RESEARCH PROFILE
- 2008 RAE Result: During the period 2001 until end-2007, over 70 per cent of our research outputs and activities were rated as world-leading or internationally excellent, with particular commendation of individuals whose work was outstanding in every category assessed.
- Research income: >£24m over the last three years.
- Current number of research teams: 30.
- Current number of research PhD students: 76.
- Recent publications:
- Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery. Science.
- CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl AcadSci USA.
- The structural basis of T cell autoimmunity. Nature Immunology.
- Retroviruses can establish filopodial bridges for efficient cell-to-cell transmission. Nature Cell Biology.
- A revised classification of monocyte, macrophage, and dendritic cell development and subsetting. Science & Annu Rev Immunology.
- A novel linkage between lymphoid stress-surveillance and atopy. Science.
- Epidermal Dendritic Cells promote carcinogenesis via metabolism of environmental hydrocarbons. Science.
KEY FACTS
Student destinations
Contact Division for details.
Head of group/division
Professor Adrian Hayday
Duration
Expected to be three years FT or up to six years PT. Registration normally October, although students may commence at any time.
Location
Mainly Guy's Campus and sometimes St Thomas' and Denmark Hill campuses.
Year of entry 2013
Offered by
School of Medicine
Closing date
Named studentships will have a closing date stipulated on the advertisement. Self-funded students should apply at least three months before your proposed starting date.
Intake
No set number.
Fees
CONTACTS
Contact information
Suzanne Creighton 0207-188-3078
Email
Website
RESEARCH DESCRIPTION
Our Division uses a range of techniques from molecular genetics and biochemistry to clinical trial design to better understand the dynamic interplay between host defence mechanisms and viral and microbial determinants. These studies have exposed novel determinants of host protection against HIV-AIDS virus, and revealed how the virus depends upon key components of cell biology such as those that direct cell division. We examine what fails when host defence mechanisms mistakenly target uninfected tissues, causing autoimmune diseases such as rheumatoid arthritis and Type I diabetes, and ask how such mechanisms respond to tumours.
One major focus is on a refined understanding of the function and turnover of monocytes; another on the characterization of a novel lymphoid stress-surveillance response; and a third on the nature of T cell dysregulation that underpins MHC-restricted autoimmune diseases. We actively consider practical approaches to enhancing host responses to pathogens and to limiting autoimmunity, and we contribute to clinical trials novel approaches to measuring disease course and treatment outcome.
Major research programmes include:
- The study of lymphoid stress-surveillance in tumour rejection and in graft rejection;
- The mechanisms of action of human regulatory T cells;
- T cell development in the thymus;
- Factors that regulate the threshold for lymphocyte responses;
- Monocyte and dendritic cell function and development;
- The maturation of B cell responses in tissues;
- Approaches to immunotherapy;
- RNA trafficking and metabolism and its roles as in host defense and HIV pathogenesis;
- Viral budding mechanisms;
- Innate, cell-autonomous anti-viral responses;
- Antigen non-specific activation of innate immunity;
- Leukocyte trafficking;
- B cell and T cell responses that operate at the body's surfaces
- Vaccine and adjuvant design for both immunoprotection (infection / tumours);
- Immunosuppression (autoimmune disease).
We actively contribute to the Biomedical Research Centre of Guy’s and St Thomas’ Hospital Trusts, in which regard research into practical cell therapy programmes have just commenced.
We also have links with large and small pharmaceutical and biotech activities, via sponsored research agreements with Genentech, NovoNordisk, GSK, ImmuoQure
Staff interests associated with the research programme and its research groups
Interests:
Primary interest: B cell repertoire analysis, and molecular events involving the immunoglobulin gene during B cell development. Combining traditional molecular biology techniques with novel mathematical analyses to devise new ways of investigating the humoral immune system.
Research into ageing: Loss of immune system function with age results in the phenomenon termed “Immunosenescence.” This is associated with increased infectious disease morbidity and mortality, poor responses to vaccination, declines in established protective immunity, and increased incidence of autoimmune disorders. Until recently, most age-associated immune failures had been attributed to changes in T cell populations. However, there are many other changes in the immune system and, as data accumulate to show that B cells have a critical role in antigen presentation and regulation - in addition to their role as antibody producers - B cells and humoral immunity becomes highly significant.
High throughput analyses of B cell repertoire are used to investigate dynamics of vaccine responses and age-related changes thereof, primary and secondary immune deficiencies, aetiology of leukaemia/lymphoma, autoimmune diseases.
Tel:
020 7188 3058
Fax:
Email:
Website:
Interests:
The CMCBI was recently established in new laboratory space in King's College London (Division of Immunology, Infection and Inflammatory Diseases) with the support of the Arthritis Research Campaign (arc).
We aim to advance knowledge of the molecular and cellular mechanisms of inflammation, and to open roads to innovative treatment of inflammation and inflammatory diseases.
We use both molecular approaches and in vivo model system, to investigates the molecular and cellular pathways and networks that control inflammation. Research teams work on basic model of inflammation, as well as on human diseases. Research teams develop extensive collaboration between them and with other groups in the DIIID and in the Randall division and with collaborators accross the world
Tools available in the lab include intravital microscopy, flow cytometry and cell sorting, mouse husbandry, and a Fly lab. A strong core facility for genetics analysis is present on Campus.
The Centre is located in New Hunts House, Guy’s Hospital Campus, and housed together with the Randall division of Molecular Biophysics with his expertise in Molecular and Cell Biology, Physics, Chemistry and Maths, and the MRC Centre for Developmental Neurobiology. Research in the CMCBI is interdiciplinary.
