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Current Filters

Recipients:
Broadfield Primary School
University of Cambridge
Amounts:
£500 - £1,000
£1,000,000 - £10,000,000
Award Year:
2017

Results

Disentangling the Myc:Max:Mad network 27 Apr 2017

<p>Myc is a transcription factor that is dysregulated and often elevated, in most tumours. However, the proteins reside in an interwoven network of effectors and shared heterodimeric partners which has been suggested to be essential for some, perhaps most of Myc functions. The goal of the project is to investigate this by separating the functions of the Myc:Max heterodimer from the rest of the network, by making use of the fact that both dimerization and specificity of network components is determined by their individual bHLH-Leucine Zipper dimerization domains. Therefore reciprocal specificity variants of Myc and Max based on the heterodimerizing HLHZip domains of the <em>S. cerevisiae </em>RTG1 and RTG3 transcription factors will be used. These domains are different to the mammalian domains so the proteins are unlikely to interfere with other mammalian HLHZip proteins, but likely to still carry out Myc:Max functions. Interactions and functions of MycRTG and MaxRTG in cultured cells, and the ability of the MycRTG/MaxRTG heterodimer to rescue cells lacking wild type Myc will be determined, with assays at the cellular level (e.g. rescue of Myc-dependent cell proliferation) and at the molecular level (ability of MycRTG/MaxRTG to bind E-box containing sequences and regulate Myc/Max transcriptional targets).</p>

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

Behaviour Change by Design: Generating and Implementing Evidence to Improve Health for All 11 Jul 2017

<p>Reducing food, alcohol and tobacco consumption would dramatically reduce non-communicable disease and, since these behaviours cluster by deprivation, would also reduce health inequalities.&nbsp; However, progress in achieving such behaviour change is slow.</p> <p>&nbsp;</p> <p>Traditional approaches to behaviour change involve providing information with, at best, modest population-level effects and sometimes increased inequalities.&nbsp;Conversely, <em>Choice Architecture</em>&nbsp;interventions (&ldquo;<em>Nudges&rdquo;</em>) have potentially larger, more equitable effects, involving re-designing environments&nbsp;<em>e.g.</em>&nbsp;reducing plate size to reduce food consumption. However, evidence of effectiveness in real-world settings and understanding of mechanisms are limited.</p> <p>&nbsp;</p> <p>We will bridge this knowledge gap through a novel collaboration between behavioural and cognitive sciences. In the most ambitious co-ordinated set of studies to date, we propose field studies to estimate effect sizes of promising <em>Choice Architecture</em> interventions to reduce food, alcohol and tobacco consumption. Enabled by unprecedented collaborations, these will be conducted in supermarkets, bars and cafeterias and interventions optimised through laboratory studies determining mechanisms.</p> <p>&nbsp;</p> <p>We will run international workshops, public engagement activities and a Behaviour Change Summit to facilitate implementing the evidence generated, overseen by an Implementation Advisory Panel. This will enable us to realise our vision of accelerating progress in changing behaviour by re-designing environments to improve health for all.</p>

Amount: £3,123,724
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding drug resistance in cancers with DNA repair mutations 30 Sep 2017

<p>The DNA damage response (DDR) is critical for maintaining genome stability. Cancer mutations have been identified in many genes linked to DNA repair, for example in ~20% of primary prostate cancers. Genes like BRCA1 are essential for mediating high-fidelity template-based Homologous Recombination (HR) repair of DNA double strand breaks (DSB). The absence of BRCA1 increases mutagenic repair and the risk of developing cancer, but also sensitises cells to treatments that generate DSBs, such as the DDR enzyme inhibitor olaparib.</p> <p>&nbsp;Cancer cells which are BRCA1-deficient can evolve drug-resistance by additional mutations which restore HR; for example, BRCA1<sup>-/-</sup> 53BP1<sup>-/-</sup> cells, which are olaparib resistant. Our aim is to identify genes which when &lsquo;inhibited&rsquo; re-sensitise for example BRCA1<sup>-/-</sup> 53BP1<sup>-/-</sup> cells, to olaparib, and in doing so gain additional mechanistic insights into HR regulation.&nbsp;</p> <p>&nbsp;This can be best achieved by conducting a CRISPR/cas9 genetic screen using a highly focused guide library containing 10 guides per gene, in order to reveal genes which are synthetically lethal with drug-resistant genotypes. By screening with guides which target protein kinases, we aim to establish druggable candidates which can be inhibited to extend the remit of pre-existing cancer therapies for HR-proficient cancers, as well as re-sensitise BRCA1-deficient cancers which have become treatment-resistant.&nbsp;</p>

