Clark, Ian - University of East Anglia - School of Biological Sciences

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University of East Anglia School of Biological Sciences
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个人简介

Ian Clark is a molecular cell biologist with a research focus on cartilage biology and osteoarthritis. A Biochemistry graduate, he undertook a PhD in the Rheumatology Research Unit in Addenbrooke’s Hospital, Cambridge developing assays to measure arthritis-relevant proteolytic enzymes. He won a Arthritis Research Campaign Copeman Fellowship to the USA where he began a project which led to the discovery of a cancer-associated SNP in the MMP1 gene. He returned to the Cambridge, UK on an Arthritis Research Campaign Postdoctoral Fellowship to develop his own interests in cartilage biology. In 2001, he spent a year on study leave working within the OA disease area in AstraZeneca Pharmaceuticals gaining an insight into drug development. Since moving to UEA in 1996, he has published a number of key papers: (i) examining chondrocyte senescence in osteoarthritis; (ii) profiling the expression of firstly extracellular matrix-degrading proteinases, and latterly, all cellular proteases in normal vs. osteoarthritic human cartilage; (iii) defining the function of recently discovered metalloproteases in cartilage chondrocytes; (iv) demonstrating that histone deacetylase inhibitors are chondroprotective via their effects on metalloproteinase gene expression. His current interests centre around (i) the impact of bioactive molecules derived from the diet on cartilage metabolism and osteoarthritis (ii) the role of microRNAs in chondrogenesis and osteoarthritis (iii) the role of proteases in Dupuytren’s disease. Career History 2006 – date: Professor of Musculoskeletal Biology, School of Biological Sciences, University of East Anglia, Norwich, UK 2001 - 2006: Reader, School of Biological Sciences, University of East Anglia, Norwich, UK 2001: Team Leader, AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, UK (sabbatical) 1996 - 2000: Arthritis Research Campaign Postdoctoral Research Fellow, School of Biological Sciences, University of East Anglia, Norwich, UK. 1994 - 1996: Arthritis Research Campaign Postdoctoral Research Fellow, Rheumatology Research Unit, Addenbrooke's Hospital, Cambridge, UK. 1993: Arthritis and Rheumatism Council Copeman Fellow. Taken up in the laboratory of Professor C.E. Brinckerhoff, Dept. of Biochemistry and Medicine, Dartmouth Medical School, New Hampshire USA. 1990 - 1992: Postdoctoral Fellow (funded by SmithKline Beecham Pharmaceuticals), Rheumatology Research Unit, Addenbrooke's Hospital, Cambridge, UK.

研究领域

Osteoarthritis Osteoarthritis is a degenerative joint disease for which there are no disease-modifying drugs. It is a leading cause of disability in the UK. Approximately 8.5 million people in the UK have moderate to severe osteoarthritis and a recent survey shows that around 70% of them are in constant pain. Increasing age and obesity are both major risk factors for osteoarthritis and the health and economic burden of this disease will increase in the future. The Clark laboratory is investigating (i) the role of microRNAs in cartilage homeostasis and (ii) the impact of dietary bioactives on joint health. (i) MicroRNAs (miRNAs) are small non-coding RNAs that have recently been recognised as important regulators of gene expression in human cells. A number of miRNAs are regulated across chondrocyte differentiation and their function is beginning to be delineated. Similarly miRNAs are differentially expressed in osteoarthritic cartilage compared to normal tissue. MicroRNA-140, highly and selectively expressed in cartilage, has been the focus of much work to date, though the full gamut of its actions is still to be defined. We are investigating miR-455 and miR-29, as well as a number of novel microRNAs that we have found in osteoarthritic chondrocytes. (ii) A number of plant-derived phytochemicals have been proposed to have positive benefit on joint health and osteoarthritis though predominantly, these have not been studied in man to date. There are some published population-based study data to suggest that dietary constituents are associated with a reduction in the progression of OA in man. However, to date, dietary intervention trials have been small and of varying design, resulting in difficulty in interpreting the available data. We are investigating the role of sulforaphane, an isothiocyanate derived from eating broccoli and related vegetables, in osteoarthritis. So far, this compound has shown efficacy in three laboratory models of disease. We are currently undertaking a proof-of-principle human trial to ascertain if it will be similarly effective in man. We are also screening a number of diet-derived compounds for similar activity in chondrocytes with a view to investigating synergy between them. Dupuytren’s disease Dupuytren’s disease (DD) is a common disabling condition leading to contracture of the fingers, affecting over 2 million people in the UK. The only current treatment for established DD is surgery with high recurrence rates. Further surgery becomes more invasive with higher complication rates and incomplete contracture correction. There are no known drug treatments for the condition at present. In the late 1980s and early 1990s, inhibitors of the matrix metalloproteinase family were developed for the treatment of cancers. Some of these compounds gave the side effect of a Dupuytren’s-like contracture. We have been trying to understand the role of metalloproteinases in Dupuytren’s disease. We measured the expression of two main families of metalloproteinases (the MMPs and the ADAMTSs) in tissue taken from Dupuytren’s patients at surgery. Furthermore, we were able to show a correlation between the levels of specific proteinases and recurrence of contracture post-surgery. We have gone on to show roles for specific proteases in models of cell-mediated contraction.