Tel:
020 7848 6902
Fax:
0207 848 6743
Email:
Website:
Interests:
Tel:
Fax:
Email:
Website:
Interests:
My research areas include rheumatic disease epidemiology and clinical trial design. In particular I am working to develop the King’s Early Phase Clinical Trial Portfolio with a focus on developing treatments to treat or, hopefully in the future, prevent rheumatoid arthritis.
Tel:
Fax:
Email:
Website:
Interests:
Immune cell biology/signalling, Advanced optical microcopy and image analysis.
Tel:
Fax:
Email:
Website:
Interests:
Tel:
Fax:
Email:
Website:
Interests:
The impact of infection on the development and functional responsiveness of DC and monocytes; the regulation of monocyte, macrophage, and DC function by lipid bodies and the relationship to artherosclerotic disease where failure of this system may alter key scavenging activities.
Tel:
+44 (0) 207-848-6907
Fax:
Email:
Website:
Academic Rheumatology
Interests:
Tel:
020 7848 8631
Fax:
0207 848 8632
Email:
Website:
Interests:
Tel:
020 7848 5215
Fax:
Email:
Website:
Interests:
My research is undertaken as part of the clinical arm of the Academic Rheumatology Research Group led by Professor David Scott at Denmark Hill though there is close collaboration with other Academic Rheumatology Group members, with other local Trusts and with the Rheumatology Specialty Group of the local Comprehensive Local Research Network.
The research is funded by a variety of agencies including Arthritis Research UK and the NIHR and involves both primary (trials and observational studies) and secondary (systematic reviews) studies.
Clinical research in inflammatory arthritis
1) Clinical trials examining the role and relative effectiveness of disease modifying drugs and biologic in rheumatoid arthritis and spondyloarthropathies
2) Observational research on patient-derived, clinical and other outcome measures and prognostic markers in inflammatory arthritis
Health services research in inflammatory arthritis
1) Patient's perspective of primary and secondary care rheumatology and musculoskeletal services
2) Evaluation of service improvements and innovation in inflammatory arthritis and other rheumatology services
Other musculoskeletal diseases
Similar projects in soft tissue rheumatic diseases
Tel:
020 7848 5215
Fax:
Email:
Website:
Interests:
My research areas include rheumatic disease epidemiology and clinical trial design. In particular I am working to develop the King’s Early Phase Clinical Trial Portfolio with a focus on developing treatments to treat or, hopefully in the future, prevent rheumatoid arthritis.
Tel:
Fax:
Email:
Website:
Interests:
Main focus of research is that of immune regulation by heat shock proteins (stress proteins) in inflammatory disorders (mainly rheumatoid arthritis, inflammatory bowel disease and cardiovascular disease).
Modulation of inflammatory arthritis with the stress proteins HSP60 and BiP.
Antigen-specific CD4+ T cells appear to be a central component in the pathogenesis of a variety of human autoimmune diseases and animal models of autoimmunity. Such T cells can home to the target tissue where autoantigen is present and, after local activation, produce pro-inflammatory cytokines. These events lead to the recruitment and activation of both lymphocytes and monocytes that ultimately destroy the target tissue. Consequently, a search for antigens which could initiate and/or perpetuate T cell responses in arthritic joints is continuing. The characterisation of target antigens in autoimmune diseases is an important step towards understanding the aetiology of this group of conditions, and in designing specific immunotherapeutic regimes. Two such antigens identified in separate studies are the 60kD heat shock protein (hsp60) and the 70kD stress protein BiP. Surprisingly, immune responses to both these proteins are not pro-inflammatory but are instead classified as anti-inflammatory or regulatory. Hence continuing studies aim to utilise their regulatory potential to develop novel immunotherapeutic interventions in inflammatory diseases such as rheumatoid arthritis.
Circulating cell stress proteins, leukocyte function and cardiovascular disease.
There is growing evidence for the hypothesis that plasma levels of extracellular molecular chaperones, such as Hsp60 or Hsp70 correlate (positively or negatively) with susceptibility to coronary heart disease and stroke. The biological consequences of having high blood levels of such proteins are unknown. Nor have associations with subclinical coronary artery disease and risk of clinical cardiac events been established. Recent evidence has revealed that human lymphocytes are exquisitely sensitive to certain molecular chaperones with both activation and inhibition of cell function being found in vitro. The hypothesis being tested is that individuals with high levels of molecular chaperones in their circulation will evoke changes in lymphocyte function that may predispose to organ, particularly cardiovascular, pathology. This is being tested in studies combining molecular biological, immunological and epidemiological methods with cardiac imaging in a subset of the Whitehall II epidemiological cohort (a large group of civil servants who have had the development of any heart disease monitored over the past 15-20 years).
Tel:
020 7848 6041
Fax:
Email:
Website:
Interests:
Using proteomics, in a search for the initiating autoantigen in RA, we discovered, isolated and identified a powerful immunomodulatory protein, BiP. Human in vitro studies have investigated the effect of BiP on the activation of human peripheral blood monocytes and differentiation of dendritic cells (DC) and regulatory T cells (CD4+/CD8+). In parallel, BiP has been shown to have prophylactic and therapeutic action in the murine collagen–induced arthritis (CIA) disease model. The therapeutic effect of BiP in CIA appears to be long-lived suggesting a re-education of the immune system to produce regulatory cells which have been used to resolve CIA in adoptive transfer experiments. Thus BiP is the first human protein to be described that will induce functional regulatory cells by intravenous administration and in vitro in human mononuclear cell cultures.
