- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 30 Sep 2020
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
The Cambridge History of Medicine 30 Sep 2020
This application is for support to develop a proposal for The Cambridge History of Medicine in six volumes. As General Editor, I will meet with a team of a dozen volume editors at a series of workshops to ask fundamental questions about what the history of medicine is, what it should be, and how best to represent it in these books.
Building on advances during our successful connectomics collaboration (2016-20), we now propose a very ambitious new goal: a complete, high-quality connectome for the male Drosophila central nervous system (CNS). With Wellcome support and leveraging Janelia’s unique electron microscopy imaging capability, we could turn image data into a fully analysed connectome. This would be the first CNS connectome of an animal with complex motor and cognitive behaviours. In contrast to existing fly datasets, it will be bilaterally complete, include brain and nerve cord and have intact sensory-motor connectivity. This connectome should have an enormous impact on the understanding of CNS-spanning circuitry underlying complex behaviour. We will publicly release initial draft and high-quality versions as soon as they are complete. We will immediately use it to study multisensory integration, memory recall, decision making, modification of brain states, the flexible organisation of motor behaviour, and sexually dimorphic circuits. It will provide a critical resource for > 200 labs worldwide studying Drosophila neurobiology (with impacts on developmental biology and molecular cell atlases) and provide new opportunities for theoretical neuroscientists to study complete, biologically-defined neural networks in a richly investigated organism. We expect general principles, applicable to all nervous systems, including those of humans, to emerge.
Targeting the gut in metabolic disease 31 Mar 2020
This project aims to identify new strategies to target the gut for the treatment of type 2 diabetes and obesity. Intestinal hormones regulate intestinal nutrient absorption, insulin secretion and appetite, and therapeutics based on the gut peptide GLP-1 are widely used for type 2 diabetes and obesity. Bariatric surgery causes weight loss and resolves diabetes at least in part via gut endocrine changes. This project will characterise human enteroendocrine cells using intestinal organoid cultures, building on our previous work using transgenic mouse models. To identify cells of interest, organoids will be engineered by CRISPR/Cas9 to express fluorescent sensors driven by hormonal promoters, allowing cellular analysis by transcriptomics, electrophysiology and real-time fluorescence imaging of e.g. Ca2+ and cAMP. We will characterize nutrient sensing pathways and identify receptors and signaling pathways potentially modifiable therapeutically. Using mouse and human tissues, we will identify circuitry involved in bidirectional cross-talk between gut endocrine cells and enteric/autonomic nerves. Building on our new methods to analyse peptides and the low molecular weight proteome by mass-spectrometry, we will investigate how plasma peptides respond to nutrient ingestion in health and metabolic diseases including diabetes, obesity, lipodystrophy and anorexia nervosa, and following bariatric surgery or dietary calorie restriction in obesity.
Plasmodium falciparum parasites still cause nearly half a million deaths each year. The repeated emergence of antimalarial drug resistance and the lack of a highly effective vaccine mean that there is an urgent need to identify new intervention targets. Erythrocyte invasion is an excellent target as it is essential for both parasite survival and for malaria pathology. Invasion involves multiple parasite ligands, but little is known about their function at the cellular level and even less about how they fit into the broader network of invasion proteins. This proposal will revolutionise our understanding of the function of two families of P. falciparum invasion ligands, the EBLs and the RHs, that are together responsible for the key decision point in the invasion process. The key goals are to: Systematically dissect functional equivalence between EBLs and RHs Establish the roles that EBLs and RHs play in discriminating between erythrocyte variants within and between humans Use innovative combinatorial approaches to move from a gene to a network understanding of EBL and RH function. The proposal will provide a step change for the field, both biologically and technically, and will identify new candidates for testing in a rationally designed, multi-component invasion-blocking vaccine.
