The Roslin Institute is an animal science research institute at Easter Bush, Midlothian, Scotland, part of the University of Edinburgh, that is sponsored by the Biotechnology and Biological science Research Council. The current director is Professor David Hume FRSE. The Institute won international fame in 1996, when Ian Wilmut, Keith Campbell and their colleagues created Dolly the sheep, the first mammal to be cloned from an adult cell, at the institute. A year later Polly and Molly were cloned, both sheep contained a human gene.Roslin has made many other contributions to animal science, especially in the area of livestock improvement and welfare through applications of Quantitative Genetics. In 2007 a Roslin team developed genetically modified chickens capable of laying eggs containing proteins needed to make cancer-fighting drugs.In April 2007, The Roslin Institute was joined by the Neuropathogenesis Unit of the Institute for Animal Health, well known for its role in deciphering the biology of transmissible spongiform encephalopathies . In 2008, the Institute was incorporated with the Royal School of Veterinary Studies within the College of Medicine and Veterinary Medicine of The University of Edinburgh. There are currently more than 400 staff and students. The Roslin Institute aims to enhance the lives of animals and humans through world class research in animal biology. The principal objectives are to: Enhance animal health and welfare through knowledge of genetic factors affecting resistance to disease. Enhance sustainability and productivity of livestock systems and food supply chains through understanding of reproductive and developmental biology. Enhance food safety by understanding interactions between disease causing organisms and animals. Enhance human health through an understanding of basic mechanisms of health and disease and comparative biology of animal species. Identify new and emerging zoonoses and understand how pathogens might cross from animals to humans. Enhance quality of life for animals by studying the mechanisms and behaviours associated with optimising their environment and life experiences.In March 2011 The Roslin Institute moved from its previous home in Roslin, a village in Midlothian, to a £60.6M building on the University of Edinburgh's Veterinary Campus at Easter Bush, across the road from the Royal School of Veterinary Studies' new teaching building. The new building was designed by global architecture firm, HDR, Inc..The Roslin Institute and Vet School are part of a formal consortium, the Easter Bush Research Consortium, with the Moredun Research Institute and the Scottish Agricultural College. Wikipedia.
Hume D.A.,Roslin Institute |
MacDonald K.P.A.,Queensland Institute for Medical Research
Blood | Year: 2012
Macrophage-colony stimulating factor (CSF-1) signaling through its receptor (CSF-1R) promotes the differentiation of myeloid progenitors into heterogeneous populations of monocytes, macrophages, dendritic cells, and bone-resorbing osteoclasts. In the periphery, CSF-1 regulates the migration, proliferation, function, and survival of macrophages, which function at multiple levels within the innate and adaptive immune systems. Macrophage populations elicited by CSF-1 are associated with, and exacerbate, a broad spectrum of pathologies, including cancer, inflammation, and bone disease. Conversely, macrophages can also contribute to immunosuppression, disease resolution, and tissue repair. Recombinant CSF-1, antibodies against the ligand and the receptor, and specific inhibitors of CSF-1R kinase activity have been each been tested in a range of animal models and in some cases, in patients. This review examines the potential clinical uses of modulators of the CSF-1/CSF-1R system. We conclude that CSF-1 promotes a resident-type macrophage phenotype. As a treatment, CSF-1 has therapeutic potential in tissue repair. Conversely, inhibition of CSF-1R is unlikely to be effective in inflammatory disease but may have utility in cancer. © 2012 by The American Society of Hematology.
Hume D.A.,Roslin Institute
Frontiers in Immunology | Year: 2015
Monocytes and macrophages provide the first line of defense against pathogens. They also initiate acquired immunity by processing and presenting antigens and provide the downstream effector functions. Analysis of large gene expression datasets from multiple cells and tissues reveals sets of genes that are co-regulated with the transcription factors that regulate them. In macrophages, the gene clusters include lineage-specific genes, interferon-responsive genes, early inflammatory genes, and genes required for endocytosis and lysosome function. Macrophages enter tissues and alter their function to deal with a wide range of challenges related to development and organogenesis, tissue injury, malignancy, sterile, or pathogenic inflammatory stimuli. These stimuli alter the gene expression to produce "activated macrophages" that are better equipped to eliminate the cause of their influx and to restore homeostasis. Activation or polarization states of macrophages have been classified as "classical" and "alternative" or M1 and M2. These proposed states of cells are not supported by large-scale transcriptomic data, including macrophage-associated signatures from large cancer tissue datasets, where the supposed markers do not correlate with other. Individual macrophage cells differ markedly from each other, and change their functions in response to doses and combinations of agonists and time. The most studied macrophage activation response is the transcriptional cascade initiated by the TLR4 agonist lipopolysaccharide. This response is reviewed herein. The network topology is conserved across species, but genes within the transcriptional network evolve rapidly and differ between mouse and human. There is also considerable divergence in the sets of target genes between mouse strains, between individuals, and in other species such as pigs. The deluge of complex information related to macrophage activation can be accessed with new analytical tools and new databases that provide access for the non-expert. © 2015 Hume.