Our present laboratory projects focussed on BiP include the following:
Search for the cell surface expressed receptor(s) for BiPInvestigation of the mechanism by which BiP directly affects T cells and DC inducing regulatory T cells and tolerogenic DC respectively.Future work will incorporate projects looking at the efficacy of BiP in osteoporosis and transplantation where preliminary in vitro data shows that BiP has therapeutic potential
As a translational project BiP has preliminary approval by the MHRA for a PhaseI/IIa clinical trial.
Tel:
020 7188 5907
Fax:
020 7188 5883
Email:
Website:
Immunobiology
Interests:
As a post-doctoral fellow with Susumu Tonegawa at MIT, I contributed to the molecular cloning and characterisation of translocated c-myc genes in human Burkitt's lymphoma, and to the T cell receptor (TCR) genes. This included the unanticipated identification of the TCR gamma chain, which was followed by the discovery of the hitherto unknown gamma delta T cells. Assuming an independent Faculty position at Yale, I adopted molecular genetic approaches, including the development of key gene knockout and transgenic models, to elucidate gamma delta T cell function and development.
Those studies collectively have illuminated several areas, including:
- 'beta-selection', a point in development where gamma delta T cell differentiation diverges from the development of most alpha beta T cells.
- the demonstration that, by contrast to the systemic distribution of diverse alpha beta T cells, gamma delta T cells are disproportionately associated with epithelial tissues, wherein they reside as oligoclonal repertoires of limited diversity.
- the demonstration that gamma delta cells can promote immunoglobulin synthesis by B cells, but that this is primarily self-reactive. In 1998, I assumed the Professorship in Immunobiology at the King's College School of Medicine on the Guy's Hospital site. Our work has continued to provide insight, including:
- identification of the role played by the c-myc proto-oncogene in T cell development
- the demonstration that skin-associated gamma delta T cells protect the skin from potentially pathologic infiltrates of systemic lymphocytes
- the demonstration that gamma delta T cells are a component of the natural resistance to skin carcinogenesis.
- the demonstration that the gene expression pattern that best distinguishes gamma delta T cells from most alpha beta T cells is shared with an unusual set of tissue-associated alpha beta T cells that we collectively term unconventional T cells
- the identification of 'trans-conditioning', a mechanism by which unconventtional T cell differentiation is strongly influenced by alpha beta T cell progenitors.
- the demonstration that trans-conditioning may also affect the body's balance of effector and regulatory T cells Our current research interests focus on how repertoires of tissue-associated unconventional T cells develop and function, including the identification of novel host-encoded molecules expressed by epithelial cells with which gamma delta T cells interact. Research findings are being applied in the clinic, where we have just completed a proof-of-principle trial of gamma delta T cell therapy in hormone-refractory prostate cancer, in collaboration with F Dieli (Palermo).
Tel:
Fax:
Email:
Website:
Interests:
Primary interest: B cell repertoire analysis, and molecular events involving the immunoglobulin gene during B cell development. Combining traditional molecular biology techniques with novel mathematical analyses to devise new ways of investigating the humoral immune system.
Research into ageing: Loss of immune system function with age results in the phenomenon termed “Immunosenescence.” This is associated with increased infectious disease morbidity and mortality, poor responses to vaccination, declines in established protective immunity, and increased incidence of autoimmune disorders. Until recently, most age-associated immune failures had been attributed to changes in T cell populations. However, there are many other changes in the immune system and, as data accumulate to show that B cells have a critical role in antigen presentation and regulation - in addition to their role as antibody producers - B cells and humoral immunity becomes highly significant.
High throughput analyses of B cell repertoire are used to investigate dynamics of vaccine responses and age-related changes thereof, primary and secondary immune deficiencies, aetiology of leukaemia/lymphoma, autoimmune diseases.
Tel:
020 7188 3058
Fax:
Email:
Website:
Interests:
The CMCBI was recently established in new laboratory space in King's College London (Division of Immunology, Infection and Inflammatory Diseases) with the support of the Arthritis Research Campaign (arc).
We aim to advance knowledge of the molecular and cellular mechanisms of inflammation, and to open roads to innovative treatment of inflammation and inflammatory diseases.
We use both molecular approaches and in vivo model system, to investigates the molecular and cellular pathways and networks that control inflammation. Research teams work on basic model of inflammation, as well as on human diseases. Research teams develop extensive collaboration between them and with other groups in the DIIID and in the Randall division and with collaborators accross the world
Tools available in the lab include intravital microscopy, flow cytometry and cell sorting, mouse husbandry, and a Fly lab. A strong core facility for genetics analysis is present on Campus.
The Centre is located in New Hunts House, Guy’s Hospital Campus, and housed together with the Randall division of Molecular Biophysics with his expertise in Molecular and Cell Biology, Physics, Chemistry and Maths, and the MRC Centre for Developmental Neurobiology. Research in the CMCBI is interdiciplinary.
Tel:
020 7848 6902
Fax:
0207 848 6743
Email:
Website:
Interests:
Mucosal immunology and development.
Tel:
Fax:
Email:
Website:
Interests:
Using (and developing in collaboration with physicists and engineers) cutting-edge microscopy techniques to investigate the molecular mechanisms of patolling monocytes in context
Defining the molecular interactions and signalling events at the monocyte and endothelial cell interface in vivo
Tel:
Fax:
Email:
Website:
Interests:
Molecular and cellular basis of HIV vaccine development; innate immunity and regulation of dendritic cell function; gene therapy development in models of rheumatoid arthritis.
Tel:
020 7188 0151
Fax:
Email:
Website:
Interests:
The activity of T cells is tightly controlled to ensure that effective immune responses can be elicited, whilst pathological inflammatory disorders are prevented. Numerous signals from cell-bound and soluble ligands influence the fate of T cells, and these need to be correctly relayed along multiple signalling pathways. We are interested in understanding the players and processes involved in these complex molecular networks. In particular, my lab focuses on the regulation of protein functions by posttranslational modifications through which we aim to gain insights into basic biological processes and to elucidate novel aspects of T cell regulation.
