Professor David Young
Professor of Musculoskeletal Biology
- Email: firstname.lastname@example.org
- Telephone: +44 (0) 191 241 8831
- Personal Website: https://blogs.ncl.ac.uk/davidyoung/
- Address: Skeletal Research Group
Institute of Genetic Medicine
Newcastle upon Tyne
Newcastle upon Tyne
1997-1998. ARC Post-doctoral Research Assistant, Wellcome Trust Centre for Matrix Research, University of Manchester.
1998-2003. ARC Senior Post-doctoral Research Assistant, School of Biological Sciences, University of East Anglia.
2003-2004. Dunhill Medical Trust Post-doctoral Research Assistant, School of Biological Sciences, University of East Anglia.
My research interests include the expression and regulation of metalloproteinases (MPs) and their inhibitors the TIMPs, particularly in the context of osteoarthritis (OA). My laboratory focus is how these genes are epigenetically regulated; by microRNAs, DNA methylation and chromatin modifications.
We have are also investigating the role of mitochondria and ubiquitination in OA.
Main techniques: Gene expression analysis/profiling (Real-time PCR, Taqman Low density arrays, microarray, RNA-seq). Cell signalling analysis. RNAi (siRNA, shRNA). miRNA analysis. Cas9/CRISPR. ChIP-seq. Transcription factor analysis (EMSA, mutagenesis, reporter assays). Epigenetic analysis. Models of osteoarthritis.
My laboratory will research the mechanisms by which HDACi block MP expression, determine the signalling pathways/mechanisms and identify the HDACs involved. We are specifically focussing on HDAC3.
Age is the major risk factor for Osteoarthritis. We are investigating the molecular mechanisms of how ageing impacts on cartilage.
Manipulating gene expression in cartilage is currently not possible therefore we have developed an interest in tissue engineering, to generate cartilage from the differentiation of stem cells. Using this model we have generated a series of -omics scale data to help understand what controls a chondrocyte phenotype.
We are developing CRISPR technology in the group both in terms of their ability to edit genes and also to regulate transcription. With collaborators we are using CRISPR to generate novel transgenics.
Postgraduate (current) Supervision
- Dimitra Tsompani, PhD, main-supervisor
- Kat Cheung, PhD,main-supervisor
- Silvia Lecci: PhD, main supervisor
- Yao Hao, PhD Main supervisor
- Laura Ridgley: PhD, co-supervisor
Clinical trainee fellow
Past Lab members
- Heather Bromby
- Steven Woods
- Rodolfo Gomez
- Katie Crossland
- Wang Hui
- Yaobo Xu
- Catherine Bui
- Christos Gavriilidis
- Jenny Scott
- Hannah Elliott
- Martin Galler
British Society for Matrix Biology (BSMB) Honorary Treasurer
Current funding is mainly from the Dunhill Medical Trust, the JGW Patterson Foundation, Arthritis Research UK, EU FP7 - Sybil, EU Horizon2020 - MSCA Global Fellowship (to Marta Radwan) and CIMA (MRC/Arthritis Research UK).
More than 7 million adults in the UK (15% of the population) have long-term health problems due to arthritis and related conditions. In 2001 incapacity benefit alone cost the nation £2.4 billion.
Metalloproteinases are the enzymes ultimately responsible for the collagen loss to cartilage seen in arthritic diseases. The design of small molecule inhibitors of the metalloproteinases remains a major focus of the pharmaceutical industry, yet has been largely unsuccessful, probably due to a lack of specificity of the compunds and side effects. Since arthritis is a debilitating, but not fatal disease, such side effects need to be minimised. We suggest that HDACi will be chondroprotective in all destructive arthritides, including both rheumatoid arthritis and osteoarthritis (other examples include: reactive arthritis, gout/pseudogout, psoriatic arthritis). They may also show utility in cartilage engineering/transplantation to protect cartilage explants or engineered/cultured cartilage from degradation. Many pharmaceutical companies are currently testing HDACi in cancer therapy trials, therefore these molecules potentially represent the next wave of drugs to fight the arthiitis.
I regularly supervise MRes/BMS students for laboratory projects and lecture on the MRes Biology or Ageing and Current trends in musculoskeletal disease modules..
I oversee MRes projects .
- Steinbusch MMF, Fang Y, Milner PI, Clegg PD, Young DA, Welting TJM, Peffers MJ. Serum snoRNAs as biomarkers for joint ageing and post traumatic osteoarthritis. Scientific Reports 2017, 7, 43558.