Jenkins S.J.,University of Edinburgh |
Hume D.A.,Roslin Institute
Trends in Immunology | Year: 2014
The mononuclear phagocyte system (MPS) is a family of functionally related cells including bone marrow precursors, blood monocytes, and tissue macrophages. We review the evidence that macrophages and dendritic cells (DCs) are separate lineages and functional entities, and examine whether the traditional view that monocytes are the immediate precursors of tissue macrophages needs to be refined based upon evidence that macrophages can extensively self-renew and can be seeded from yolk sac/foetal liver progenitors with little input from monocytes thereafter. We review the role of the growth factor colony-stimulating factor (CSF)1, and present a model consistent with the concept of the MPS in which local proliferation and monocyte recruitment are connected to ensure macrophages occupy their well-defined niche in most tissues. © 2014 Elsevier Ltd.
Hume D.A.,Roslin Institute |
Freeman T.C.,Roslin Institute
Immunological Reviews | Year: 2014
Monocytes and macrophages differentiate from progenitor cells under the influence of colony-stimulating factors. Genome-scale data have enabled the identification of the sets of genes that are associated with specific functions and the mechanisms by which thousands of genes are regulated in response to pathogen challenge. In large datasets, it is possible to identify large sets of genes that are coregulated with the transcription factors that regulate them. They include macrophage-specific genes, interferon-responsive genes, early inflammatory genes, and those associated with endocytosis. Such analyses can also extract macrophage-associated signatures from large cancer tissue datasets. However, cluster analysis provides no support for a signature that distinguishes macrophages from antigen-presenting dendritic cells, nor the classification of macrophage activation states as classical versus alternative, or M1 versus M2. Although there has been a focus on a small subset of lineage-enriched transcription factors, such as PU.1, more than half of the transcription factors in the genome can be expressed in macrophage lineage cells under some state of activation, and they interact in a complex network. The network architecture is conserved across species, but many of the target genes evolve rapidly and differ between mouse and human. The data and publication deluge related to macrophage biology require the development of new analytical tools and ways of presenting information in an accessible form. © 2014 John Wiley & Sons A/S.
Hume D.A.,Roslin Institute
Journal of Leukocyte Biology | Year: 2012
Monocytes and macrophages differentiate from progenitor cells under the influence of colony-stimulating factors. Genome-scale data have enabled the identification of the set of genes that distinguishes macrophages from other cell types and the ways in which thousands of genes are regulated in response to pathogen challenge. Although there has been a focus on a small subset of lineage-enriched transcription factors, such as PU.1, more than one-half of the transcription factors in the genome can be expressed in macrophage lineage cells under some state of activation, and they interact in a complex network. The network architecture is conserved across species, but many of the target genes evolve rapidly and differ between mouse and human. The data and publication deluge related to macrophage biology require the development of new analytical tools and ways of presenting information in an accessible form. The website www.macrophages. com is a community website that partly fills this niche. © Society for Leukocyte Biology.
Brunton P.J.,Roslin Institute
Reproduction | Year: 2013
A suboptimal in utero environment, for example, as a result of maternal stress, can have detrimental effects on the pregnancy and long-term adverse 'programming' effects on the offspring. This article focuses on the effects of prenatal social stress on the mother, her pregnancy and the offspring, since these issues have ethological relevance in both animals and humans. The consequences of social stress exposure depend on when during pregnancy the stress occurs, and many of the effects on the offspring are sex specific. Social stress during early pregnancy tends to result in pregnancy loss, whereas stress exposure later in pregnancy, when the mother has already invested considerable resources in the foetuses, results in programmed offspring of low birth weight: a risk factor for various adulthood diseases. Neuroendocrine and behavioural responses to stress in the offspring are particularly sensitive to foetal programming by prenatal stress, indicated by enhanced hypothalamo-pituitary- adrenal (HPA) axis responses and increased anxiety behaviour, which result from permanent changes in the offspring's brain. The dysregulation of HPA axis function may also interfere with other systems, for example, the hypothalamic-pituitary-gonadal axis, as there is evidence for alterations in steroidogenesis, reproductive potential and impaired reproductive/social behaviours in prenatally stressed offspring. Prenatal social stress also programmes future maternal behaviour, highlighting the potential for negative phenotypes to be transmitted to future generations. The possible mechanisms through which maternal stress during pregnancy is transmitted to the foetuses and the foetal brain is programmed by prenatal stress and the potential to overwrite programming of the offspring are discussed. © 2013 Society for Reproduction and Fertility.