A longterm interest is the regulation of the tyrosine kinase Lck, a Src family member that is essential for T cell development and activation. In particular, we have investigated the palmitoylation and ubiquitination of this protein, two dynamic reversible modifications. More recently, we have begun to characterize novel ubiquitin ligases with functions in the immune system. Ubiquitination critically regulates many cellular processes by influencing substrate functions in a variety of degradation-dependent and independent ways, but the proteins that mediate this modification remain poorly characterized. We are specifically studying the functions of the ubiquitin ligase RNF125, which influences T cell activation and may additionally be involved in innate anti-viral responses. A protein related to RNF125, RNF114, was recently identified as a psoriasis susceptibility gene in a whole genome association scan. The functions of this protein, and how it contributes to psoriasis, is another major research area in the lab.
Tel:
020 7188 3060
Fax:
Email:
Website:
Interests:
Type 1 diabetes; T lymphocyte function; endocrine autoimmunity; immunotherapy.
Tel:
020 7188 0148
Fax:
020 7188 3385
Email:
Website:
Interests:
Our background is in viral recognition by dendritic cells and we have studied dendritic cell activation via several pattern recognition receptors in the past. The main viral pathogen-associated molecular patterns that are recognised by the innate immune system are viral nucleic acids and there are cytoplasmic and endosomal pattern recognition receptors with the ability to sense viral single-stranded RNA, viral double-stranded RNA and viral DNA. Dendritic cells are not the only cells expressing these pattern recognition receptors, but because of their crucial role in the instruction of adaptive immune responses, the mechanisms of their activation is of particular importance.
We have an interest in developing new vaccination approaches for tumour immunotherapy. Tumours can express tumour-associated antigens that are recognized by the adaptive immune system. Nevertheless, tumour cells are poor inducers of immune responses since they lack stimuli such as pathogen-associated molecular patterns that efficiently activate the innate immune system. Viral nucleic acids represent ideal, molecularly defined adjuvants to promote the induction of effective anti-tumour immune responses. Therefore, we explore the application of synthetic mimics of viral nucleic acids as adjuvants in the context of tumour immunotherapy.
Tel:
020 7188 1181
Fax:
020 7188 3385
Email:
Website:
Interests:
Cytokines are potent mediators of cell-cell communication, whose expression and functions are tightly regulated at the level of magnitude and duration, by transcriptional and post-translational mechanisms. Upon binding to their cognate receptors, virtually all cytokines signal by activating the evolutionarily conserved JAK-STAT signalling pathway leading to regulation of diverse cellular functions ranging from embryonic stem cell renewal to regulation of the immune system. There are four Janus activated Kinases (JAK1-3 and Tyk2) and seven signal transducers and activators of transcription proteins (STAT1-4, 5a, 5b and 6).
The biological importance of the JAK-STAT signalling pathway was indicated by the severe combined immunodeficiency (SCID) of patients lacking functional JAK3 kinase, that associates exclusively with the common gamma-chain (γc), which is shared by members of the immunologically important IL-2-family of cytokines. Additionally, genetic mutations in Tyk2, STAT1, STAT3, and STAT5B have been shown to cause various immunodeficiencies, indicating the profound importance of an intact JAK-STAT signaling pathway to normal cellular integrity and immune function.
By virtue of the fact that STAT proteins play vital roles in the proliferative, differentiation and survival decisions of cells, constitutively activated STATs, particularly STAT3 and STAT5, have been detected in a variety of human primary tumours, haematopoietic tumours such as leukaemias, lymphomas, multiple myelomas and cellular transformation by viral or cellular oncogenes. Previously, we showed that dysregulation of STAT5 proteins contributes to the pathology of malignant T cells in Sezary Syndrome. Moreover, over-expression of constitutively activated STAT3 and STAT5, or wild-type or a C-terminally truncated form of Stat5 (Stat5t), induced tumours in transgenic mouse models, suggesting that these two STAT proteins regulate transcription of important target genes, whose aberrant expression can lead to cellular transformation.
We are interested in understanding the molecular mechanisms by which STAT5A, STAT5B and to a lesser extent STAT3, mediate the actions of IL-2 in T cells. As IL-2 regulates many critical aspects of immunity, such as activation induced cell death (AICD) of T cells, tolerance and autoimmunity, via the JAK-STAT5 pathway, a detailed molecular understanding of how these STAT proteins are regulated, and the target genes they regulate should enable us to identify novel therapeutic targets for use in diseases associated with the dysregulation of IL-2/IL-2R system. To this extent we are undertaking structure-function studies of the two highly homologous proteins, STAT5A and STAT5B to understand how they interact with DNA, and whether they differ in this process. In other studies, we have identified a number of novel IL-2-induced target genes of STAT5A and STAT5B by chromatin immunoprecipitation, and studies are underway to validate and evaluate several of these candidate genes at the expression and functional level. We also have on-going collaboration with the lab of Prof. Giovanna Lombardi and Prof. Robert Lechler on the role of STAT3/STAT5 in Treg cell differentiation under inflammatory conditions.
Tel:
020 7188 3071
Fax:
0207-188-3385
Email:
Website:
Interests:
Role of autoreactive and regulatory T cells in human health, disease and transplantation. Developing statergies to strengthen immune regulation.
Tel:
020 7188 1182
Fax:
020 7188 3385
Email:
Website:
Infectious Diseases
Interests:
HIV research - mechanisms of resistance to HIV infection at the CD4+ T cell level; immunological marker of disease; gene therapy in HIV infection.