- Crowe N, Swingler TE, Le LTT, Barter MJ, Wheeler G, Pais H, Donell ST, Young DA, Dalmay T, Clark IM. Detecting new microRNAs in human osteoarthritic chondrocytes identifies miR-3085 as a human, chondrocyte-selective, microRNA. Osteoarthritis and Cartilage 2016, 24(3), 534-543.
- Le LTT, Swingler TE, Crowe N, Vincent TL, Barter MJ, Donell ST, Delany AM, Dalmay T, Young DA, Clark IM. The microRNA-29 family in cartilage homeostasis and osteoarthritis. Journal of Molecular Medicine 2016, 94(5), 583-596.
- Rushton MD, Young DA, Loughlin J, Reynard LN. Differential DNA methylation and expression of inflammatory and zinc transporter genes defines subgroups of osteoarthritic hip patients. Annals of the Rheumatic Diseases 2015, 74(9), 1778-1782.
- Barter MJ, Tselepi M, Gomez R, Woods S, Hui W, Smith GR, Shanley DP, Clark IM, Young DA. Genome-wide microRNA and gene analysis of mesenchymal stem cell chondrogenesis identifies an essential role and multiple targets for miR-140-5p. Stem Cells 2015, 33(11), 3266-3280.
- Rushton MD, Reynard LN, Young DA, Shepherd C, Aubourg G, Gee F, Darlay R, Deehan D, Cordell HJ, Loughlin J. Methylation quantitative trait locus (meQTL) analysis of osteoarthritis links epigenetics with genetic risk. Human Molecular Genetics 2015, 24(25), 7432-7444.
- Purvis HA, Anderson AE, Young DA, Isaacs JD, Hilkens CMU. A Negative Feedback Loop Mediated by STAT3 Limits Human Th17 Responses. Journal of Immunology 2014, 193(3), 1142-1150.
- Rushton MD, Reynard LN, Barter MJ, Refaie R, Rankin KS, Young DA, Loughlin J. Characterization of the cartilage DNA methylome in knee and hip osteoarthritis. Arthritis & Rheumatology 2014, 66(9), 2450–2460.
- Litherland GJ, Hui W, Elias MS, Wilkinson DJ, Watson S, Huesa C, Young DA, Rowan AD. Glycogen Synthase Kinase 3 Inhibition Stimulates Human Cartilage Destruction and Exacerbates Murine Osteoarthritis. Arthritis & Rheumatology 2014, 66(8), 2175-2187.
- Hui W, Young DA, Rowan AD, Xu X, Cawston TE, Proctor CJ. Oxidative changes and signalling pathways are pivotal in initiating age-related changes in articular cartilage. Annals of the Rheumatic Diseases 2014, 1-10.
- Radwan M, Wilkinson DJ, Hui W, Destrument AP, Charlton SH, Barter MJ, Gibson B, Coulombe J, Gray DA, Rowan AD, Young DA. Protection against murine osteoarthritis by inhibition of the 26S proteasome and lysine-48 linked ubiquitination. Annals of the Rheumatic Diseases 2014.
- Cawston TE, Young DA, Rowan DD. Tissue destruction and repair. In: Hochberg MC; Silman AJ; Smolen JS; Weinblatt ME; Weisman MH, ed. Rheumatology: Sixth Edition. Philadelphia, PA: Elsevier Inc, 2014, pp.152-159.
- Barter MJ, Young DA. Epigenetic Mechanisms and Non-coding RNAs in Osteoarthritis. Current Rheumatology Reports 2013, 15(9), 353.
- Radwan M, Gavriilidis C, Robinson JH, Davidson R, Clark IM, Rowan AD, Young DA. Matrix metalloproteinase-13 expression in response to double-stranded RNA in human chondrocytes. Arthritis & Rheumatism 2013, 65(5), 1290-1301.
- Gavriilidis C, Miwa S, von Zglinicki T, Taylor RW, Young DA. Mitochondrial dysfunction in osteoarthritis is associated with down-regulation of superoxide dismutase 2. Arthritis & Rheumatism 2013, 65(2), 378-387.
- Young DA. More evidence for a role of CpG methylation in the pathogenesis of osteoarthritis. Arthritis and Rheumatism 2013, 65(3), 555-558.
- Syddall CM, Reynard LN, Young DA, Loughlin J. The Identification of Trans-acting Factors That Regulate the Expression of GDF5 via the Osteoarthritis Susceptibility SNP rs143383. PLoS Genetics 2013, 9(6), e1003557.
