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Award Year:
2015
Currency:
GBP
Recipients:
University of Cambridge

Results

Medical Publishers, Obscenity Law, and the Business of Sexual Knowledge in Victorian Britain. 12 Jan 2015

This project will combine archival research with bibliographic, textual, and cultural analysis to chart the changing structures of Victorian medical publishing as it investigates how the period's emergent specialist medical publishers negotiated the precarious legal and cultural position of explicit medical books as borderline obscenity. I will uncover the strategies that four representative publishers used to protect their businesses from accusations of impropriety and even prosecution under ch anging obscenity laws, and assess the extent to which those strategies established certain kinds of medical books on sexual health as respectable works amid the nascent medical profession's struggle to establish its own social authority. Intersecting with the Wellcome Library's three-year initiative to digitise over 25,000 nineteenth-century medical books for free public access through the Internet Archive's Medical Heritage Library, this research will provide a fresh context for scholarly and p ublic engagement with such collections. It will shed new light on complex historical links between business history, cultural attempts to manage sexuality, and the development of the medical book, and build a foundation for new lines of enquiry in the medical humanities by outlining key structures of the Victorian medical publishing business.

Amount: £129,751
Funder: The Wellcome Trust
Recipient: University of Cambridge

Imaging remyelination in the central nervous system. 26 Feb 2015

There are currently no outcome measures that provide direct evidence for the differentiation of oligodendrocyte progenitor cells (OPCs) into remyelinating oligodendrocytes in vivo. The aim of this project is to image differentiation of endogenous and transplanted OPCs into remyelinating oligodendrocytes in vivo. This will be achieved by developing a molecular imaging strategy in which differentiating progenitor cells express organic anion transporting polypeptide (oatp), which allows upta ke of gadohexate for detection by T1-weighted MRI, or luciferin for detection by bioluminescence, in models of CNS de/remyelination. I will use lentiviral vectors to express oatp in OPCs as they differentiate by controlling oatp expression using an MBP promoter. These vectors will be used to transfect cultured OPCs which will be transplanted into areas of CNS demyelination, or transfect endogenous OPCs in areas of demyelination undergoing spontaneous remyelination. Some cells labelled in vi tro will be co-labeled with SPIO. Animals receiving transfected cells or virus will receive systemic gadoxetate. Oatp expressing cells will be detected with 9.4T T1 MRI (and T2 for cells co labelled with SPIO).

Amount: £274,305
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding the biophysical basis of energy storage in adipocyte lipid droplets and the metabolic consequences of the failure of this process. 01 Apr 2015

My proposal hinges on the hypothesis that having evolved in a nutritionally challenging environment, humans are particularly well adapted to ensuring sufficient energy intake, but considerably less well adapted to coping with sustained access to energy dense foodstuffs. And that failure to optimally store surplus energy as neutral lipid within cytosolic lipid droplets (CLDs) in adipocytes, results in lipid accumulation in other tissues such as the liver where it plays a seminal role in causing i nsulin resistance, type 2 diabetes, fatty liver, dyslipidaemia and ultimately cardiovascular disease. The aim is therefore to deepen and broaden understanding of the molecular basis of lipid storage within CLDs as well as the physiological consequences of overload/failure of this process. The approach we have adopted is distinguished by being primarily based on studies involving patients with a rare disease characterised by a lack of body fat i.e. lipodystrophy. Paradoxically, lipodystrophy leads to severe manifestations of the same metabolic diseases typically associated with obesity. In both cases, we hypothesise that metabolic disease arises as a result of a mismatch between the need and capacity to store surplus energy in adipocytes. This mismatch is particularly extreme in lipodystrophy, providing a more tractable model in which to study the pathophysiology of this problem. Having made some important genetic discoveries recently, we are now seeking to address fundamental biol ogical questions which have emerged from our primary genetic discoveries, whilst also seeking to broaden our knowledge of the genetic basis of other rare adipose tissue diseases.

Amount: £1,487,351
Funder: The Wellcome Trust
Recipient: University of Cambridge

Regulatory signalling networks between stem and niche cells in lung regeneration. 27 May 2015

For multipotent stem cells to properly orchestrate injury repair, it is necessary for signals to instruct stem cells to produce specialised cells that replace injured epithelia. The precise signals from the stromal/niche cells that can stimulate differentiation for lung injury repair are under-investigated. In this proposal, I will directly address gaps in the understanding of the regulation of stem cell lineage differentiation by characterising novel stromal cell populations expressing Lgr6 in the murine distal lung and their functional interactions with region-specific stem cells during injury repair. Aim 1 will define dynamics of Lgr6-expressing cells by tracking them in homeostasis and during injury repair. In vitro organoid co-culture of regional epithelial stem/progenitor cells with Lgr6+ cells will address functional interactions between epithelia and Lgr6+ stromal cells. I will also determine if Lgr6+ cells are essential for stem cell lineage differentiation in vivo. Aim 2 will further dissect regulatory signalling molecules derived from Lgr6+ cells. Gene expression profiling of Lgr6+ cells with regional epithelial cells will describe key signalling pathways that will be evaluated by in vitro organoid co-culture assay and by in vivo mouse genetics. This work will enhance our understanding of regulatory networks between stem-niche interactions in lung regeneration.