Tel:
Fax:
Email:
Website:
Interests:
Clinical trials in HIV infection; especially immunopathogenesis, vaccine,metabolic and drug trials.
Tel:
020 7188 2662
Fax:
Email:
Website:
Interests:
The major focus of my research is to understand how the composition and structure of retroviral genomic ribonucleoprotein particles (gRNPs), particularly that of HIV-1, regulates the different steps of their lifecycle. Currently, we are focusing on how HIV-1 Gag translation is regulated and how this is similar and different to that of cellular transcripts. Other research interests include how the composition of the HIV-1 gRNP regulates virion assembly and reverse transcription.
Tel:
020 7188 8272
Fax:
Email:
Website:
Interests:
The laboratory has combined efforts in virology, stem cell biology and molecular biology to elucidate the mechanism of site-specific integration of adeno-associated virus (AAV). In order to establish latency, this non-pathogenic, non-autonomous parvovirus has evolved to integrate its genome site-specifically into human chromosome 19. It is this unique mechanism that could potentially be exploited in the development of safe gene and cell based therapies. To date, gene therapy studies have mainly employed gamma-retroviral vectors, which establish persistence through integration in a largely random fashion. Inherent to this approach is that the chromosomal context and thus the expression of a transgene will vary between vector-transduced cells. In addition, while in differentiated cells the potential for insertional mutagenesis might be negligible, in cells with high proliferation potential, e.g. stem cells, this aspect becomes important. The mutagenesis potential has been documented by the emergence of leukemia as a result of retrovirally mediated gene therapy of X-linked SCID in an otherwise highly successful clinical trial. At the basis of the development of technologies that employ site-specific integration is a thorough understanding of the site and mechanism of integration. Our findings that the chromosomal signals required for human site-specific integration are conserved in the mouse genome in a region corresponding to the human target site opened up the possibility to study site-specific integration in mouse embryonic stem cells (ES). Stringent in vitro and in vivo assays developed for this cell type allowed for the read-out of potential effects of disruption of the genes that are embedded in the integration site. Detailed molecular analysis of the integration event in mouse ES cells as well as other human cell types demonstrated that site-specific integration of transgenes or wild type virus occurs predominantly in a gene called MBS85, and this without causing a functional disruption of the gene. This was confirmed using the various ES-cell specific in vitro and in vivo assays. In addition, we could demonstrate that transgene expression from this particular site remained robust throughout differentiation of mouse ES cells, a prerequisite for the development of gene transfer technologies in stem cells that incorporate the mechanism of site-specific integration. Future experiments will be designed to unravel the intricacies of the integration mechanism. We will address questions such as which proteins, besides the viral Rep protein, are involved and do genomic structures play a role? In addition, we will continue our efforts to optimize gene targeting strategies in human ES cells (and iPS cells) as preliminary experiments have shown that AAV-mediated transgene integration is feasible in the cell type that holds the promise to be used in future cell therapies. The study of human ES cell differentiation and derivation of mature tissue-specific cells will likely require genetic manipulation and in a setting in which stem cells will be expanded, differentiated and ultimately transplanted, prior knowledge of the site of integration and possible effects of the transgene cassette on the regulation of surrounding genes will be most advantageous. Finally, we are exploring new technologies that would allow for Rep-mediated site-specific transgene integration in hematopoietic stem cells that have proven to be resistant to AAV infection.
Tel:
020 7188 8276
Fax:
020 7188 3385
Email:
Website:
Interests:
Tel:
Fax:
Email:
Website:
Interests:
The role of iron in development of immunity, particularly in its role in driving inflammatory processes both in autoimmune diseases such as rheumatoid arthritis as well as infectious diseases.
Tel:
020 7848 6044
Fax:
Email:
Website:
Interests:
virus-host interactions during HIV-1 infections. Interests include host restriction factors, factors that support HIV-1 replication and the metabolic demand exerted by HIV infections.
Tel:
020 7188 8275
Fax:
na
Email:
Website:
Interests:
With the successful introduction of effective vaccines against the oncogenic types of human papillomavirruses the focus of my research has been retargetted against human immunodeficiency virus. In particular I am interested in the potential virological and host factors which may be involved in the delay of disease onset. To this end we are currently studying patients who have an extended disease-free period (long term non-progressors).
Tel:
020 7188 1180
Fax:
Email:
Website:
Interests:
The two main research projects focus on understanding mechanisms of staphylococcal (predominantly methicillin-resistant Staphylococcus aureus MRSA) disease pathogenesis and transmission in the hospital setting.
- Identification of a highly bacteraemic strain of MRSA. During 2003/2004 the Trust had high rates of MRSA bacteremia. The result of a detailed epidemiological study identified that a significant reason for this was an extended outbreak on the ICU with a novel variant of MRSA, designated TW. This strain had an enhanced capacity to bind vascular access devices leading to bloodstream invasion. A targeted introduction of basic infection control and a novel decolonisation strategy led to termination of the outbreak. We have performed microarray-based analysis of this strain and are performing full genomic sequencing (collaborators Dr Jodi Lindsay, St George's University of London and Dr Julian Parkhill, Sanger Insititute, Cambridge). We are currently investigating the mechanism of adhesion and invasion in vitro which combined with the awaited genome sequence will potentially provide insight into the basic mechanism of MRSA bacteraemia and identify novel approaches to prevention. It may also identify genetic markers for hyperinvasive strains that can be used to assess the distribution of such strains across the UK for targeted enhanced infection control strategies.