近期论文

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Crowe, N., Swingler, T., Le, L., Barter, M., Wheeler, G., Pais, H., Donell, S., Young, D., Dalmay, T., Clark, I.(2016)Detecting new microRNAs in human osteoarthritic chondrocytes identifies miR-3085 as a human, chondrocyte-selective, microRNAin Osteoarthritis and Cartilage24.pp. 534-543 Full Text UEA Repository(Article) Le, L. T., Swingler, T. E., Crowe, N., Vincent, T. L., Barter, M. J., Donell, S. T., Delany, A. M., Dalmay, T., Young, D. A., Clark, I. M.(2016)The microRNA-29 family in cartilage homeostasis and osteoarthritisin Journal of Molecular Medicine94.pp. 583-596 Full Text UEA Repository(Article) Snelling, S., Davidson, R., Swingler, T., Le, T., Barter, M., Culley, K., Price, A., Carr, A., Clark, I.(2016)Dickkopf-3 is upregulated in osteoarthritis and has a chondroprotective rolein Osteoarthritis and Cartilage24.pp. 883–891 Full Text UEA Repository(Article) Davidson, R., Jupp, O., Bao, Y., Macgregor, A., Donell, S., Cassidy, A., Clark, I.(2016)Can sulforaphane prevent the onset or slow the progression of osteoarthritis?in Nutrition Bulletin41.pp. 175-179 Full Text UEA Repository(Article) Karkampouna, S., Kreulen, M., Obdeijn, M. C., Kloen, P., Dorjée, A. L., Rivellese, F., Chojnowski, A., Clark, I., Kruithof-de Julio, M.(2016)Connective Tissue Degeneration: Mechanisms of Palmar Fascia Degeneration (Dupuytren’s Disease)in Current Molecular Biology Reports2.pp. 133–140 Full Text UEA Repository(Article) Jupp, O., Pullinger, M., Marjoram, T., Lott, M., Chojnowski, A. J., Clark, I. M.(2016)Biomarkers of Postsurgical Outcome in Dupuytren DiseaseSpringer International Publishingpp. 55-61ISBN 978-3-319-32197-4 Full Text(Other chapter contribution)Barter, M. J., Tselepi, M., Gómez, R., Woods, S., Hui, W., Smith, G. R., Shanley, D. P., Clark, I. M., Young, D. A.(2015)Genome-wide microRNA and gene analysis of mesenchymal stem cell chondrogenesis identifies an essential role and multiple targets for miR-140-5pin Stem Cells33.pp. 3266-3280 Full Text UEA Repository(Article) Green, J. A., Hirst-Jones, K. L., Davidson, R. K., Jupp, O., Bao, Y., Macgregor, A. J., Donell, S. T., Cassidy, A., Clark, I. M.(2014)The potential for dietary factors to prevent or treat osteoarthritisin Proceedings of the Nutrition Society73.pp. 278-288 Full Text UEA Repository(Article) Snelling, S., Rout, R., Davidson, R., Clark, I., Carr, A., Hulley, P., Price, A.(2014)A gene expression study of normal and damaged cartilage in anteromedial gonarthrosis, a phenotype of osteoarthritisin Osteoarthritis and Cartilage22.pp. 334-343 Full Text UEA Repository(Article) Karkampouna, S., Kruithof, B., Kloen, P., Obdeijn, M., Van Der Laan, A., Tanke, H., Kemaladewi, D., Hoogaars, W., 'T Hoen, P., Aartsma-Rus, A., Clark, I., Ten Dijke, P., Goumans, M., Kruithof-De Julio, M.(2014)Novel ex vivo culture method for the study of dupuytren's disease: Effects of TGFβ Type 1 receptor modulation by antisense oligonucleotidesin Molecular Therapy - Nucleic Acids3. Full Text UEA Repository(Article) Culley, K. L., Hui, W., Barter, M. J., Davidson, R. K., Swingler, T. E., Destrument, A. P. M., Scott, J. L., Donell, S. T., Fenwick, S., Rowan, A. D., Young, D. A., Clark, I. M.