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Recipients:
6th East Paddington Brownie Guide Unit
University of Cambridge
Currency:
GBP
Amounts:
£0 - £500
£500 - £1,000
Award Year:
2018

Results

Evolutionary basis of human diseases in western Eurasia: Insights from ancient genomics 27 Nov 2018

<p>Although large differences in disease susceptibility among present-day human populations have been widely reported, their evolutionary underpinnings remain poorly understood. This project aims to examine how, and to what extent, pathogens shaped disease susceptibility among present-day western Eurasians. We will use whole-genome sequence data from ancient humans and their pathogens to identify novel human genetic variants targeted by past selection, and catalogue novel pathogen variability, including that of now-extinct lineages. Next we will reconstruct the evolutionary history of these newly identified variants and lineages, along with those already known to be associated with disease susceptibility in present-day populations. Finally, we will uncover new associations between human genetic variants and infectious diseases. The focus will be on the last 10,000 years of human history, which encompass some of the greatest changes in our lifestyle, including the agricultural revolution, first known epidemics, and early urbanisation. The proposed study will provide fundamental insights into the evolutionary basis of disease susceptibility in present-day human populations, as well as the evolution of human pathogens. These findings will inform future experimental and clinical research, impact upon current and future healthcare strategies, including the design of diagnostic tests and drug development, and improve global pathogen outbreak monitoring.</p>

Amount: £4,153,544
Funder: The Wellcome Trust
Recipient: University of Cambridge

The proteomic architectures of apicomplexan cells: the molecular complexity of pathogens revealed 27 Nov 2018

<table border="1" cellspacing="0"> <tbody> <tr> <td> <p>Apicomplexan parasites represent highly adapted eukaryotic pathogens that have evolved to exploit multiple human and animal niches causing widespread disease and food deprivation. Key to their success as parasites are novel organelles and structures adapted for invasion and mediation of interactions with their hosts. They have also reprogrammed canonical cell compartments with modified metabolic capacities and regulatory control. An overwhelming obstacle to understanding the biology of these parasites and their mechanisms of pathogenesis is that much of the parasite proteome is unique in Apicomplexa, with most proteins of unknown location or function.</p> <p>My group uses a novel method for whole-cell spatial proteomics in apicomplexan parasite-host systems that simultaneously captures the locations and associations of thousands of parasites proteins. This provides intimate and thorough illumination of the architecture and adaptations of these devastating pathogens at an organelle-, sub-compartment- and protein complex-level. We will define the commonalities and differences between major pathogen groups <em>Plasmodium</em> and <em>Toxoplasma</em>, the destinations of proteins they export into their hosts, and the spatial dynamics of their proteomes during infection developmental cycles. This comprehensive knowledge will enable molecular mechanistic understanding of these pathogens that is essential for effective design and implementation of disease management and prevention strategies.</p> </td> </tr> </tbody> </table>

Amount: £1,687,461
Funder: The Wellcome Trust
Recipient: University of Cambridge

Contribution of transposable elements in cell fate decision 31 Oct 2018

<p>Transposable elements (TEs) are long known to be expressed in different cells during early mammalian development. However, the role of TEs in cellular differentiation has remained elusive. This proposal aims to develop new experimental and computational methods to understand the role of TEs in cellular differentiation. Single cell (sc) RNA sequencing (RNA-seq) has been developed extensively in recent years to study cell-to-cell variability of gene expression. These methods, however, have exclusively used short read sequencing technologies, which do not allow for TE mapping. I will develop a novel plate-based long read scRNA-seq protocol, which will overcome this limitation. Transcripts will be tagged with unique molecular identifiers (UMIs) prior to amplification, permitting accurate transcript counting. I will devise a computational method to error correct reads using UMIs, by calculating a consensus from multiple sequence alignments of all reads flagged as PCR duplicates. This protocol thus allows for accurate sequencing of complete transcripts in single cells, which I will apply to cells during mouse embryonic development to investigate the role of TEs in cellular differentiation. In particular, I will investigate whether TEs exhibit heterogeneous expression across cells. Together, these methods and experiments will improve our understandings of TEs in mammalian development.</p>

Amount: £300,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Salary support 2018 - 2023 30 Sep 2018

<p>N/A</p>

Amount: £1,494,699
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding Medical Black Boxes: A Philosophical Analysis of AI Explainability 26 Jul 2018

