527
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

<p>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&nbsp;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&nbsp;advanced microscope capable of&nbsp;high resolution structure determination to complement and extend our existing instrumentations.</p>

Amount: £3,000,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

<p>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.&nbsp;</p> <p>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 (PI3K&delta;), and that inhibition PI3K&delta; will be protective via the following mechanisms.</p> <p>1)&nbsp;&nbsp;&nbsp; Influenza-induced expansion of immunosuppressive regulatory T-cells (T<sub>reg</sub>) which depend on PI3K&delta; for suppressive functioning</p> <p>2)&nbsp;&nbsp;&nbsp; Viral and T<sub>reg</sub> mediated suppression of neutrophil function</p> <p>3)&nbsp;&nbsp;&nbsp; A change in the lung microbiome as a result of the effects 1 and 2, leading to established infection by <em>Streptococcus pneumoniae</em>.</p> <p>&nbsp;</p> <p>The goals are:</p> <p>1) To determin whether PI3K&delta;-null animals are resistant to secondary streptococcal pneumonia.</p> <p>2) To use tools including T<sub>reg</sub> depleted animals, conditional knockout animals and small molecule PI3K&delta; inhibitors to explore mechanisms of resistance.</p> <p>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.</p> <p>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.&nbsp;</p>

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

Adaptive decision templates in the human brain 30 Nov 2016

<p>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&rsquo;s capacity for adaptive and resilient behaviour with implications for promoting lifelong learning.</p>

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

<p>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 <em>Drosophila</em> 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.</p>

Amount: £1,763,361
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

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

<p>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 <em>after</em> 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.&nbsp;</p>

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

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

<p>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.</p>

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

<p>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.</p>

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

<p>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.</p> <p>HBC are likely to regulate placenta development, in particular the trophoblast cells that are the ultimate barrier between mother and fetus.&nbsp; HBC are also an important fetal defense against transplacental infections and <em>in utero</em> 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.</p> <p>Keywords: Human extra-embryonic macrophages, Hofbauer cells, placenta, vertical-transmission, fetus, immunity.</p>

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

University of Cambridge PhD Programme for Clinicians 30 Nov 2016

<p>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.</p>

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

Cambridge Stem Cell Institute 30 Oct 2016

<p><strong>&nbsp;</strong>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.</p> <p>&nbsp;</p> <p>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.</p>

Amount: £12,516,309
Funder: The Wellcome Trust
Recipient: University of Cambridge