Centre staff
Dr Alison Cross
Research lecturer in biomedical science
Phone 0114 225 4061
Email a.k.cross@shu.ac.uk
Research interests
Molecular pathology of multiple sclerosis and stroke
Studies into the role of ADAMTS-1, 4 and -5 in central nervous system disease
The ADAMTSs (A Disintegrin and Metalloproteinase with Thrombospondin motifs), ADAMTS-1, -4, -5, belong to a recently described group of metalloproteinase enzymes which possess proteoglycanase and anti-angiogenic activities. The ADAMTS proteoglycanases are inhibited by tissue inhibitor of metalloproteinases (TIMP)-3 which, like the ADAMTSs, is sequestered in the extracellular matrix (ECM) via interactions with sulphated glycosaminoglycans. ADAMTS-1, 4 and 5 cleave aggregating chondroitin sulphate proteoglycans such as aggrecan, versican and brevican which are ECM proteins found in the central nervous system (CNS). These extracellular matrix proteins are important to brain structure through maintenance of the correct hydrodynamics and in their interactions with other ECM components. They also contribute to disease processes and their synthesis is modulated by injury. They may therefore play a role in CNS ECM turnover in both normal physiology and pathology. Our recent research has shown ADAMTS expression in the normal central nervous system and alteration of expression in Multiple Sclerosis (MS) and Stroke. We are also currently interested in expression of CNS ECM proteins in MS and stroke.
Studies into the role of ADAMTS-13 in stroke and transient ischaemic attack (TIA)
Stroke is a leading cause of death and major disability worldwide and is caused in most cases by blocking of an artery by a blood clot. Blood clotting involves many regulatory pathways required to maintain a balance which if altered, may lead to unwanted clotting. Von Willebrand Factor (VWF) is a protein involved in the normal clotting process. Large forms of VWF (ULVWF) are normally regulated by the enzyme ADAMTS-13. The enzymatic activity of ADAMTS-13 ensures a balance between multimeric and dimeric forms of VWF maintaining appropriate levels of platelet adhesion and aggregation. ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin type-1 motifs-13) is a circulating protease that is highly expressed in hepatic stellate cells and shares homology and domain structure with other members of the ADAMTS family. Its expression has been noted in normal brain tissue and endothelial cells although the cellular localisation of ADAMTS-13 in the brain has not yet been described. Deficiency of ADAMTS-13 can lead to unwanted clotting. Our current work involves studies into the control of expression of ADAMTS-13 in brain derived cells as well as measurement of the serum levels of ADAMTS-13 in stroke/TIA patients and compare these to age/sex matched controls. The results from this study may lead to novel therapies for stroke and also identify people at risk of stroke. Better understanding of the regulation of VWF by ADAMTS-13 will have implications for future management of cerebrovascular disease.
Collaborators
- Dr Kirsty Harkness
Consultant neurologist with special interest in stroke and dementia
Royal Hallamshire Hospital, Sheffield - Dr David Buttle
Reader, Division of Genomic Medicine, Sheffield University
Publications
Reid MJ, Cross AK, Haddock G, Allan SM, Stock CJ, Woodroofe MN, Buttle DJ, Bunning RAD (2009) ADAMTS-9 expression is up-regulated following transient middle cerebral artery occlusion (tMCAo) in the RAT. Neuroscience Letter 452: 252-257.
Haddock G, Cross AK, Allan S, Sharrack B, Callaghan J, Buttle DJ, Woodroofe MN (2007) Brevican and phosphacan expression and localization following transient middle cerebral artery occlusion in the rat. Biochemical Society Transactions 2007; 35:692-694
Cross AK, Allan S, Haddock G, Surr J, Bunning RAD, Buttle DJ, Stock CJ, Woodroofe MN (2006) ADAMTS-1 and -4 are up-regulated following transient middle cerebral artery occlusion in the rat and their expression is modulated by TNF in cultured astrocytes. Brain Research. 1088:19-30.
Cross AK, Haddock G, Surr J, Plumb J, Bunning RAD, Buttle DJ, Woodroofe MN (2006) Differential expression of ADAMTS-1, -4, -5 and TIMP-3 in rat spinal cord at different stages of acute experimental autoimmune encephalomyelitis. Journal of Autoimmunity. 26:16-23.
Haddock G, Cross AK, Plumb J, Surr J, Buttle DJ, Bunning RAD and Woodroofe MN (2006) Expression of ADAMTS-1, -4, -5 and TIMP-3 in normal and multiple sclerosis CNS white matter. Multiple Sclerosis. 12:386-396.
Plumb J, McQuaid S, Cross AK, Surr J, Haddock G, Bunning RAD, Woodroofe MN (2006) Upregulation of ADAM-17 expression in active lesions in multiple sclerosis. Multiple Sclerosis, 12:375-386.
Plumb, J, Cross, AK, Surr, J, Haddock, G, Smith, T, Bunning, RAD, Woodroofe, MN (2005) ADAM-17 protein and mRNA expression in the spinal cord of rats with acute experimental autoimmune encephalomyelitis. J Neuroimmunology, 164:1-9
Cross AK and Woodroofe MN (2001) Immunoregulation of microglial functional properties. Microsc Res Tech. 2001 Jul 1;54(1):10-7.