<p>I plan during the next two years to develop a major, multi-year project into AI explainability in medical contexts. This project will connect existing literatures in philosophy of science, philosophy of medicine and medical ethics, where problems of understanding and explanation have been extensively studied, to the emerging literature on explainability in machine learning and the ethics of AI. The aim will be (i) to enhance our understanding of the problems AI systems raise for explainability in medical contexts and (ii) to collaborate with machine learning researchers to develop technical research apt to address these problems.</p> <p><br> The existing literatures on explainability and understanding in medicine are vast and have not previously been systematically connected to the ethics of AI. To lay the groundworks for a later grant proposal, this application proposes to conduct three pilot-studies, focusing on potential challenges from AI to: (1) mechanistic understanding, (2) clinical judgement and diagnostic reasoning and (3) informed consent. A part-time research assistant will assist in scoping the relevant literatures. Travel to groups at other universities and a workshop in Cambridge will furthermore help establish contacts with a network of researchers interested in the ethics of AI and AI explainability in medical contexts.</p>

Amount: £86,561
Funder: The Wellcome Trust
Recipient: University of Cambridge

Health, Medicine and Society 11 Jul 2018

<p>The MPhil in Health, Medicine and Society (HMS) provides students with interdisciplinary training in the history, philosophy, anthropology and sociology of health and medicine. The programme is structured around taught modules across the four disciplines. These are keyed to three research essays (one pass/fail of 3,000 words; two of 5,000 words), supported by one-to-one supervisions. Students are guided by an overall course manager and individual subject managers to choose their modules and to identify a dissertation topic. The 15,000-word dissertation, also supported by one-to-one supervision, allows students to master a particular topic and the appropriate methods for addressing it. The programme is distinctive in training students in these four disciplines. No other programme in the UK does this. Moreover, because it is situated within a vibrant international hub of humanities and social sciences research in health and medicine, students are supervised by leading scholars in the field. Students arrive with a first-class degree (or equivalent) and learn to think critically and independently, employing a range of methods, about the meanings of health and medicine. HMS was launched in 2017, and from the outset has attracted outstanding students with tremendous promise for the future.</p>

Amount: £94,994
Funder: The Wellcome Trust
Recipient: University of Cambridge

Mechanisms of lineage restriction in development and reprogramming. 17 Jul 2018

<p>Mechanisms that lead to the establishment and maintenance of cell identity are paramount for organismal health.&nbsp; They also underpin successful cellular reprogramming for disease modelling and cell replacement therapies. We will investigate the roles played by the epigenome and co-factors in regulating lineage transcription factor-mediated establishment and stabilisation of cell fate <em>in vivo</em> and <em>in vitro</em>.</p> <p>&nbsp;</p> <p>Firstly, controlled activation and degradation of engineered transcription factors (TFs) will be used to challenge cell identity in developing frog embryos.&nbsp; We will compare transcriptional profiles and chromatin landscape in &ldquo;permissive&rdquo; tissues that respond to TF over-expression by undergoing full lineage reprogramming, and &ldquo;non-permissive&rdquo; tissues that resist reprogramming, as well as probing heterogeneity of transcriptional response in individual cells. Secondly, mechanisms responsible for differential response to TF will be identified through interference with the epigenome as well as via alteration of the co-factors repertoire present in embryonic tissue. Finally, we will explore mechanisms underlying lineage fidelity in mammalian ES cells that have been engineered to co-express TFs specifying conflicting lineages.</p> <p>&nbsp;</p> <p>Overall, this work will reveal how the response to lineage determining TFs is controlled by integration of epigenetic features and co-factor availability in both the developing embryo and in reprogrammed mammalian cells.</p>