- MRSA transmission dynamics. Following the detailed ICU analysis it became apparent that our enhanced infection control efforts led to a sustained (more than 2 years) prevention of MRSA cluster outbreaks on the ICU and only a residuum of sporadic acquisitions. We are developing mathematical models of transmission dynamics through analysis of data from the ICU over the last 5 years to assess the reduction in risk of MRSA acquisition, assess the confidence with which the reduction can be ascribed to the enhanced interventions and to compare the transmissibility of different strains including TW in collaboration with Dr Ben Cooper, Health Protection Agency).
Tel:
020 7188 1285
Fax:
Email:
Website:
Interests:
The last step in retroviral life cycle is the separation of the nascent viral particle from the infected cell. HIV-1 and other retroviruses encode a so-called Late Budding domain (L-domain) whose mutation induces the accumulation of immature virions that remain tethered to the plasma membrane by a membranous stalk. Work by our group and other laboratories has identified the cellular protein Tsg101 as the cellular partner that facilitates HIV-1 and Ebola virus budding thorough the interaction with a highly conserved aminoacid motif (PTAP) in the L-domain of these pathogens. Subsequently, it has been shown that other viruses that include HIV-2, HTLV and Lassa fever virus also require Tsg101 for particle budding, thus emphasizing the importance of this protein in human disease. Tsg101, the mammalian orthologue of the yeast protein Vps23, is one of the subunits of a 350 kd complex (endosomal sorting complex required for transport-I, ESCRT-I) which also includes Vps28 and Vps37. Tsg101 is a component of the class E pathway and is required both for the budding of viruses that encode PTAP type L-domains and the topologically equivalent process of vesicle budding into Multivesicular Bodies (MVB). Recent work by our laboratory and others has identified 19 human genes of the class E pathway that participate in budding of highly divergent enveloped viruses and, perhaps, MVB biogenesis. Importantly, a greater understanding of how HIV-1 viruses exploit the host cell to facilitate the budding process could provide opportunities for chemotherapeutic intervention using a completely novel class of antiviral compounds that would be active against a number of human pathogens including HIV-1, HIV-2, Ebola virus, HTLV, Lassa fever virus and essentially any virus that exploits the PTAP/Tsg101 interaction during budding. Our work with the ESCRT proteins has recently led to the discovery of and exciting link between retroviral budding and abscission, the last step in cell division. We have described that Tsg101 and ALIX are recruited to the midbody by Cep55 to mediate the separation of the daughter cells through a mechanism that is topologically similar to HIV-1 budding.
Tel:
020 7188 7137
Fax:
Email:
Website:
Interests:
Our lab is interested in the broad fields of virus-host interactions and HIV/AIDS molecular pathogenesis. To this end, we employ assorted molecular-genetic, cultured cell, biochemical, structural, bioinformatic and cohort-based methods to study the biological principles that underpin HIV infection, replication and disease. Indeed, over the last twenty years, our research has spanned many facets of HIV replication, including viral RNA processing and nuclear export, virus particle assembly, the infection of non-proliferating cells and the role(s) played by the regulatory/accessory proteins of HIV.
Current work in the group addresses: 1) the activity of the cellular viral resistance factor, APOBEC3G, its antagonism by the virus-encoded Vif protein; 2) the impact of cellular RNA-rich microdomains, P-bodies and stress granules, in HIV replication and APOBEC3G biology; 3) the immediate cellular response to HIV infection and the interplay between alpha interferon and HIV infection; and 4) the link between viral RNA trafficking and HIV particle assembly.
Tel:
020 7188 0149
Fax:
020 7188 0147
Email:
Website:
Interests:
I am interested in understanding the mechanisms by which mammalian cells coordinate the reorganization of their cytoskeleton with membrane remodeling events, a key step during physiological processes like viral infection and the last steps of cell division. For this purpose we are using comprehensive and interdisciplinary experimental methods in cell biology and virology.
Tel:
Fax:
Email:
Website:
Interests:
The study of adeno-associated virus (AAV) has brought our laboratory to the intersection of basic virological, genetic and biochemical studies with translational efforts, both in the gene transfer arena and the newly evolving stem cell discipline. In addition, we have committed considerable efforts to the establishment of an AAV vector core, with particular emphasis on scientific and organizational issues that allow for an efficient and appropriate process in providing recombinant AAV to a number of collaborating laboratories. The biology of AAV and AAV-based vectors Adeno-associated viruses (AAVs) have been studied since the early 1960s. In contrast to other human DNA viruses it has become clear that there is no significant correlation between the widespread infection by AAV throughout the population and any known disease entity. Studies throughout the past several decades have led to an emerging view that AAV might have evolved a possibly optimal relationship with its host through a unique life style that allows the virus to only replicate in cells that are infected by other viruses, which by themselves are deleterious to the host cell. Through this dependency AAV might have overcome an apparent challenge to viral life cycles in general: on one hand viruses depend on their respective hosts for replication, on the other, most viruses hurt the hosts through their replication to various degrees. Through its dependency, AAV will only replicate in cells that are affected by the consequences of helper virus infection. Thus, if our findings from tissue culture studies can be extrapolated to the human host, infection by AAV could indeed be viewed as beneficial to the host in that cells that are infected by adenovirus, herpes viruses and possibly papilloma viruses will die as a result of AAV replication. In light of this aspect it is no surprise that the AAVs appear widespread throughout the vertebrate kingdom. Molecular aspects. Possibly one of the most intriguing aspects of AAV biology is that it is the only known eukaryotic virus with the unique ability to integrate site-specifically into the human genome (Berns and Linden, 1995; Linden and Berns, 2000; Linden et al., 1996, Dutheil and Linden, 2006). On this background our laboratory has been active for a number of years in efforts to elucidate the molecular mechanisms underlying AAV2 site-specific integration