Amount: £233,577
Funder: The Wellcome Trust
Recipient: University of Cambridge

Contextual determinants of surprise in health, development and disorder. 31 May 2017

<p>The goal of this research proposal is to build a theoretical and experimental framework to understand the contextual determinants of &ldquo;surprise&rdquo; (expectation violations/prediction errors) in health, development, and disorder. I have the following three aims:</p> <p><strong>1) &nbsp;</strong>To exploit high-field neuroimaging and pharmacological manipulations in healthy adults to reveal the precise neural mechanisms that alter surprise processing&nbsp;in response to volatility,&nbsp;and validate different pupil metrics as a window into central neuromodulatory function.</p> <p><strong>2) </strong>To conduct model-based neuroimaging in infants, for the first time, to predict risk for the dimensional symptoms of autism, and reveal the computational neurodevelopment of probabilistic and volatility learning in infants.</p> <p><strong>3) </strong>To develop a unified computational framework of surprise-driven learning that has the specificity to reveal separable mechanisms of psychopathology in different neuropsychiatric conditions and the potential to be used as a clinical tool.</p> <p>To achieve these objectives I will utilise the same cognitive tasks, pupillometric measurements and computational models of learning across three research themes. This ensures that while the individual projects are strongly hypothesis-driven the findings can be directly translated across developmental, adult, and disordered&nbsp;states.</p> <p><strong>Key words</strong>: autism, neurodevelopment, predictive coding, surprise, computational models, 7T fMRI, pharmacology, noradrenaline, psychosis.</p>

Amount: £983,275
Funder: The Wellcome Trust
Recipient: University of Cambridge

KRAB-ZFPs and the establishment of lineage- and species-specific gene regulatory networks 31 May 2017

<p>KRAB-ZFPs constitute a large yet neglected family of proteins with around 350 members in human and mouse. Collectively, they target transposable elements and until recently were thought to be mostly involved in their transcriptional repression in embryonic stem cells. During my post-doctoral work, I unveiled the binding sites of most (222) human KRAB-ZFPs, but the role played by the majority of them could not be fully explained by current theorems. Instead, we found that many target ancient transposable elements which often contain regulatory platforms; we also obtained correlative evidence that these could affect the expression of nearby genes. We hypothesize that evolutionary conserved KRAB-ZFPs can use their heterochromatin-inducing capabilities to modify accessibility of these transposable element-derived regulatory elements. We propose to functionally demonstrate this potential by using large scale enhancer screens in multiple cell types. Furthermore, we want to follow-up on these findings by genetic manipulations aimed at characterizing the biological processes affected by a few KRAB-ZFPs, including the generation of mouse models. Finally, we want to better understand the evolution dynamics of KRAB-ZFP binding sites and verify if they can lead to lineage- and species-specific rewiring of gene regulatory networks.</p>

Amount: £1,393,506
Funder: The Wellcome Trust
Recipient: University of Cambridge

Space distortions: Towards a general framework of the hippocampal cognitive map 31 May 2017