To treat and prevent dementia in patients, it is essential to understand how microscopic changes in the human brain cause complex cognitive and behavioural disorders. My program addresses this critical gap in translational research, to facilitate clinical application of basic science discoveries. I have three goals, set in the context of frontotemproal dementia and progressive supranuclear palsy. First, I will develop quantitative biophysical models of human brain function that capture key cellular and pharmacological pathologies in vivo, with regional, laminar and synaptic specificity. These models of degenerating neuronal circuits are informed by individual measures of synaptic density (PET imaging with a SV2a ligand), GABA and glutamate (ultrahigh-field MR spectroscopy). They are optimised in vivo by inversion to magnetoencephalography, and tested post-mortem against neuropathology. This synergy of multi-modal imaging, together with Bayesian model comparison of Dynamic Casual Models, means one can drill down to the best mechanistic model of the human cognitive disorder. Second, I will show how harmful effects of dementia like apathy can be explained in terms of changes in synaptic density and loss of precision in hierarchical brain networks. Third, I will I demonstrate the readiness of my approach for experimental medicine, through longitudinal designs and pharmacological interventions.
Exploring mitochondrial metabolism in health and disease using targeted biological chemistry 31 Mar 2020
The molecular mechanisms by which mitochondrial reactive species, metabolites and redox signals contribute to physiology and pathology are unclear. This is in large part because these processes are difficult to assess and modulate in vivo. Our goals are to establish general chemical biology approaches to determine the mechanisms of mitochondrial physiology and dysfunction in vivo and from this develop new therapeutic strategies. The aims are based on the success of our previous Joint Investigator Award, but the specific chemical biology approaches to be used, the insights to be attained and the models have been refined and developed, based on our work over the past four years. These goals will be achieved by addressing three research challenges in cells and in vivo: A: Can we determine how mitochondria operate during normal physiology, and are disrupted during pathology, by targeting probes to measure reactive species and alterations to signaling pathways? B: Can targeting bioactive molecules to mitochondria prevent pathological disruption of mitochondrial function and generate potential therapies? C: Can the above methods to monitor and modulate mitochondrial function be assessed in animal models of human diseases and thus drive the development of rational, translatable therapies?
Mechanisms and roles of transmissible RNA 04 Mar 2020
Protein coding and non-coding RNA can spread between cells and tissues of an organism. RNA mobility between organisms has been documented within and among different kingdoms of life including fungi, plants and animals. However, the underlying mechanisms and roles of such transmissible RNA are poorly understood. Our recent studies demonstrated that honeybees share biologically active RNA among members of the hive through secretion and ingestion of worker and royal jellies. The jellies harbor naturally occurring exogenous (e.g. viral) and endogenous RNA. These findings suggest that RNA transfer plays a role in social immunity and signaling between honeybees. Therefore, the key goals of this proposal are: to establish a metabolic RNA labeling system in honeybees; and to apply this system to study natural RNA transfer-mediated antiviral immunity and impacts on the physiology of recipient bees. To achieve these goals, I will combine RNA biology techniques and imaging with high-throughput sequencing to establish a functional transmissible RNA pathway in honeybees. This project will provide knowledge and tools that will enable studying the biology of RNA flow in other organisms, including humans, in diverse biological aspects; hence, will ultimately contribute to the development of RNA-based applications to promote health and disease control.