Amount: £1,998,310
Funder: The Wellcome Trust
Recipient: University of Cambridge

Neural circuits underlying fertility 17 Jul 2018

<p>This programme aims to establish in detail the characteristics and <em>in vivo</em> significance of the arcuate (ARN<sup>KISS</sup>) and rostral periventricular area of the third ventricle (RP3V<sup>KISS</sup>) kisspeptin neurons in driving the pulsatile and surge patterns of luteinising hormone (LH), respectively. Genetic cFOS-dependent activation and rabies trans-synaptic strategies will enable permanent GFP/mCherry tagging of RP3V<sup>KISS</sup> neurons activated at the time of the surge, or projecting directly to GnRH neurons, for subsequent electrophysiological and RNAseq analyses. GCaMP-based fiber photometry and GRIN lens miniscopes will be used to evaluate RP3V<sup>KISS</sup> neuron and population activity. This will be combined with microfluidics delivering pharmacological agents or adeno-associated viruses bearing CRISPR components to interrogate the key factors regulating the activity of RP3V<sup>KISS</sup> neurons <em>in vivo</em>. Studies aimed at understanding how the ARN<sup>KISS</sup> neurons synchronise to generate LH pulses will use the same strategies in addition to expansion microscopy and brain slice dual calcium and electrophysiological recordings. Novel strategies for slowing LH pulses in an animal model of polycystic ovary syndrome will be explored. It is expected that the in-depth understanding of these two kisspeptin populations will provide opportunities for developing new therapeutics aimed at the beneficial regulation of fertility in the clinic.</p>

Amount: £2,250,889
Funder: The Wellcome Trust
Recipient: University of Cambridge

Neural circuits underlying fertility 17 Jul 2018

<p>This programme aims to establish in detail the characteristics and <em>in vivo</em> significance of the arcuate (ARN<sup>KISS</sup>) and rostral periventricular area of the third ventricle (RP3V<sup>KISS</sup>) kisspeptin neurons in driving the pulsatile and surge patterns of luteinising hormone (LH), respectively. Genetic cFOS-dependent activation and rabies trans-synaptic strategies will enable permanent GFP/mCherry tagging of RP3V<sup>KISS</sup> neurons activated at the time of the surge, or projecting directly to GnRH neurons, for subsequent electrophysiological and RNAseq analyses. GCaMP-based fiber photometry and GRIN lens miniscopes will be used to evaluate RP3V<sup>KISS</sup> neuron and population activity. This will be combined with microfluidics delivering pharmacological agents or adeno-associated viruses bearing CRISPR components to interrogate the key factors regulating the activity of RP3V<sup>KISS</sup> neurons <em>in vivo</em>. Studies aimed at understanding how the ARN<sup>KISS</sup> neurons synchronise to generate LH pulses will use the same strategies in addition to expansion microscopy and brain slice dual calcium and electrophysiological recordings. Novel strategies for slowing LH pulses in an animal model of polycystic ovary syndrome will be explored. It is expected that the in-depth understanding of these two kisspeptin populations will provide opportunities for developing new therapeutics aimed at the beneficial regulation of fertility in the clinic.</p>

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

An Extended Pilot for the Human Cell Atlas: Adult tissues, human development and inflammation-mediated pathologies 30 Sep 2018

<p>The Human Cell Atlas (HCA) is an international, collaborative effort that &ldquo;&hellip;aims to define all human cell types in terms of their distinctive patterns of gene expression, physiological states, developmental trajectories, and location&rdquo;.</p> <p>&nbsp;</p> <p>Here, we will contribute directly to the first phase of the HCA by forming an &lsquo;extended pilot&rsquo; to implement UK infrastructure for large-scale, high quality human cell atlas experiments. We will generate a high-level atlas, with spatial resolution, for multiple adult human tissues along with matched data from human fetal material. We will then illustrate the power of a deep and focused investigation of a single tissue (skin) to produce highly-detailed data describing its cellular composition and spatial organisation. Finally, for selected tissues that have been profiled in adults and fetal material, we will analyse samples from immune-mediated disorders as a comparison with our reference data to gain deeper understanding of the pathological mechanisms. This will demonstrate the utility of the HCA as a &lsquo;healthy reference&rsquo; for comparison with disease.</p> <p>&nbsp;</p> <p>Throughout, we will generate profound biological insight from primary human cells and lay a foundation of technology development and optimisation with a set of hardened and scalable methods for single-cell RNA-sequencing, spatially-resolved gene expression, and tissue imaging.</p>

Amount: £765,117
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of RNA modifications in myeloid leukaemogenesis 24 Apr 2018