<p>A fundamental question in system neuroscience is where spatial cognition is generated and how it is used for navigation. Strong evidence points at the hippocampus as a cognitive map. Hippocampal place cells are active in restricted fields and hippocampal lesion impairs navigation. Recent experiments showed that spatial representations are also found in the entorhinal cortex, an interface between the hippocampus and neocortex. Entorhinal grid cells are active in many fields arranged in equilateral triangles. How these cells interact to provide a cognitive space remains elusive. It has been suggested that grid cells represent a spatial metric system and provide major inputs to the place cells. A number of recent experiments indicate a greater role of place cells in constructing grid cell pattern. Here, we propose to investigate how these cells interact and what role they play in navigation. We will test whether grid cells act as a spatial metric of the brain. Alternatively, we suggested that they could act as a matrix system conveying the information about the proximity of locations. Furthermore, we will study how single-cell perturbations affect interconnected grid-place cell network as well as an animal&rsquo;s ability to navigate.</p>

Amount: £1,377,847
Funder: The Wellcome Trust
Recipient: University of Cambridge

Schwann cell-axonal communication during axonal degeneration and regrowth 25 May 2017

<p>Myelinating and non-myelinating Schwann cells are reprogrammed after nerve injury into repair Schwann cells, specialized for maintaining survival of injured neurons and supporting axonal regeneration. This process is regulated by Schwann cell-intrinsic signals, such as the transcription factor c-Jun, however few other candidates have been identified. It is, currently, unknown how Schwann cell reprogramming is initiated, but unidentified extrinsic signals from injured axons are likely candidates.</p> <p>&nbsp;</p> <p>I aim to delineate the spatial and temporal regulation of Schwann cell-intrinsic downstream signals in real-time and define their role in repair Schwann cell function and axonal regeneration. Secondly, I aim to test the hypothesis that axon-derived signals initiate Schwann cell reprogramming during nerve injury. I will use cell culture<em>, in vivo</em> mouse models and a live and dynamic zebrafish larval model of nerve injury. This study will be the first to investigate how axon-intrinsic mechanisms of nervous system injury interplay with glial cell molecular responses to nerve damage, in real-time.</p> <p>&nbsp;</p> <p>Using cutting edge techniques in two species, this project will significantly advance our understanding of Schwann cell-axonal biology and tissue repair. Excitingly, this research may identify new potential therapeutic targets to improve poorly regenerating human nerves and treat patients with neuropathies.</p>

Amount: £426,876
Funder: The Wellcome Trust
Recipient: University of Cambridge

B cell dependent susceptibility to airway infection in Activated PI3K-delta syndrome 25 May 2017

<p>PI3K&delta; plays a critical role in development of the immune system. We have identified a cohort of patients with an immunodeficiency caused by gain of function mutations in PI3K&delta;, which we have named Activated PI3K&delta; syndrome (APDS). My fellowship proposal will determine how dysfunctional B cells contribute towards recurrent pneumonia associated with APDS.</p> <p>I have shown that aberrant PI3K&delta; signalling leads to significant defects in B cell development and function. I have found that hyper-activated PI3K signalling in B cells alone is responsible for increased susceptibility to <em>Streptococcus pneumoniae</em> in a mouse model. Surprisingly, this defect appears to be antibody independent. I have discovered a subpopulation of IL10 producing B cells that I believe represents a new type of B cell with immune-regulatory properties. I hypothesise that this B cell subset is contributing to the immunopathology secondary to pneumococcal infections in APDS, leading to bronchiectasis.</p> <p><strong>My aims are:</strong></p> <ol> <li>To characterise this newly discovered subset of B cells and explore the role of PI3K&delta; in their ontogeny.</li> <li>To determine whether IL10 is the innate cytokine that triggers antigen non-specific activation and immunopathology.</li> <li>To explore whether these pathogenic cells can be manipulated therapeutically using oral or inhaled PI3K&delta; inhibitors.</li> </ol>

Amount: £466,653
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of Eros in Innate and Adaptive Immunity 25 May 2017