and, related to this mechanism, DNA replication (Ward et al., 2003; Ward et al., 2001; Ward and Linden, 2000). We have approached these questions from different angles, including the genetic characterization of the human target locus for site-specific integration (Dutheil et al., 2000; Dutheil et al., 2004), the biochemical characterization of the AAV Rep proteins that are responsible for all aspects of the AAV life cycle, including site-specific integration (Smith et al., 1999; Yoon et al., 2001; Yoon-Robarts et al., 2004; Yoon-Robarts and Linden, 2003) and, more recently, the biophysical/structural basis for Rep action (James et al., 2004; James et al., 2003). These efforts have led us to be among the first to define the structure of SF3 helicases, and, as a result, to conclude that these proteins that are frequently found in viruses such as papilloma and polyoma viruses, in fact belong to the AAA+ proteins, a broad family of ATPases that are associated with a variety of functions ranging from membrane fusion, protein degradation and now also functions that are relating to several viral mechanisms. These include, but are not limited to DNA replication and genome packaging. Based on these findings we are now actively engaged in dissecting the biochemical and structural determinants underlying the molecular mechanisms supported by these viral AAA+ (vAAA+) proteins. Recombinant AAV vector core. During the past years we have spent considerable efforts in establishing a viral vector core that generates and purifies recombinant AAV vectors followed by stringent quality control assessments. At this point these vectors are distributed to a range of collaborators that are actively engaged in gene transfer experiments. Our current gene transfer collaborations include studies on pancreatic islet transplants, liver-mediated gene delivery for a number of monogenic diseases such as lysosomal storage diseases, a program that is aimed at the developmental aspects of kidney disease as well as several additional exploratory projects in neurology, neuroscience and Ophthalmology. The underlying philosophy to our efforts is to provide our strength to programs and projects that are founded on long-term and in-depth experience in the disease and animal models by our preclinical and clinical collaborators. In summary, our ongoing studies on the biology of viruses and AAV in particular has provided us with the opportunity to study unique viral and cellular mechanisms and to become part of the efforts in developing strategies that might ultimately become components of future gene and cell-based therapies.
Tel:
020 7188 3162
Fax:
020 7188 3385
Email:
Website:
Interests:
Mammals have evolved a variety of innate cellular defences that block the replication of retroviruses. Primate lentiviruses in turn have developed mechanisms to evade these host restrictions, helping them to establish chronic infections that, in the case of Human Immunodeficiency Viruses (HIV), eventually lead to AIDS. My interest is in how the small accessory protein Vpu, encoded by HIV-1, overcomes such a cellular defence. We identified a human IFN-induced plasma membrane protein, Tetherin/CD317 that restricts retroviral particle release but can be overcome by Vpu expression. Tetherin/CD317 has an unusual topology and traffics between multiple cellular compartments. Understanding the cellular and molecular basis for Vpu antagonism of Tetherin-mediated restriction of HIV-1 release should indicate novel targets for antiretroviral drug development.
Tel:
Fax:
Email:
Website:
Molecular and Cellular Biology of Inflammation
Interests:
The focus of our research is to understand at the molecular and cellular level pathways of T cell activation and differentiation that promote autoimmunity, and which contribute to the persistence of chronic immune and inflammatory responses. Specifically, we are interested in investigating the impact of altered T cell antigen receptor signalling (TCR) thresholds (both inherited and acquired) on (1) pathways of T helper cell activation, differentiation and cytokine gene expression, (2) pathways of cell migration, and (3) the mechanisms through which T lymphocytes regulate innate immune responses in vivo.
Tel:
020 7848 8631
Fax:
0207 848 8632
Email:
Website:
Interests:
Members of the Geissmann Lab (Development and Functions of Mononuclear Phagocytes) focus their efforts on understanding the molecular and cellular basis for the functional heterogeneity of the mononuclear phagocyte system in vivo. We have described the common precursor for macrophage, monocytes and dendritic cells (Fogg et al., Science 2006; Auffray et al., JEM 2009), discovered specialized population of monocytes (Geissmann et al., Immunity 2003, Auffray et al., Science 2007, Auffray et al., Annu. Rev. Immunol. 2009), and investigated the pathophysiology of diseases of this cellular system, including Langerhan’s cell histiocytosis (Senechal et al., Plos Meddicine 2007). To study the development and functions of phagocytes in vivo, in animal models and in man, we use fate mapping strategies and intravital imaging in mouse models in vivo, high-throughput or multiplex analysis of gene and protein expression ex-vivo from human cells purified by flow cytometry, and we develop new models for the study of the genetic control of phagocytes development and functions, such as the fruit fly Drosphila melanogaster. We plan to build on hypotheses and results generated using mouse and drosophila models to identify candidate genes responsible for human inflammatory diseases, to model and test (ex vivo) the functions of human monocytes and their roles in diseases, and - in collaboration with clinicians - to develop prospective cohorts to test biomarkers, diagnostic tools and therapeutic strategies.
Tel:
020 7848 6902
Fax:
0207 848 6743
Email:
Website:
Interests:
The Taams lab investigates regulation of the immune response in humans, during health and inflammation. Immune regulation is an essential process to prevent autoimmunity or chronic inflammation such as occurs in rheumatoid arthritis. We are particularly interested in the cross-talk between CD4+ T cell subsets and monocytes, and how this contributes to inflammation and regulation.
Part of our research focuses on a subset of CD4+ T lymphocytes with specialised immunosuppressive function. These so-called regulatory T cells (Tregs) have been previously shown to potently suppress adaptive immune responses. More recent work from our lab and others indicates that these Tregs also have distinct suppressive effects on innate immune cells, such as monocytes. Our current work is aimed at determining the molecular basis and the functional consequences of Treg-mediated monocyte modulation. We also investigate if and how inflammatory conditions alter Treg function, with a particular focus on activated monocytes.