Amount: £1,226,049
Funder: The Wellcome Trust
Recipient: University of Cambridge

Hedgehog signalling in T cell effector and memory function in vivo. 27 May 2015

The aim of my research is to characterize the role of Hedgehog (Hh) signalling - known as a key determinant of tissue differentiation and development - in regulating CD8 effector and memory formation and function in vivo. I will utilize Hh reporter mice to determine the level of Hh signalling in effector and memory subsets during the course of the CD8 response to infection and tumour challenge. By comparing Hh-deficient and wildtype, antigen-specific CD8 T cells, I will interrogate the functiona l relevance and clinical importance of Hh signalling. RNASeq analysis on CD8 subsets and single cells will be carried out to reveal the Hh-specific CD8 target gene signature responsible for the observed effects in the different CD8 subsets. Novel Hh target genes identified in this analysis will be functionally characterized. In parallel I investigate the effects of Hh pathway manipulation on the CD8 anti-tumour response using live-imaging approaches of whole animals and tumour slices. The prop osed study will not only reveal the spatio-temporal activation and functional relevance of Hh signalling during the CD8 immune response in vivo but will also identify the underlying molecular mechanisms and determine the effects of Hh inhibitors and agonists on this response.

Amount: £1,019,562
Funder: The Wellcome Trust
Recipient: University of Cambridge

China Repro Tech - an international, interdisciplinary conference on reproductive technologies in China 30 Sep 2015

In recent years the development and use of assisted reproductive technologies have exploded in China. Since China's first IVF baby was born in 1988, over 350 treatment centres have opened, potentially offering services to the over 90 million estimated infertile individuals in the country today. In addition to IVF, prenatal screening and genetic testing have also increased. This increase in reproductive technologies corresponds with a rise in popular concern about the impact of Chinas rapid social and environmental change on the nation's reproductive health. Such scientific action and medical attention takes place as the nation struggles to strengthen the quality of the Chinese population while managing population quantity after decades of explicitly eugenic governmental policies.Our international, interdisciplinary conference, China Repro Tech, offers historical, sociological, and anthropological perspective on these issues. Held at University of Cambridge, the conference is programmed to reflect the topical specializations of our participants - from the implications of IVF and infertility to the medicalization of gendered bodies and population policies. Our goals include, sharing research, methodologies, and discussion on the socio-cultural, economic, political and historical landscapes shaping reproduction in China today. We expect the workshop to result in both future collaborations and publications.

Amount: £10,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge Stem Cell Institute Four year PhD studentships - Stem Cell Biology - Loukia Yiangou 30 Jan 2015

This proposal is to facilitate creation of a world-leading centre for fundamental and translational stem cell research. The Cambridge Stem Cell Institute (SCI) will build upon previous Wellcome Trust and Medical Research Council funding by drawing together 30 research teams into a cohesive centre. These groups will ultimately be co-located in a purpose-designed 8000m2 facility to be constructed on the Cambridge Biomedical Research Campus. Platform technologies supported by a Centre grant will en able SCI to recruit and retain the most talented investigators and empower them to make ground-breaking advances in understanding stem cells and their medical applications. Fundamental research will focus at the molecular level on mechanisms of self-renewal, commitment, differentiation and reprogramming. Functional studies will address the role of stem cells in development, repair, ageing, physiology and pathologies including cancer. Disease-specific induced pluripotent stem cells will be exploi ted to unravel mechanisms of cellular pathogenesis and define drug targets. Strategies to mobilise endogenous stem

Amount: £29,998
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the role of TL1A-DR3 in immune complex-mediated autoimmune disease. 12 Jan 2015

In this project we propose to focus on the role of the DR3-TL1A axis in autoimmune disease and more specifically on its involvement in lupus nephritis. We will determine which subset of kidney-resident mononuclear phagocytes express TL1A following immune complex-dependent FcgammaR-cross-linking. We will also investigate the relative importance of DR3 expression on myeloid cells versus lymphocytes in disease pathogenesis. Finally we will address how the myeloid cells and lymphocytes interact in the kidney in vivo and determine the role of the DR3-TL1A axis in these interactions