<p>I will investigate the role of a novel protein, Eros, in immunity. I discovered the fundamental importance of this protein by demonstrating that Eros-deficient mice die from Salmonella infection because their phagocytes cannot make reactive oxygen species. This is because Eros is essential for expression of vital components of the phagocyte NADPH oxidase. My work represents&nbsp;the only paper on this protein. I&nbsp;have found that Eros-deficiency has effects that go far beyond the generation of reactive oxygen species. In particular:</p> <ul> <li>Eros regulates the expression of other key macrophage proteins including P2X7, a key activator of the NLRP3 inflammasome</li> <li>Eros regulates the expression of numerous cytokines from CD4+ T cells. Eros -/- T cells make 10-fold more IL-4 than control cells</li> </ul> <p>In mouse and human systems, I will investigate the molecular mechanisms by which Eros:</p> <ul> <li>controls the abundance of a subset of proteins working on the hypothesis that it is a novel component of the protein quality control pathway&nbsp;using structural, biochemical and cell biological techniques.</li> <li>controls T cell cytokine secretion. I will spend time working with John O'Shea, a world leader in this field.&nbsp;&nbsp;</li> </ul>

Amount: £1,319,075
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of Eros in Innate and Adaptive Immunity 30 Sep 2017

<p>I will investigate the role of a novel protein, Eros, in immunity. I discovered the fundamental importance of this protein by demonstrating that Eros-deficient mice die from Salmonella infection because their phagocytes cannot make reactive oxygen species. This is because Eros is essential for expression of vital components of the phagocyte NADPH oxidase. My work represents&nbsp;the only paper on this protein. I&nbsp;have found that Eros-deficiency has effects that go far beyond the generation of reactive oxygen species. In particular:</p> <ul> <li>Eros regulates the expression of other key macrophage proteins including P2X7, a key activator of the NLRP3 inflammasome</li> <li>Eros regulates the expression of numerous cytokines from CD4+ T cells. Eros -/- T cells make 10-fold more IL-4 than control cells</li> </ul> <p>In mouse and human systems, I will investigate the molecular mechanisms by which Eros:</p> <ul> <li>controls the abundance of a subset of proteins working on the hypothesis that it is a novel component of the protein quality control pathway&nbsp;using structural, biochemical and cell biological techniques.</li> <li>controls T cell cytokine secretion. I will spend time working with John O'Shea, a world leader in this field.&nbsp;&nbsp;</li> </ul>

Amount: £25,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding the role of the viral polymerase in influenza virus virulence 31 May 2017

<p>The development of novel strategies against influenza viruses depends on our understanding of influenza virus replication and pathogenicity. The former largely depends on the activity of the viral <strong>RNA polymerase</strong>, which copies and transcribes the viral genome, while the latter is multifaceted and influenced by both viral and host factors. Interestingly, recent findings show that the RNA polymerases of <strong>highly pathogenic influenza A viruses</strong> produce short RNAs, or <strong>mini viral RNAs</strong> (mvRNAs), which are non-contiguous in the viral genome and strong inducers of the interferon response. Because they are not made by RNA polymerases of seasonal influenza strains, mvRNA synthesis may be a transformational advance in our understanding of&nbsp;the &lsquo;cytokine storm&rsquo; that underlies the pathogenicity of virulent influenza viruses. Unfortunately, our basic understanding of the influenza RNA polymerase is limited and it is unclear how the mvRNAs are made. I here plan to use single-molecule FRET, deep-sequencing and structure-guided mutagenesis to advance our basic understanding of influenza virus RNA synthesis, focussing on&nbsp;the molecular mechanics behind i) influenza transcription initiation, ii) the differences between the RNA polymerases of highly pathogenic and&nbsp;seasonal influenza strains, and iii) the action of influenza inhibitors that&nbsp;target&nbsp;the RNA polymerase.</p>

Amount: £922,885
Funder: The Wellcome Trust
Recipient: University of Cambridge

Explaining the heterogeneity and topography in inferior temporal cortex with deep neural networks 19 Apr 2017