Fitzgerald J.R.,Roslin Institute
Trends in Microbiology | Year: 2012
Staphylococcus aureus is a major pathogen responsible for severe nosocomial and community-associated infections of humans and infections of economically important livestock species. In recent years, studies into livestock-associated S. aureus including methicillin-resistant (MRSA) strains have provided new information regarding their origin and host adaptation, and their capacity to cause zoonotic infections of humans. Furthermore, a potential role for human activities such as domestication and industrialisation in the emergence of S. aureus clones affecting livestock has been highlighted. Here, I summarise recent developments in this emerging field and suggest questions of importance for future research efforts. © 2012 Elsevier Ltd.
Grey F.,Roslin Institute
Journal of General Virology | Year: 2015
The identification of virally encoded microRNAs (miRNAs) has had a major impact on the field of herpes virology. Given their ability to target cellular and viral transcripts, and the lack of immune response to small RNAs, miRNAs represent an ideal mechanism of gene regulation during viral latency and persistence. In this review, we discuss the role of miRNAs in virus latency and persistence, specifically focusing on herpesviruses. We cover the current knowledge on miRNAs in establishing and maintaining virus latency and promoting survival of infected cells through targeting of both viral and cellular transcripts, highlighting key publications in the field. We also discuss potential areas of future research and how novel technologies may aid in determining how miRNAs shape virus latency in the context of herpesvirus infections. © 2015 The Authors.
Mabbott N.A.,Roslin Institute
Immunology | Year: 2011
Follicular dendritic cells (FDC) are an important subset of stromal cells within the germinal centres of lymphoid tissues. They are specialized to trap and retain antigen-containing immune complexes on their surfaces to promote B-cell maturation and immunoglobulin isotype class-switching. However, little is known of the cell types from which FDC originate. To address fundamental questions associated with the relationships between FDC and other cell populations, we took advantage of the growing body of publicly available data for transcriptome analysis. We obtained a large number of gene expression data files from a range of different primary mouse cells and cell lines and subjected these data to network-based cluster analysis using BiolayoutExpress(3D) . Genes with related function clustered together in distinct regions of the graph and enabled the identification of transcriptional networks that underpin the functional activity of distinct cell populations. Several gene clusters were identified that were selectively expressed by cells of mesenchymal lineage and contained classic mesenchymal cell markers and extracellular matrix genes including various collagens, Acta2, Bgn, Fbn1 and Twist1. Our analysis showed that FDC also express highly many of these mesenchyme-associated genes. Promoter analysis of the genes comprising the mesenchymal clusters identified several regulatory motifs that are binding sites for candidate transcription factors previously known to be candidate regulators of mesenchyme-specific genes. Together, these data suggest FDC are a specialized mesenchymal cell population within the germinal centres of lymphoid tissues. © 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.
Simmonds P.,Roslin Institute
Current Topics in Microbiology and Immunology | Year: 2013
The origin of hepatitis C virus (HCV) can be conceptualised at several levels. Firstly, origins might refer to its dramatic spread throughout the Western world and developing countries throughout the twentieth century. As a blood-borne virus, this epidemic was fuelled by new parenteral transmission routes associated with medical treatments, immunisation, blood transfusion and more recently injecting drug use. At another level, however, origins might refer to the immediate sources of HCV associated with its pandemic spread, now identified as areas in Central and West sub-Saharan Africa and South and South East Asia where genetically diverse variants of HCV appear to have circulated for hundreds of years. Going back a final step to the actual source of HCV infection in these endemic areas, non-human primates have been long suspected as harbouring viruses related to HCV with potential cross-species transmission of variants corresponding to the 7 main genotypes into humans. Although there is tempting analogy between this and the clearly zoonotic origin of HIV-1 from chimpanzees in Central Africa, no published evidence to date has been obtained for infection of HCV-like viruses in either apes or Old World monkey species. Indeed, a radical re-think of both the host range and host-specificity of hepaciviruses is now required following the very recent findings of a non-primate hepacivirus (NPHV) in horses and potentially in dogs. Further research on a much wider range of mammals is needed to better understand the true genetic diversity of HCV-like viruses and their host ranges in the search for the ultimate origin of HCV in humans. © 2013 Springer-Verlag Berlin Heidelberg.