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SEVENTH FRAMEWORK PROGRAMME

The University of Cambridge

The University of Cambridge
Cambridge Institute for Medical Research and Department of Medicine
Box 139, Addenbrooke's Hospital
Cambridge, UK, CB20XY

Cambridge Immunology website http://www.immunology.cam.ac.uk/ Cambridge Institute for Medical Research website   http://www.cimr.cam.ac.uk/investigators/smith/index.html

Scientist-in-charge


Prof. Kenneth G. C. Smith Prof. Kenneth G. C. Smith
Professor of Medicine and Head of Department of Medicine 
Phone: +44 1223 762645 
Fax: +44 1223 762640 
E-Mail to Prof. Kenneth G. C. Smith Contact  

Prof Smith's website:

Prof Smith's website http://www.immunology.cam.ac.uk/directory/profile.php?kgcs2

The Smith lab has two main components. The first studies how changes in regulatory control of the immune system can lead to autoimmunity and alter defence against infection. Recent work includes a focus on how FcgRIIb, an inhibitory receptor for IgG, controls the immune system, and how polymorphic variants in it modulate immunity and influence autoimmunity and protection against bacterial infection and malaria. This has provided an insight into the evolution of predisposition to autoimmunity, and identified potential therapeutic strategies. The second component is a translational programme studying patients with autoimmune diseases (esp. SLE and vasculitis) and correlating clinical data before and after treatment with data generated from RNA microarrays. This is leading to the design of better informed clinical trials, and the identification of important genes involved in disease pathogenesis.

Publications:

Publications http://www.ncbi.nlm.nih.gov/pubmed?term=%22Smith%20KG%22%5BAuthor%5D






Project Supervisor


Dr Paul Lyons Dr Paul Lyons
Senior Research Associate, Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge, UK 
Phone: +44 1223 762642 
Fax: +44 1223 762640 
E-Mail to Dr Paul Lyons Contact  

Paul Lyon's website:

Paul Lyon's website http://www.immunology.cam.ac.uk/directory/profile.php?pal34

My primary research interest is understanding the molecular basis of autoimmune disease.  For a number of years I have been interested in applying high-throughput genomic approaches to the study of autoimmune disease [1].  Primarily this has focused on combining gene expression profiling using microarrays with congenic strain analysis to facilitate the identification of potential candidate genes underlying type 1 diabetes loci [2].  As an adjunct to this I have also been involved in two international collaborative ventures which have generated resources for the wider academic community.  The first was the FANTOM consortium which annotated a panel of 60K full-length cDNA clones that acts as a valuable resource for functional genomic research [3].  The second was the development of an open-source long oligonucleotide microarray resource for the study of human and mouse transcriptomics [4].

Finally, more recently I have been involved in the establishment of the Cambridge Hinxton Centre for Translational Research in Autoimmune Disease.  This is a collaboration between clinicians, basic scientists and bioinformaticians that aims to apply expression profiling to the clinical management of autoimmune diseases such as SLE and small vessel vasculitits.  We have developed and optimised a cell selection strategy that enables us to expression profile purified leukocyte subsets isolated from patients with active disease pre- and post-treatment [5].  This approach has proved more successful in identifying cell type specific, disease-associated expression signatures than simply profiling unseparated peripheral blood mononuclear cells, where many of the signatures identified have simply reflected relative differences in the cellular composition of the starting material [6]. Specifically, it has led to the development of novel diagnostic biomarkers that can be used to classify patients at presentation [7], as well as a prognostic biomarker that predicts clinical response following treatment and which may inform clinical management in both SLE and vasculitis [8].  In addition, it has also directly led to studies that have provided insight into the molecular pathogenesis of disease [9].

References:

  1. Lyons PA. Gene-expression profiling and the genetic dissection of complex disease. Curr Opin Immunol 2002;14:627-30.
  2. Eaves IA, Wicker LS, Ghandour G, et al. Combining mouse congenic strains and microarray gene expression analyses to study a complex trait: the NOD model of type 1 diabetes. Genome Res 2002;12:232-43.
  3. Okazaki Y, Furuno M, Kasukawa T, et al. Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs. Nature 2002;420:563-73.
  4. Le Brigand K, Russell R, Moreilhon C, et al. An open-access long oligonucleotide microarray resource for analysis of the human and mouse transcriptomes. Nucleic Acids Res 2006;34:e87.
  5. Lyons PA, Koukoulaki M, Hatton A, et al. Microarray analysis of human leucocyte subsets: the advantages of positive selection and rapid purification. BMC Genomics 2007;8:64.
  6. Lyons PA, McKinney EF, Rayner TF, et al. Novel expression signatures identified by transcriptional analysis of separated leukocyte subsets in SLE and vasculitis. Ann Rheum Dis 2009;In Press.
  7. Savage DB, Semple RK, Clatworthy MR, et al. Complement abnormalities in acquired lipodystrophy revisited. J Clin Endocrinol Metab 2009;94:10-16.
  8. McKinney EF, Lyons PA, Carr EJ, et al. A CD8 T cell transcription signature predicts prognosis in autoimmune disease. Nature Medicine 2010;In Press.
  9. Willcocks LC, Lyons PA, Clatworthy MR, et al. Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake. J Exp Med 2008;205:1573-82.
Publications http://www.ncbi.nlm.nih.gov/pubmed?term=%22Lyons%20PA%22%5BAuthor%5D


Institute Presentation


The Cambridge Institute for Medical Research (CIMR) is a cross-departmental institute, within the University of Cambridge Clinical School, that is housed in the Wellcome Trust/MRC Building on the Addenbrooke's HTranSVIRtal Site of the Cambridge Biomedical Campus.
It provides a unique interface between basic and clinical science that underpins its high level objective of determining and understanding the molecular mechanisms of disease.  Currently, CIMR comprises approximately 250 scientists, about a quarter of whom are graduate students.  They are organised into around 40 research groups each led by a Principal Investigator (PI) who, along with their group members, is also a member of one of seven home University departments (Medicine, Pathology, Medical Genetics, Clinical Biochemistry, Haematology or Clinical Neurosciences).
Since the establishment of CIMR in 1998, we have aimed to maintain a healthy proportion (around 40%) of PIs who are medically qualified and clinically active. We have also encouraged collaboration amongst our scientists and it is commonplace for these collaborations to be cross-departmental.  There are excellent scientific facilities in CIMR including bioinformatics, genotyping/sequencing, flow cytometry and imaging as well as access to the proteomics facilities in the MRC Mitochondrial Biology Unit housed in the same building.


Training

The Cambridge Institute will provide a Technical Platform for expression arrays and advanced Bioinformatics. The scientist-in-charge (Smith) is a clinician and an immunologist with special expertise in translational medicine. He is Genzyme Professor of Experimental Medicine and heads the Cambridge Hinxton Centre for Translational Research in Autoimmune Disease (CHiC TRIAD) - a collaboration between clinicians, bioinformaticians, and immunologists to identify biomarkers and novel therapeutic targets in vasculitis and related diseases by integrating clinical, immunological and leukocyte transcriptomal data using new informatics tools generated by the European Bioinformatics Institute. Lyons is a molecular geneticist with expertise in genetic and transcriptomal analysis.

The University of Cambridge