Object recognition is accomplished by the ventral visual pathway, also known as inferior temporal (IT) cortex. IT contains regions that respond preferentially to faces, color, and places. However, we still do not understand the principles underlying the emergence and organisation of these regions. Currently, there are no computational models that take into account the heterogeneity of IT, including the spatial clustering of neurons with similar selectivity and the spatial organisation of these clusters on the cortical surface. Therefore, we would like to answer two questions regarding IT: 1) Does the heterogeneity of IT simply emerge from exposure to many images, or are specialized mechanisms and/or innate constraints involved in its development? 2) What are the organisational principles reflected in IT topography? We will determine whether the heterogeneity of populations of units, like that empirically observed in IT, can emerge spontaneously in deep neural networks (DNNs) without specialized architecture, or whether we need an architecture that specifically accounts for it. We will then build a DNN that incorporates the spatial information about selective populations of units and assigns these populations to topographical maps. We will test the models’ predictions using electrophysiology and fMRI data.

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

Applying causal interventions to brain networks underlying adaptive perceptual decision making. 19 Apr 2017

<p>The contribution of individual brain regions to perception is not static, and is determined both by task experience and particular stimulus demands. To investigate these dynamic contributions, I propose to use non-invasive brain stimulation combined with electrophysiological measurements. This combination will provide a window into the dynamics of causal relationships between behaviour and specific patterns of brain activity across regions.</p> <p>&nbsp;</p> <p>The first experimental series will establish the causal contribution of parietal and lateral prefrontal regions to perceptual choice, and relate these behavioural changes to the underlying neural activity. Critically, I will track how the brain-behaviour relationship changes as participants are given extensive task training. A key prediction for this phase is that parietal cortex will be critical for task performance when the task is new, and requires the parsing of signal from task-irrelevant noise. &nbsp;</p> <p>&nbsp;</p> <p>A second phase of work will investigate the mechanisms supporting these cortical interactions and brain-behavioural relationships. I will use TMS adaptation to measure changes in visual representation, and TMS entrainment protocols to test the relevance of alpha oscillations to decision-making and perceptual learning. Together, this ambitious program of research will address basic questions on perceptual representation and the impact of neural plasticity at the network level.&nbsp;&nbsp;</p>

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

Genetic and functional interactions in the mammalian DNA-damage response 05 Apr 2017

<p>DNA in our cells is frequently subject to a wide array of molecularly-distinct forms of damage. To cope with this, life has evolved multiple DNA repair and associated processes, collectively termed the DNA-damage response (DDR). While considerable progress has been made in identifying DDR proteins and their regulators, much remains to be learned about how they operate and are controlled. Building on our successful proof-of-concept studies, we will carry out genome-wide and focused genetic screens via state-of-the-art CRISPR-Cas9 approaches and haploid-cell based chemical mutagenesis. Together with ensuing validation and mechanistic studies, the proposed research has the following interconnected goals:</p> <ul> <li>To identify novel genetic and functional relationships between DDR genes/proteins, and between these and other cellular components, thereby providing fundamental insights into how mammalian cells respond to DNA damage and defining how such responses are controlled and coordinated.</li> <li>To establish how defects and deregulation of certain DDR processes affect cellular sensitivity and resistance to established and emerging cancer therapies, and to explore the potential clinical relevance of these affects.</li> <li>To expand our knowledge of how DDR processes are affected by protein post-translational modifications, particularly ubiquitylation and phosphorylation.</li> </ul>

Amount: £1,636,331
Funder: The Wellcome Trust
Recipient: University of Cambridge

The cognitive neuroscience of over-eating: normative and clinical studies of goal-driven and stimulus-driven responses 05 Apr 2017