<p>Acute myeloid leukaemia (AML) is a devastating cancer with a long-term survival below 30% for which mainstream treatments remain unchanged for several decades. Advances in genomics have highlighted the importance of epigenetic corruption in both initiating and maintaining the disease, making the epigenome an important therapeutic focus. Recently, using CRISPR-Cas9 recessive genetic screens, we identified several RNA-binding/modifying proteins as essential for AML cell survival. We have since confirmed that the RNA methyltransferase METTL3 is required for AML maintenance through its role in co-transcriptional N6 adenosine methylation of target RNAs, but is dispensable for normal haematopoiesis proposing it as a novel &ldquo;druggable&rdquo; therapeutic target in AML (Barbieri, Tzelepis&nbsp;et al, <em>Nature</em> 2017). Here, I propose to extend the investigation of the epitranscriptome as a new therapeutic focus in AML by studying&nbsp;promising AML-essential RNA-binding/modifying proteins, including METTL1&nbsp;and&nbsp;METTL16<em>,</em>&nbsp;using unique reagents and expertise as well as access to clinically&nbsp;relevant&nbsp;bespoke models and human samples.</p>

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

Unbiased in vivo CRISPR screen to identify novel T-cell immune checkpoints for cancer immunotherapy 24 Apr 2018

<p>Harnessing the anti-tumour potential of T-cells for cancer treatment has been successful for a number of malignancies. The blockade of immune checkpoints, such as the T-cell receptor PD-1, reduces tumour burden in patients and can lead to durable cures for some. Treatment efficiency is further improved when PD-1 is targeted simultaneously with other checkpoints such as CTLA4 or LAG3. Despite the potential of co-targeting multiple checkpoints, the combinatorial co-inhibition of all known as well as yet undiscovered immune checkpoints has not been systematically assessed. Furthermore, genome-wide screening to identify novel checkpoints as well as modifiers of such checkpoints has been technically challenging. The objective of this proposal is to map the combinatorial landscape of known checkpoints coupled with PD-1 blockade as well as discover potentially new targets for immune activation against cancer. We propose to use of transplanted hematopoietic stem cells with different combinations of disabled T-cell surface proteins to screen for combinations which enable T-cell infiltration and tumour reduction in a PD-1 suppressed mouse melanoma model. Initially combinations of known checkpoints will be assessed, subsequently the screen will be expanded to all T-cell membrane proteins to identify novel immune checkpoints.</p>

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

The role of the Wallerian axon-death pathway in neuronal and axonal vulnerability in Parkinson's disease 24 Apr 2018

<p>Parkinson&rsquo;s disease (PD) involves preferential loss of substantia nigra pars compacta (SNc) dopaminergic neurons and their projecting axons to the striatum. SNc neurons have huge, highly branched and vulnerable axons,<strong> </strong>whose distal ends are lost first in PD, so preventing this will be essential for any disease modifying therapy.</p> <p>Our preliminary data suggest the involvement of an axon-death pathway in PD shared with the loss of injured axons (Wallerian degeneration). The Wallerian pathway is initiated by loss of the activity of the essential NAD-biosynthetic enzyme NMNAT2 in axons. Crucially, axons expressing lower levels of NMNAT2 are more vulnerable, raising the possibility that SNc neuron and axon susceptibility in PD reflects a particular sensitivity to Wallerian pathway activation. To test this hypothesis, I will use cutting-edge research strategies from three leading laboratories in axon degeneration and Parkinson&rsquo;s disease, combining expertise in mouse primary neuronal cultures, human iPSC-derived dopaminergic neurons and mouse and zebrafish <em>in vivo </em>models of PD.</p> <p>The proposed research will greatly advance our understanding of mechanisms of SNc neuron and axon death in PD. In the longer term, this work has significant clinical implications since axons are lost early in PD and the Wallerian pathway can be potently blocked.</p>

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

Dissecting the neural circuits for visual perceptual learning 06 Jun 2018

<p>Visual perceptual learning (VPL) is an improvement of performance of a visually guided task as a result of visual experience. However, it is not well understood whether improvements are due to changes in lower-level visual or in higher-level association brain areas, and whether improvements can transfer to untrained visual features and tasks.</p> <p>&nbsp;</p> <p>Here I propose to dissect the neural circuits of VPL in mice and test the theory that VPL consists of both:</p> <p>1) enhanced task-independent encoding of sensory features in low-level areas in cells with selective feature-preference, generalising poorly to different features.</p> <p>2) enhancement of task-relevant features, initially in higher level areas with broad feature-preference, generalising to a broader range of features.</p> <p>&nbsp;</p> <p>Mice can quickly learn a visual discrimination task, which I will combine with cell-type specific 2-photon calcium imaging and optogenetic manipulation of neural activity. I hypothesize that PV interneurons are necessary for task-independent learning, while SOM interneurons can gate feedback from high-level areas to boost task-relevant features.&nbsp;</p> <p>&nbsp;</p> <p>I will address the following specific aims: 1) identify the changes during VPL in visual and association areas during learning 2) determine the role of task-engagement in VPL 3) determine how VPL generalises to untrained or previously irrelevant features.</p>

