Dr Mike D Barker
Academic Unit of Inflammation and Tumour Targeting
Department of Infection and Immunity
The University of Sheffield Medical School
Beech Hill Road
Tel: +44 (0)114 271 2547
Fax: +44 (0)114 226 1464
I began my research career working as a Research Assistant for Eric Blair at the University of Leeds before studying for a PhD in leukocyte chemotaxis with Dennis Burton at the University of Sheffield. I was then awarded two independent 5-year fellowships; firstly by the Arthritis Research Campaign and then by the British Heart Foundation. During the latter fellowship I moved from the Molecular Biology & Biotechnology Department to a lectureship in the Medical School in 1997.
Structure/function relationships of tissue inhibitors of metalloproteinases (TIMPs):
The matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that exist in both secreted and membrane bound forms. The activity of MMPs is tightly regulated by the tissue inhibitors of metalloproteinases (TIMPs), a family of secreted proteins comprising four members (TIMPs 1-4). The balance between MMPs and TIMPs regulates the integrity of the extracellular matrix (ECM) and thus plays a key role in a wide range of physiological processes that include embryonic development, connective tissue remodelling, wound healing, glandular morphogenesis and angiogenesis. An imbalance in MMP/TIMP expression has been implicated in various diseases including erosive joint disease, cardiovascular disease and cancer. Work in my laboratory has focused specifically on TIMP-3. Like the other members of the family, TIMP-3 is a potent MMP inhibitor. However the molecule also exhibits a variety of specific functions including growth factor activity, stimulation of apoptosis and inhibition of angiogenesis. While the latter is in part a result of MMP inhibition, the molecule has also been shown to bind to and inhibit VEGFR2, a key receptor for vascular endothelial cell growth factor (VEGF), which plays a central role in angiogenesis. The molecule is expressed by a variety of tissues, including the eye where it seems to play a unique role. This is highlighted by the fact that specific mutations in TIMP-3 cause the eye disease Sorsby's fundus dystrophy (SFD), a dominantly inherited disease that leads to blindness in middle age. While SFD is rare it closely resembles age-related macular degeneration (AMD), the most common cause of blindness in the elderly in developed countries. The aims of our work are to determine the mechanisms by which TIMP-3 mediates its specific functions, both in terms of identifying the molecular targets involved, and in localizing these functions to specific regions of the TIMP-3 molecule. Achievement of these goals may lead to the development of novel treatments for a variety of diseases including macular degeneration and cancer.
Transgenic Engineered Tissue Models:
Tissue engineering aims to combine biological and engineering principles to construct functional tissues for the replacement of damaged or diseased body parts. However by genetically modifying cells prior to engineering such tissue it is possible to create human tissues in which specific proteins are suppressed or over-expressed and thus determine function. We are using this technique to determine the function of specific cell matrix associated proteins in human cartilage.
I contribute to various aspects of the Molecular Medicine MSc course, including the Bioinformatics practical class, and teach laboratory health and safety on the MBChB and BMedSci courses. I am also postgraduate research tutor and admissions selector for the department.
I am a member of the Biochemical Society and British Society for Matrix Biology.
- Characterization of a Novel VEGF Receptor Antagonist.
- Characterization and Therapeutic Targeting of TIMP-3 in Sorsby’s Fundus Dystrophy.
- Transgenic human tissue: a powerful new tool for research and therapeutic targeting.
- Langton K.P., McKie, N., Curtis A., Goodship, J.A., Bond P.M., Barker, M.D. and Clarke M (2000). A Novel TIMP-3 Mutation Reveals a Common Molecular Phenotype in Sorsby’s Fundus Dystrophy. J. Biol. Chem. 275, 27027-27031.
- Kafienah W, Al-Fayez F, Hollander AP & Barker MD. (2003). Inhibition of Cartilage Degradation: A combined tissue engineering and gene therapy approach. Arthritis & Rheumatism 48, 709-718.
- Langton KP, McKie N, Smith BM, Brown NJ, Barker MD. (2005) Sorsby's fundus dystrophy mutations impair turnover of TIMP-3 by retinal pigment epithelial cells. Hum Mol Genet. 14:3579-86.
- Bigg HF, Rowan AD, Barker MD & Cawston TE (2007). Activity of matrix metalloproteinase-9 against native collagen types I and III. FEBS J 274:1246-55.
- Coughlan T, Crawford A, Hatton P and Barker M (2010) A knockdown study of ADAMTS-5 and -9 in 3D chondrocyte culture. J Tissue Eng. Regen. Med. (in press).