<p>There is a pressing need to understand the phenotypic variations of obesity in order to elucidate the diverse pathways and mechanisms by which it arises and, ultimately, to offer suitably tailored interventions. My proposed work aims to provide insights into the cognitive neuroscience of health-harming over-consumption.&nbsp; Its ultimate goals are to characterise cognitive mechanisms underlying eating behaviours, exploring how these are selected and deployed in ways that are shaped by both internal and environmental signals. The work is based on the view that obesity is ultimately driven by a complex integration of environmental and bodily signals and that a comprehensive approach must characterise this integration in order to determine how it may be altered in over-eating.</p> <p>&nbsp;</p> <p>My proposal has the following goals:</p> <ol> <li>To understand how stimulus-driven (automatic) and goal-directed (reflective) reward behaviours are balanced in relation to eating choices and to explore how this balance may differ across hungry and sated, lean and obese people.</li> <li>To relate these underlying processes to hormonal/metabolic signals as well and to real-world eating choices.</li> <li>To characterise the effects of three specific perturbations to this integrated system: (i) elective gastrectomy, (ii) single gene mutations affecting hypothalamic circuitry and (iii) psychopharmacological manipulations</li> </ol>

Amount: £1,500,053
Funder: The Wellcome Trust
Recipient: University of Cambridge

Defining the Haematopoietic System through Integrated Multi-Scale Analysis 05 Apr 2017

<p>Biological processes operate at vastly different scales ranging from molecules to entire organs. However, relating molecular insights to whole tissue function remains difficult since biomedical research commonly focusses on just a single scale. The G&ouml;ttgens group has taken advantage of new single cell profiling technologies to generate a comprehensive landscape of the transcriptional states that a blood stem cell may traverse through when it differentiates into the various blood lineages. Here it is proposed to use this single cell transcriptional landscape to connect different scales ranging from molecular to cellular to whole tissue function, and thus advance our understanding of cell fate decision making in blood stem and progenitor cells. Complementary experimental and computational approaches will address how molecular regulatory networks control cellular identity, and how tissue-scale computer models of the blood system can be grounded in comprehensive molecular information. The proposed experiments are designed to provide new leads for subsequent studies, including potential new therapeutic targets from analysis of pre-leukaemic models. Moreover, empowering single cell transcriptional landscapes to link &ldquo;molecular&rdquo; observations with the function of the entire haematopoietic system will generate a framework that is broadly applicable to advance our understanding of all normal and pathological organ systems.</p>

Amount: £2,028,031
Funder: The Wellcome Trust
Recipient: University of Cambridge

Putting genomic surveillance at the heart of viral epidemic response. 05 Apr 2017

<p>This proposal is to develop an end-to-end system for processing samples from viral outbreaks to generate real-time epidemiological information that is interpretable and actionable by public health bodies. Fast evolving RNA viruses (such as&nbsp;Ebola, MERS, SARS, influenza etc) continually accumulate changes in their genomes that can be used to reconstruct the epidemiological processes that drive the epidemic. Based around a recently developed, single-molecule portable sequencing instrument,&nbsp;the MinION, we will create a 'lab-in-a-suitcase' that will be deployed to remote and resource-limited locations. These will be used to sequence viral genomes from infected patients which will then be uploaded to&nbsp;a central database for rapid analysis. We will develop methods for a wide-range of emerging viral diseases. Novel molecular biology methods will allow us to sequence&nbsp;individual viruses within a patient. Bioinformatics tools will be developed simple enough for non-bioinformaticians to use, without reliance on Internet connectivity. We will develop software to integrate these data and associated epidemiological knowledge to&nbsp;reveal the processes of transmission, virus evolution and epidemiological linkage. Finally we will develop a web-based visualization platform where the outputs of the statistical&nbsp;analyses can be interrogated for epidemiological insights within days of samples being taken from patients.&nbsp;</p>

Amount: £482,639
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding mammalian interphase genome structure in mouse ES cells 05 Apr 2017