Amount: £80,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the function of group 3 innate lymphoid cells in the renal tract 19 Nov 2015

The kidneys play a critical role in homeostasis but can be affected by a number of prevalent and/or life-threatening pathologies, including acute kidney injury (AKI) and infection. Tissue-resident immune cells are vital for initiating and propagating the local immune response to these challenges, but our understanding of nature and function of these cells in the human renal tract is limited. A newly defined family of immune cells, the innate lymphoid cells (ILCs) have been identified in a number of tissues, and we have preliminary data showing that one subset, ILC3s, are present in kidney and bladder. We hypothesise that kidney-resident ILC3s contribute to local immune responses that may be beneficial for defence against UTI, but exacerbate inflammation in AKI. Key goals: Determine the anatomical location of ILC3s in kidney and bladder of mice and humans with reference to other immune sentinels. Investigate the functional characteristics of ILC3s in health and disease (AKI and urinary tract infection (UTI)) in humans and mice. Interrogate the role of ILC3s in murine models of AKI and uropathogenic Escherichia coli UTI. Use 2-Photon intravital imaging to determine the dynamic interactions of ILC3s with other immune-resident sentinels of the bladder and kidney.

Amount: £216,425
Funder: The Wellcome Trust
Recipient: University of Cambridge

Using genomics to understand the role of cystic fibrosis pathogens in pulmonary exacerbations. 11 Nov 2015

CF is an inherited, life-limiting, multi-system disorder, for which acute deteriorations in lung function termed 'acute pulmonary exacerbations' (APEs) are the single most important cause of morbidity and mortality. Despite this, little is understood about the pathophysiological processes that trigger APEs, although they are thought to be driven by respiratory infections. However, there is no substantive evidence to date that the presence or load of individual species is driving this process. Th is may reflect the complex underlying microbial diversity found in the CF lung at both the inter and intra species level. Therefore, directly sampling of this diversity using high-throughput sequencing will enable major advances in our understanding of APEs. This project involves two approaches which may lead to the discovery of the microbial factors which drive the progression of APE's:(a)Targeted enrichment technology to enable genomic sequencing of multiple CF pathogens concurrently. This w ill enable a greater understanding of the evolutionary dynamics of CF pathogens in the context of APEs. (b)Temporal clonal analysis of Pseudomonas aeruginosa isolates which have been phenotyped for characteristics related to bacterial virulence. By applying a genome wide association analysis we will gain a greater understanding of the relationship between genetic diversity and phenotype.

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

Establishing an in vitro model for embryonic patterning using a novel micropatterning system 11 Nov 2015

An in vitro micropatterning system (MPS) was developed, using human ESCs, which apparently mimics patterning within the embryo. This 'embryo in a dish' develops a presumptive primitive streak, introducing the possibility of studying gastrulation dynamically in vitro. This MPS gastrulation model resembles 3D organoids emerging for a number of systems and enables signalling manipulation in time and 3D space. While this system was established in human, it cannot be validated by comparisons with in vivo human development. The mouse model represents an essential bridge between pluripotent cell cultures and the embryo. I will establish the MPS in mouse and compare the expression of lineage markers in the MPS directly to mouse embryos to ask whether this system recapitulates in utero development. I will use the MPS to compare mouse and human development and analyse the basis of patterning defects in mouse mutants. I will use transcription factor and signalling pathway fluorescent reporters to map the spatial and temporal requirements of BMP, Activin/Nodal and Wnt pathways for patterning at a quantitative single cell resolution in real-time. Using this data, in collaboration with the Siggia lab, mathematical models will be generated and tested to predict the phenotypic outcome of signalling combinations.

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

The role of the mitotic spindle assembly checkpoint (SAC) protein BUB3 in tumourigenesis. 13 Apr 2015

The spindle assembly checkpoint (SAC) ensures the correct partition of chromosomes during mitosis. Depleting SAC proteins together with apoptosis inhibition leads to tumourigenesis. This project builds on a tumourigenesis model in Drosophila to address the role of SAC in hyperproliferation, metabolic regulation and tumour evolution. Initially I will study candidate genes uncovered by microarray analysis of a tumour generated by knocking down the SAC gene Bub3. As the cells' metabolic response ad apts to proliferation requirements it is clear that there must be a cross talk between cell cycle and metabolic control. To address this hypothesis, an enhancer/suppressor screen looking for metabolic proteins with links to cell cycle will be performed. The tumorigenic model derived from cell cycle defects affecting genomic integrity, will also be used to study tumour evolution. The use of a tumourigenesis fly model will exclude some difficulties of these studies in humans as tumours can be samp led at multiple stages. In addition, the tumour growth will not be limited by the life span of the hosts as the immortalized tumour can grow indefinitely through serial transplantations in inbred flies. Altogether the results will identify novel genomic loci and alterations responsible for tumour growth and cellular survival.