- Pratt AG, Swan DC, Richardson S, Wilson G, Hilkens C, Young DA, Isaacs JD. A CD4 T cell gene signature for early rheumatoid arthritis implicates interleukin 6-mediated STAT3 signalling, particularly anti-citrullinated peptide antibody-negative disease. Annals of the Rheumatic Diseases 2012, 71(8), 1374-1381.
- Bui C, Barter MJ, Scott JL, Xu Y, Galler M, Reynard LN, Rowan AD, Young DA. cAMP response element-binding (CREB) recruitment following a specific CpG demethylation leads to the elevated expression of the matrix metalloproteinase 13 in human articular chondrocytes and osteoarthritis. FASEB Journal 2012, 26(7), 3000-3011.
- Barter MJ, Bui C, Young DA. Epigenetic mechanisms in cartilage and osteoarthritis: DNA methylation, histone modifications and microRNAs. Osteoarthritis and Cartilage 2012, 20(5), 339-349.
- Xu Y, Barter MJ, Swan DC, Rankin KS, Rowan AD, Santibanez-Koref M, Loughlin J, Young DA. Identification of the pathogenic pathways in osteoarthritic hip cartilage: commonality and discord between hip and knee OA. Osteoarthritis and Cartilage 2012, 20(9), 1029-1038.
- Hui W, Litherland GJ, Elias MS, Kitson GI, Cawston TE, Rowan AD, Young DA. Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases. Annals of the Rheumatic Diseases 2012, 71(3), 455-462.
- Swingler TE, Wheeler G, Carmont V, Elliott HR, Barter MJ, Abu-Elmagd M, Donell ST, Boot-Handford RP, Hajihosseini MK, Münsterberg A, Dalmay T, Young DA, Clark IM. The expression and function of microRNAs in chondrogenesis and osteoarthritis. Arthritis and Rheumatism 2012, 64(6), 1909-1919.
- Young DA, Bui C, Barter MJ. Understanding CpG methylation in the context of osteoarthritis. Epigenomics 2012, 4(6), 593-595.
- Reynard LN, Bui C, Canty-Laird EG, Young DA, Loughlin J. Expression of the osteoarthritis-associated gene GDF5 is modulated epigenetically by DNA methylation. Human Molecular Genetics 2011, 20(17), 3450-3460.
- Cui Y, Yu J, Urban JPG, Young DA. Differential Gene Expression Profiling of Metalloproteinases and Their Inhibitors A Comparison Between Bovine Intervertebral Disc Nucleus Pulposus Cells and Articular Chondrocytes. Spine 2010, 35(11), 1101-1108.
- Barter MJ, Pybus L, Litherland GJ, Rowan AD, Clark IM, Edwards DR, Cawston TE, Young DA. HDAC-mediated control of ERK- and PI3K-dependent TGF-beta-induced extracellular matrix-regulating genes. Matrix Biology 2010, 29(7), 602-612.
- Barter MJ, Hui W, Lakey RL, Catterall JB, Cawston TE, Young DA. Lipophilic statins prevent matrix metalloproteinase-mediated cartilage collagen breakdown by inhibiting protein geranylgeranylation. Annals of the Rheumatic Diseases 2010, 69(12), 2189-2198.
- Hui W, Litherland GJ, Jefferson M, Barter MJ, Elias MS, Cawston TE, Rowan AD, Young DA. Lithium protects cartilage from cytokine-mediated degradation by reducing collagen-degrading MMP production via inhibition of the P38 mitogen-activated protein kinase pathway. Rheumatology 2010, 49(11), 2043-2053.
- Milner JM, Patel A, Davidson RK, Swingler TE, Desilets A, Young DA, Kelso EB, Donell ST, Cawston TE, Clark IM, Ferrell WR, Plevin R, Lockhart JC, Leduc R, Rowan AD. Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis. Arthritis & Rheumatism 2010, 62(7), 1955-1966.
- Swingler TE, Kevorkian L, Culley KL, Illman SA, Young DA, Parker AE, Lohi J, Clark IM. MMP28 gene expression is regulated by Sp1 transcription factor acetylation. Biochemical Journal 2010, 427, 391-400.
- Cawston TE, Young DA. Proteinases involved in matrix turnover during cartilage and bone breakdown. Cell and Tissue Research 2010, 339(1), 221-235.
- Scott JL, Gabrielides C, Davidson RK, Swingler TE, Clark IM, Wallis GA, Boot-Handford RP, Kirkwood TBL, Talyor RW, Young DA. Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease. Annals of the Rheumatic Diseases 2010, 69(8), 1502-1510.