<p>The folding of genomic DNA from the beads-on-a-string like structure of nucleosomes into higher order assemblies is critically linked to nuclear processes, but it is unclear to what degree it is a cause or consequence of function. We aim to understand whether the Nucleosome Remodeling and Deacetylation (NuRD) complex regulates chromatin structure to control transcription, or whether it is NuRD&rsquo;s regulation of transcription that results in global changes in chromosome structure.</p> <p>&nbsp;</p> <p>We have calculated the first 3D structures of entire mammalian genomes using a new chromosome conformation capture procedure, which combines imaging with Hi-C processing of the same single cell. Our objectives are now:</p> <p>&nbsp;</p> <ul> <li><em>To study: 1) </em><em>how interphase mammalian genome structure is established in G1; 2) the factors that drive this formation and; 3) how this organisation is regulated by chromatin remodellers (such as the NuRD complex) as mESC&rsquo;s differentiate.</em></li> </ul> <ul> <li><em>To build a dedicated bespoke microscope for 3D double helix point spread function detection with light sheet activation, optimised for 3D single-molecule/super-resolution imaging of proteins such as the NuRD complex. </em></li> </ul> <ul> <li><em>To combine 3D super-resolution imaging and the biochemical processing steps of single cell Hi-C to directly correlate binding of protein complexes to regions of the structures.</em></li> </ul>

Amount: £2,031,409
Funder: The Wellcome Trust
Recipient: University of Cambridge

Molecular mechanisms controlling germline stem cell biology 22 Feb 2017

<p>The ability of stem cells to replenish and differentiate is critical for tissue growth, repair, and homeostasis. Yet, our understanding of the molecular mechanisms governing stem cell fate transitions remains limited. Through a systematic RNAi screen using the Drosophila germline as a model for stem cell biology, I uncovered a central role for ribosome biogenesis and protein synthesis regulation in controlling fate transitions. My current goal is to dissect the molecular mechanisms by which protein synthesis control - a new frontier in genomic regulation - governs stem cell maintenance and differentiation <em>in vivo</em>. In particular, I propose to generate a systematic and detailed translation-based roadmap of the differentiation process. This will be achieved by coupling genetic tools with high-throughput techniques, and aims to determine the set of actively translated mRNAs at consecutive differentiation stages. This unbiased approach will allow me to reveal the set of regulated targets and to uncover the cascades dictating fate transitions during germline differentiation. In parallel, I will combine developmental and molecular analysis to explore the mechanisms by which specific translation regulators support key developmental aspects. Dissecting such regulatory mechanisms will provide new insights into the principles dictating stem cell fate transitions <em>in vivo</em>.</p>

Amount: £1,138,543
Funder: The Wellcome Trust
Recipient: University of Cambridge

Self-propagating protein conformations as targets of intracellular immunity 22 Feb 2017

<p>Recent discoveries in neurodegeneration support the cell-to-cell transmission and replication of certain &lsquo;prion-like&rsquo; proteins in a manner highly reminiscent of viral infection. This suggests that antiviral mechanisms could potentially be used to treat neurodegenerative diseases. The novel antibody receptor TRIM21 engages immune complexes&nbsp;in the cytoplasm and elicits their proteasome-dependent destruction. This activity prevents infection by viruses that enter the cell with antibodies attached to them. Preliminary data show that seeds of tau, a cytoplasmic prion-like protein that aggregates in Alzheimer&rsquo;s disease, can similarly be neutralized in this way. This study will combine high-content cellular seeding assays, degradation assays and two mouse models of tau pathology to investigate the mechanism of antibody protection during immunotherapy. Using antibody engineering and knockout mice lines, I will quantify the contribution of TRIM21 and classical Fc receptors to immunotherapeutic protection against neurodegeneration. I will determine how cellular machinery elicits the inactivation of prion-like proteins. This combined approach will support an understanding of intracellular inactivation of prion-like proteins and relate it to disease progression. Current understanding has not translated into disease-modifying therapeutic interventions for neurodegeneration. These studies may inform new strategies aimed at limiting spread of pathogenic protein assemblies using antibodies.</p>

Amount: £964,847
Funder: The Wellcome Trust
Recipient: University of Cambridge