(2013)Class I Histone Deacetylase Inhibition Modulates Metalloproteinase Expression and Blocks Cytokine-Induced Cartilage Degradation: Class I HDAC Inhibition is Chondroprotectivein Arthritis & Rheumatism65.pp. 1822-1830 Full Text UEA Repository(Article) Radwan, M., Gavriilidis, C., Robinson, J. H., Davidson, R., Clark, I. M., Rowan, A. D., Young, D. A.(2013)Matrix Metalloproteinase 13 Expression in Response to Double-Stranded RNA in Human Chondrocytesin Arthritis & Rheumatism65.pp. 1290-1301 Full Text UEA Repository(Article) Soond, S. M., Smith, P. G., Wahl, L., Swingler, T. E., Clark, I. M., Hemmings, A. M., Chantry, A.(2013)Novel WWP2 ubiquitin ligase isoforms as potential prognostic markers and molecular targets in cancerin Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease1832.pp. 2127-2135 Full Text UEA Repository(Article) Le, L. T. T., Swingler, T. E., Clark, I. M.(2013)Review: The Role of MicroRNAs in Osteoarthritis and Chondrogenesis: MicroRNAS in OAin Arthritis & Rheumatism65.pp. 1963-1974 Full Text UEA Repository(Article) Davidson, R. K., Jupp, O., de Ferrars, R., Kay, C. D., Culley, K. L., Norton, R., Driscoll, C., Vincent, T. L., Donell, S. T., Bao, Y., Clark, I. M., Arthritis, Experimental, Cartilage, Articular(2013)Sulforaphane represses matrix-degrading proteases and protects cartilage from destruction in vitro and in vivo: Sulforaphane is protective in the articular Jointin Arthritis and Rheumatism65.pp. 3130-3140 Full Text UEA Repository(Article) Ollivere, B., Wimhurst, J., Clark, I., Donell, S.(2012)Current concepts in osteolysisin Journal of Bone and Joint Surgery - British Volume94-B.pp. 10-15 Full Text UEA Repository(Article) Swingler, T., Wheeler, G., Carmont, V., Elliott, H., Barter, M., Abu-Elmagd, M., Donell, S., Boot-Handford, R., Hajihosseini, M., Munsterberg, A., Dalmay, T., Young, D., Clark, I.(2012)The expression and function of microRNAs in chondrogenesis and osteoarthritisin Arthritis & Rheumatism64.pp. 1909-1919 Full Text UEA Repository(Article) Wilkinson, J., Davidson, R., Swingler, T., Jones, E., Corps, A., Johnston, P., Riley, G., Chojnowski, A., Clark, I.(2012)MMP-14 and MMP-2 are key metalloproteases in Dupuytren's disease fibroblast-mediated contractionin Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease1822.pp. 897-905 Full Text UEA Repository(Article) Wilkinson, J., Jones, E., Riley, G., Chojnowski, A., Clark, I.(2012)The Expression of Collagen-Degrading Proteases Involved in Dupuytren’s Disease Fibroblast-Mediated Contractionpp. 143-149 Full Text UEA Repository(Chapter)Fields, J., Gardner-Mercer, J., Borgmann, K., Clark, I., Ghorpade, A.(2011)CCAAT/enhancer binding protein β expression is increased in the brain during HIV-1-infection and contributes to regulation of astrocyte tissue inhibitor of metalloproteinase-1in Journal of Neurochemistry118.pp. 93-104 Full Text UEA Repository(Article)

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