<p>This award is for 6 students per year for 5 years. It includes ?a salary at the national living wage plus holiday pay and national insurance or equivalent,?as well as?funds to cover or significantly subsidise accommodation and travel (£1500 outside of London and up to £2000 in London).??? It includes £500 to each studentship towards research expenses.??? Unspent funds can be repurposed on further students or recruitment costs. Wellcome wishes to ensure a greater diversity of students (in relation to socio-economic background and ethnicity) progress to postgraduate research. <br> Over 5 years of the Programme we encourage organisations to aim for: <br> <br> -At least 50% of students recruited to the programme to be from underrepresented or disadvantaged groups, depending on priorities set by each organisation. <br> <br> -At least 50% of students recruited to the programme to be from non-Russell Group Universities. For the remaining 50%, organisations should consider how to recruit students from other universities as well as their own. Wellcome has included this recommended target as research indicates that most of the high-achieving STEMM graduates from minority ethnic backgrounds are located outside of Russell Group universities. </p>
<p>Specialist post-graduate training in Stem Cell Biology and Medicine is essential to produce a stream of highly skilled and innovative investigators equipped with a deep understanding of stem cell science and its significance for future medicine. In this context, the Wellcome PhD Programme in Stem Cell Biology and Medicine is unique in the UK in focus and scope. The enduring popularity of the programme, which receives on average 200 applications per year, and the quality of research outputs and next destinations are testament to both the calibre of students we are able to recruit and to the high-quality training they receive. Our programme provides an environment that is intellectually rigorous and personally supportive for students, enabling them to set and attain research objectives. The programme is designed to develop analytical and critically-minded individuals. Since its inception in 2008, the PhD Programme has evolved in response to the expressed needs of students and continuous developments in modern Stem Cell Biology. Our overarching goal is to produce well-trained and rounded PhD graduates who have generated significant and original research findings and are fully prepared for an ambitious and challenging career, whether continuing in stem cell science or moving to another profession.<br> </p>
Adaptive Molecular Diagnostics 30 Sep 2019
<p>Our project will use genomic data and a detailed understanding of pathogen evolution to<br> deliver a robust, rapid, accurate and cost-effective pathogen detection kit for use in the field.</p> <p>Current methods are unsuitable for detection as they are slow, inaccurate and cannot be<br> field deployed. Our work has already changed the basic understanding of how cholera<br> spreads and identified high and low epidemic risks that are the cornerstones of disease<br> prevention. By making robust molecular indicator kits adapted to field settings we are able to<br> rapidly probe the likely behaviour of cholera strains and provide actionable data that can<br> make a direct contribution to a major human health challenge.</p>
Darwin Tree of Life 30 Sep 2019
<p>Life has evolved from a single origin to generate >1.5 million eukaryotic species. Sequencing all species will provide an inventory of life, transform understanding of evolution, catalogue eukaryotic gene toolkits for biology and biotechnology, and enable monitoring of ecosystems under increasing stress. The Darwin Tree of Life (DToL) is a new initiative that will exploit long read technologies to sequence all 60000 species in the British Isles and play a leading role in the Earth BioGenome Project. This data resource will underpin bioscience for the coming century.</p> <p>We are a consortium of partners who will build and prove an end-to-end pipeline of sample collection, sequencing, genome assembly, annotation and data dissemination that can deliver this visionary project. We will:</p> <ul> <li> <p>Establish sample collection networks (to collect, record and voucher ~8000 species)</p> </li> <li> <p>Put in place large-scale sequencing and analytic processes (including for single cells and small-bodied taxa)</p> </li> <li> <p>Generate reference quality, deeply annotated genome assemblies for 2000 species</p> </li> <li> <p>Develop portals to disseminate the reference genomes, empowering wider scientific communities to embrace genomics in their future endeavours</p> </li> <li> <p>Share expertise in protocol development and informatics among the Darwin Tree of Life partners to strengthen institutional capacities across the consortium, and with the global EBP.</p> </li> </ul>
Biocontainment Level 2 high-parameter FACS: applications for the Cambridge biological sciences community 04 Jul 2019
<p><strong>Provision of cutting edge cell-sorter, with class II biocontainment to allow flexible workflows as applied to a broad range of studies within the Cambridge biomedical research community.</strong></p> <p>The acquisition of a CL2 high-parameter cell-sorter will provide critical ability to purify live-cell populations. This capability is desperately needed to match the explosive growth in high-parameter single-cell analysis in the Cambridge biomedical community (high-parameter flow-cytometry, CyTOF mass-spec, single-cell (sc)-RNA-seq). Parallel cell-sorting capacity of mouse and human live-cells is crucial for validation of findings, and in-depth exploration of the biology of highly purified cell populations. Currently, there is no capacity in Cambridge for high-parameter CL2-designated cell-sorting. This Wellcome Trust multi-user equipment grant application will provide a critical resource to the Cancer Research UK, Cambridge Institute (CRUK-CI), and wider Cambridge biomedical community.</p>