Amount: £1,317,544
Funder: The Wellcome Trust
Recipient: University of Cambridge

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £900,031
Funder: The Wellcome Trust
Recipient: University of Cambridge

Youth, gender and teenage sexual counselling in Britain: The making of the Brook Advisory Centre, 1964-2000 23 Jan 2018

<p>This research uses the history of Brook Advisory Centres (BAC) as a case study through which to reassess the history of teenage sexuality and of the anxieties it caused in postwar Britain. From the first Centre opened in 1964 in London to the present, BAC has been an important provider of contraceptive advice and sexual counselling for unmarried people and teenagers. Although the centres have provoked fierce opposition and triggered recurrent public debates on teenage sexuality, little is known of their history. As a non-governmental organisation which however had clear connections with the Family Planning Association and the National Health Service, BAC provides an insightful locus to explore the way teenage sexuality was handled and debated publicly. Using the newly catalogued archives of BAC together with other sources, this research is divided in three parts. Part I examines the relationship between sexual culture and sexual politics by exploring the conditions under which teenagers and unmarried people became target for contraceptive advice. Part II looks at the content of sexual counselling and the extent to which clients&rsquo; demands and experiences shaped them. Part III explores the cultural dimension of reproductive politics by uncovering the impact of mass media on BAC&rsquo;s orientation.</p>

Amount: £155,453
Funder: The Wellcome Trust
Recipient: University of Cambridge

The University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Cambridge 30 Sep 2018

<p>Since 2013, the University of Cambridge Metabolic Research Laboratories (MRL) has developed into a world-leading centre for basic and applied research in obesity and related metabolic disease. Underpinning funding from Wellcome, which has provided new clinical research facilities and other crucial core support, has been central to this success. Importantly, this endeavour has been undertaken in partnership with the MRC, who have funded a new Unit, the Metabolic Diseases Unit (MDU), which is embedded in the MRL. The MRL, together with the MRC Epidemiology Unit (Dir. Wareham) and cognate clinical facilities, form the Wellcome Trust-MRC Institute of Metabolic Science (IMS) which operates seamlessly from basic science through to population science, translational research and delivery of ambulatory care within a single co-ordinated institute. The current bid is focused on further developing world-class metabolic research within the MRL through core support for clinical and animal model research as well as underpinning laboratory science at an internationally leading level. Given the centrality of bioinformatics to all contemporary biomedical research, we have placed a particular emphasis on development of this area for the next phase of our evolution.</p>

Amount: £4,795,450
Funder: The Wellcome Trust
Recipient: University of Cambridge

The University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Cambridge 30 Sep 2018

<p>Since 2013, the University of Cambridge Metabolic Research Laboratories (MRL) has developed into a world-leading centre for basic and applied research in obesity and related metabolic disease. Underpinning funding from Wellcome, which has provided new clinical research facilities and other crucial core support, has been central to this success. Importantly, this endeavour has been undertaken in partnership with the MRC, who have funded a new Unit, the Metabolic Diseases Unit (MDU), which is embedded in the MRL. The MRL, together with the MRC Epidemiology Unit (Dir. Wareham) and cognate clinical facilities, form the Wellcome Trust-MRC Institute of Metabolic Science (IMS) which operates seamlessly from basic science through to population science, translational research and delivery of ambulatory care within a single co-ordinated institute. The current bid is focused on further developing world-class metabolic research within the MRL through core support for clinical and animal model research as well as underpinning laboratory science at an internationally leading level. Given the centrality of bioinformatics to all contemporary biomedical research, we have placed a particular emphasis on development of this area for the next phase of our evolution.</p>

Amount: £249,032
Funder: The Wellcome Trust
Recipient: University of Cambridge

Tissue Resident Regulatory Cells 30 Sep 2018

Not available

Amount: £234,092
Funder: The Wellcome Trust
Recipient: University of Cambridge