A second research focus is on the role of Th17 cells during pathogenesis of rheumatoid arthritis (RA). Th17 cells are highly pro-inflammatory CD4+ T cells that are thought to contribute to inflammation and bone destruction in RA. Our aim is to define the molecular and cellular processes that drive IL-17 producing Th17 cells in RA, with a view to block this process. In addition, we are actively investigating if and how we can use Power Dopper Ultrasound to identify RA patients that have a more Th17-mediated, and therefore potentially more destructive, disease.
Tel:
020 7848 8633
Fax:
Email:
Website:
Interests:
Signals from immune cells to other tissues are critical regulators of physiology and pathophysiology. Conversely, signals from non-immune tissues are often critical regulators of the immune response. However, these signals are poorly-understood biologically. The Dionne lab uses the fruit-fly Drosophila melanogaster to tease apart these interactions. The virtue of Drosophila for this kind of work is two-fold: its small size, quick generation time and extensively-annotated genome make it tractable via forward and reverse genetics and bioinformatic techniques, while its mechanisms of physiological regulation and the components of its immune system are recognizably closer to those of humans than those of other invertebrate model systems.
Our current focus is on the infection of Drosophila with Mycobacterium marinum. M marinum causes an invariably-lethal infection in Drosophila, with many similarities to human tuberculosis (Dionne et al., Infect Immun 2002; Dionne et al., Curr Biol 2006). We have previously described how this infection disrupts insulin signalling in the host, with resulting defects in anabolism that result in a cachexia-like condition. One current goal is to understand the mechanisms that generate this blockade to insulin signalling. As an outgrowth of this work, we are also investigating the mechanisms by which metabolic balance is ordinarily maintained. A second project in the lab is focussed on continuing our screen for host factors that regulate this infection; we have recently complemented the unbiased genetic approach with which we began with a more-targeted approach based on a bioinformatic survey of transcription-factor binding to genomic loci. A third project, in collaboration with the Geissmann laboratory, focuses on developing imaging techniques and genetic tools with which we can refine our understanding of the development and function of myeloid lineages in the fly.
Our longer-term goal is to develop a full understanding of the ways immune and non-immune tissues interact in healthy animals; how these interactions are altered by infection and inflammation; and how inflammatory responses are regulated. We hope to be able to translate our findings in the fly to mammalian models and ultimately to the clinical context.
Tel:
020 7848 8635
Fax:
020 7848 6743
Email:
Website:
Interests:
Tel:
+44 (0) 207-848-6907
Fax:
Email:
Website:
Interests:
Immuno-inflammatory mechanisms in rheumatoid arthritis.
Tel:
020 7188 5907
Fax:
020 7188 5883
Email:
Website:
ACADEMIC ENTRY REQUIREMENTS
General entry advice
A first class or 2:1 first degree in an appropriate subject, or the overseas equivalent is normally required, although an exception may be made if the applicant has a good MSc with a merit or above.
APPLYING TO KING'S
To apply for graduate study at King's you will need to complete our graduate online application form. Applying online makes applying easier and quicker for you, and means we can receive your application faster and more securely.
King's does not normally accept paper copies of the graduate application form as applications must be made online. However, if you are unable to access the online graduate application form, please contact the relevant admissions/School Office at King's for advice.
APPLICATION PROCEDURE
Studentships will be advertised in
New Scientist Study,
Nature Jobs,
findaphd.com, the College’s
Health Schools Studentships website or
onhttp://www.jobs.ac.uk./Short-listed applicants will be interviewed by at least two academics. Proposed research projects must be approved by the School Postgraduate Research Committee before an offer can be made.
PERSONAL STATEMENT & SUPPORTING INFORMATION
No information required.
FUNDING
A small number of studentships for specific named projects, funded by external funding agencies such as the research councils (MRC, BBSRC), or charitable bodies (Oliver Bird Studentships, Nuffield Foundation) are usually available (usually advertised on the College's website, in the New Scientist or Nature journals, or on
http://www.jobs.ac.uk ). These usually provide a stipend and the payment of tuition fees at the home/EU rate. Other than this, applicants will be expected to be self-funded through a personal scholarship or private means.
Student profiles
Immunology, Infection & Inflammatory Disease (DIIID) (Research Division) MPhil/PhD
My academic support has been excellent, I meet with my supervisor once a week and present my work to my committee every six months. I have been exposed to the forefront of research in the HIV field having had the opportunity to present my findings at two international meetings in the USA, at the MRC centre in The Gambia, and in Cambridge, UK.
In addition to my lab work I have been involved in tutoring undergraduate students and have taken part in the Researchers in Residence Scheme in which I spent four days working with secondary school pupils. These experiences have given me valuable transferable skills in addition to my research training. There are also plenty of social activities for graduate students to get involved with; I am a member of the GKT Music Society choir. I am funded by King's College and the Medical Research Council, the studentship is adjusted for London living. With the facilities, support and good supervision, I think King's has the ingredients for a successful PhD.
Staff profiles
Immunology, Infection & Inflammatory Disease (DIIID) (Research Division) MPhil/PhD
'Our research team use laboratory models to study the growth and spread of human immunodeficiency virus (HIV), the causative agent of AIDS. Of particular interest to us is the seesaw battle that exists between the infected host and the virus, and how it might be possible to manipulate or perturb this to therapeutic advantage. The group is comprised of a highly interactive mix of PhD students and post-doctoral fellows from all over the world.'