Amount: £446,052
Funder: The Wellcome Trust
Recipient: University of Cambridge

Bioinformatics analysis of the mammalian germline and early development. 09 Feb 2015

Germ cells exhibit unique and comprehensive erasure and re-establishment ofepigenetic information, which is critical for totipotency and the transmission of geneticand epigenetic information with long-term consequences for subsequent generations1.The principles of germline biology have the potential to provide core knowledge for thecontrol and manipulation of cell fates in developing and diseased tissues.A clear understanding of the transient state of competence is required first, together withhow these primed cells respond specifically to the critical regulators of mouse primordialgerm cell (PGC) specification. Importantly, with germ cells we also have a uniqueopportunity to identify and understand how epigenetic regulators can systematicallyreset the epigenome, even of the somatic nuclei when exposed in oocytes.Understandably, we know least about the largely inaccessible early human germ cells(hPGC), but we have opportunities to establish credible in vitro models through inductionof competence in pluripotent and induced stem cells (hESC and hiPS) for the generationand systematic studies of hPGCs.Accumulation of genome scale information on early mammalian germ cells mightimprove the prospects for the integration and modelling of dynamic changes regulatingkey germline properties, and allow testable predictions about the performance of thiscrucial lineage. This may also help to build experimental models that mimic keygermline properties and through this, a route to the experimental manipulation of cellfates and physiology.

Amount: £163,156
Funder: The Wellcome Trust
Recipient: University of Cambridge

Exploring the impact of obesity and ageing on brain structure in a large cohort of healthy people. 08 Jun 2015

The funds are requested to provide support for the development of a program ofstructural neuroimaging data analysis, extending existing preliminary work carried out opportunistically under the support of the existing award. The flexibility provided by this award enabled me and my post-doctoral research (Dr Lisa Ronan) to develop preliminary ideas and perform exploratory analyses concerning the functional significance of traditional structural measures and of a novel measure that we have developed (Ronan et al, 2011). This has been extended both to empirically-supported theoretical insights about the significance of these structural measures (Ronan et al, 2012, 2014; Ronan and Fletcher 2015; Wagstyl et al 2015) and to direct applications to patient datasets (Ronan et al 2014). I have been especially excited at the implications that this developing work has for offering new ways of interpreting MRI measures of brain structure in health and disease.

Amount: £130,314
Funder: The Wellcome Trust
Recipient: University of Cambridge

Structural cell biology of transport vesicle and organelle biogenesis 07 Aug 2015

My two main and interrelated research questions are: How are different cargoesselected for incorporation into different transport vesicles? How are organelle biogenesis membrane fusion events regulated? Both processes require the complex interplay between many proteins and must also involve interactions with phospholipid membrane components. In the cell, all of theseinteractions must be temporally and spatially regulated to allow cellular lifeto continue and so we also want to understand how such regulation is achieved.We also wish to investigate how certain pathogens, especially retroviruses, recruit the cell's vesicle trafficking machinery to facilitate infection.

Amount: £108,864
Funder: The Wellcome Trust
Recipient: University of Cambridge

High resolution imaging . 11 Jun 2015

Microscopy is a fundamental tool for studying cellular processes at subcellular resolution, and for dissecting in fine detail the mechanisms by which these occur. Research at the CIMR aims to understand the cellular basis of disease, and the microscopes requested in this application will be vital for our continued study of fundamental cell biological processes, with particular emphasis on membrane trafficking, organelle function, protein homeostasis and folding, the cytoskeleton and autophagy. R esearch goals of the co-applicants highlighted here include the study of adaptor proteins in the formation of specific transport vesicles and control of cargo selection (Robinson lab); the regulation of endosome to Golgi transport (Seaman lab); the roles of myosin motors in membrane transport processes and autophagy (Buss lab); and the mechanisms driving T cell polarization during immune synapse formation and killing (Griffiths lab). The microscopy equipment requested will permit complementary essential analyses for this research, including improved quantification of phenotypes and unbiased cell screening, increased resolution for live cell imaging, improved widefield imaging over longer time periods, and analysis of ultrastructural detail in fixed samples.

Amount: £500,000
Funder: The Wellcome Trust
Recipient: University of Cambridge
Amount: £164,033
Funder: The Wellcome Trust
Recipient: University of Cambridge
Amount: £164,033
Funder: The Wellcome Trust
Recipient: University of Cambridge
Amount: £164,033
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge, Developmental mechanisms. 22 Jun 2015

Not available

Amount: £164,033
Funder: The Wellcome Trust
Recipient: University of Cambridge