<p style="margin-left: 0cm; margin-right: 0cm">Because basic molecular mechanisms are shared universally, model organism databases are pivotal resources and drivers of research across species. We will enhance PomBase, the fission yeast model organism database, to place investigations using fission yeast in contexts that illuminate equivalent processes in other species, particularly human.</p> <p style="margin-left: 0cm; margin-right: 0cm">Through data stewardship, literature curation, and data integration, we will create emergent knowledge of eukaryotic cell biology, encompassing how proteins are connected into pathways, how pathways are connected to each other, what genes and pathways relate to human diseases, and what proteins remain unstudied across species.</p> <p style="margin-left: 0cm; margin-right: 0cm">We will develop generic open-source, modular, customisable tools to integrate diverse data types, thereby providing clear, user-responsive presentations of increasing volumes of complex data. We will continue to make substantial contributions to the development of shared infrastructures for semantic standardization of biology, supporting increased data propagation and re-use. We will engage closely with the research community through outreach activities.</p> <p style="margin-left: 0cm; margin-right: 0cm">Our proposal addresses four interconnected key objectives:</p> <p style="margin-left: 0cm; margin-right: 0cm">A1 Enabling fresh biological insights across organisms from quality-assured, standardised curation.</p> <p style="margin-left: 0cm; margin-right: 0cm">A2 Improving core infrastructure and providing innovative tools.</p> <p style="margin-left: 0cm; margin-right: 0cm">A3 Enhancing data acquisition, interoperability, and dissemination.</p> <p style="margin-left: 0cm; margin-right: 0cm">A4 Increasing outreach, community curation and promoting the fission yeast model system.</p>
Living Assessment: measurement, thresholds and the health of disabled and at-risk children in England, 1989-present 29 Jan 2019
<p><em>Living Assessment </em>will explore two assessments of children in England since 1989: attempts to measure the support requirements of disabled children; and attempts to measure threats of harm to children’s health and development in statutory social work practice. How have measurements been made about how and when state provision is necessary? How have thresholds for provision operated and been justified? How do people experience these assessments, and what are their concerns? These are important questions for understanding the role of health and measurement in welfare assessments of children, and for deepening and contextualising debates about the assessments, which have been intensified by austerity. To address these questions first we will study historical materials, drawing on new sources. Second, we will gather oral testimonies. Third, we will study patient records. Fourth, we will pursue action research, including a Parliamentary Inquiry, in collaboration with MPs and Lords from the All-Party Parliamentary Group for Children. We will work closely with three groups of Experts by Experience: disabled children and adolescents, adult care leavers, and parents who have experienced social work intervention. Experts by Experience will be involved in research design, interpreting findings, analysing transcripts, and co-designing and co-implementing the action research.<br> <br> </p>
Assisted Reproductive Technologies in the Islamic Republic: Infertility, Inequality and Masculinities in Iran 05 May 2019
<p>This research examines how (in)fertile couples, men in particular, can access and utilize assisted reproductive technologies (ARTs) in the socio-cultural, legal, religious and medical context of contemporary Iran. Iran is the only Muslim country in which ARTs, including the use of donor gametes and embryos, have been regulated by the state. Although the state partly subsidizes ARTs, they are not equally accessible to all. In Iran, infertility—a stigmatized condition—is considered a ‘woman’s problem’; male infertility is hardly recognized in families, society or in social science. This ethnographic study will yield insights into male infertility and the use of ARTs in Iran and how this relates to dominant notions of masculinity. It will build on four core theoretical notions—‘reproductive navigation’, ‘(Islamic) biopolitics’, ‘stratified reproduction’ and ‘emerging masculinities’—and take an intersectional perspective considering gender, class and religion. Conducted in Tehran and Yazd, the research methods will include: observation in hospitals and in the mundane lives of (in)fertile couples; interviews with couples and religious authorities, medical professionals and policymakers. This research will further our understanding of how gender, class and religion inform disparities in the use of and access to ARTs, and speak to reproduction policies in Iran and countries with similar conditions.</p>
From Collection to Cultivation: Historical Perspectives on Crop Diversity and Food Security 30 Jul 2019
<p>Many experts agree that crop genetic diversity is essential to agricultural productivity, present and future, and therefore an important determinant of human health and well-being. Yet the routes through which this diversity is made valuable in agriculture, for example in breeding more disease-resistant or nutritious crops, remain underexplored. The dominant narrative credits plant breeders alone with generating value from crop diversity and has enabled breeders and seed companies to claim ownership over plant varieties. This in turn has encouraged a dramatic consolidation of the seed industry that many consider a threat to global food security.</p> <p><br> The narrative of breeder-generated value must be assessed and challenged. Through four historical case studies and a synthetic account, this project argues for a more encompassing view of how diverse materials give rise to the crops eaten around the world. It documents the contributions of researchers engaged in plant exploration, introduction, conservation, and utilisation. It charts efforts to locate disease-resistant varieties, prevent the spread of crop pathogens, ensure access to dietary diversity, and locate the genes that give rise to nutrient-rich varieties. By following neglected actors and methods, the project changes our understanding of how and by whom modern agricultural crops have been made.</p>
<p style="margin-left: 0in; margin-right: 0in">Viruses depend on cellular machinery to express and replicate their genes. Viral RNA must therefore be delivered or generated in the cytosol. Some viruses also deliver genomic DNA into the nucleus, for integration into the host cell genome. The cell’s principal innate defenses are to mount a potent inflammatory response upon sensing cytosolic viral RNA and to repress the transcription of integrated viral DNA. To be effective, these responses must be sensitive, specific and appropriately calibrated to minimize toxicity and autoinflammation. Our overarching goal is to gain a molecular understanding of how the cell recognizes cytosolic viral RNA and how it silences viral gene expression with the necessary sensitivity and specificity. In pursuit of this goal we are applying a complementary set of biophysical, biochemical and cell biological approaches, with a focus on using high-resolution structural information to obtain detailed mechanistic insights with atomic-level detail. <br> <br> <strong>Our key goals are to understand:</strong><br> <br> -how cells distinguish viral from endogenous nucleic acids;<br> -how the immune response against double-stranded RNA is generated and amplified; <br> -how cells recognize and silence integrated viral DNA;<br> <br> This will provide invaluable insights on fundamental principles of host-pathogen recognition, chromatin regulation and host-virus coevolution.</p>
<p>To understand how the genome directs development, we need to know the cell-to-cell changes in genomic activity at individual loci and how changes are regulated. Advances in single-cell profiling provide a new ability to determine the regulatory configuration of individual cells genome-wide through profiling gene expression and chromatin accessibility. However, determining the connections between mother and daughter cells remains difficult. The invariant and known cell lineage of <em>C. elegans</em> solves this problem, making it possible with single-cell profiling to determine locus-specific activity in every cell from the zygote to the differentiated state. In Aim 1 we study the early events of genome quiescence, zygotic genome activation (ZGA), and lineage commitment by profiling all cells from the zygote to the 26-cell stage, and germ cells through their later ZGA. In Aim 2 we use the 20-cell intestine as a paradigm to study progression through a complete developmental trajectory. We will investigate mechanisms of key transitions and further study the relationship of activity patterns to genome 3D structure. In Aim 3, we focus on the impacts and regulation of active and PRC2/Polycomb chromatin domains. Our work will impact understanding of core principles of genome regulation relevant across animals. <br> </p>
<p style="margin-left: 0in; margin-right: 0in">African trypanosomes have remarkable cell surfaces which mediate their interactions with the molecules of infected mammals. These surfaces are packed with a dense layer of the variant surface glycoprotein (VSG), allowing a population survival strategy based on antigenic variation. Within thisVSG coat operate receptors for mammalian ligands such as transferrin and haptoglobin-haemoglobin. We have shown how these receptors have evolved to bind ligands while minimising exposing of the trypanosome to the adaptive immune system. We have also shown that trypanosome receptors bind to complement components, identifying and characterising receptors for factor H and complement C3. This latter work validated a bioinformatics screen that identified a further 25 putative receptors. The aim of this proposal is to now identify the complete receptor repertoire used by <em>Trypanosoma brucei</em>to exploit and survive within its host. We will assess whether receptors are virulence factors and whether they represent new biology. We will understand the molecular basis for their action. We will also determine what causes the distribution and dynamics of different receptor types within the cell. This will produce detailed mechanistic insight into the cell and molecular biology of trypanosome receptors, yielding a greater understanding of both the trypanosome and the disease.</p>