Prof Anthony DayBA, MA, DPhil

Professor of Biochemistry

Full contact details
View graph of relations

Research interests

Glycosaminoglycan-protein interactions in inflammatory processes

My main area of interest is the role of glycosaminoglycan-binding proteins in inflammatory disease (e.g. arthritis and age-related macular degeneration) and inflammation-like processes (e.g. ovulation). Glycosaminoglycans (GAGs) are linear polysaccharides that are key components of extracellular matrix as well as being found ubiquitously on cell surfaces. For example, the interactions of hyaluronan (HA) – a high molecular weight GAG – with specific HA-binding proteins (hyaladherins) are responsible for the mechanical properties of cartilage and blood vessel walls, the formation of a viscoelastic “cumulus” matrix around the oocyte that is required for ovulation/fertilisation as well as mediating immune cell trafficking. One of the long-standing aims of our research is to determine the structural basis and molecular regulation of HA-protein interactions. We have already made significant progress on this, for example, through X-ray crystallographic and NMR analysis of TSG-6, a secreted protein often associated with inflammation, and CD44, the major cell surface receptor for HA. We are also using biophysical techniques such as AUC, SEC-MALLS and SAXS to help characterise multi-molecular hyaladherin/HA complexes and provide models for non-HA-binding proteins that are implicated in HA matrix organisation, e.g. PTX3. In addition to HA, TSG-6 binds to sulphated GAGs (i.e. chondroitin-4-sulphate, dermatan sulphate (DS), heparan sulphate (HS) and heparin) as well as a growing list of proteins (e.g. CXCL8, inter-α-inhibitor (IαI) and RANKL) where these interactions underpin a wide range of different functional activities. For example, TSG-6 catalyses the covalent transfer of heavy chains from IαI onto HA to form HC•HA complexes that are essential for the formation/stability of the cumulus matrix and where this modification of HA can also occur at sites of inflammation; our recent studies have shown that PTX3 plays a critical role in cross-linking these HC•HA complexes to form a stable network. Furthermore, TSG-6 has been shown to be a potent inhibitor of neutrophil migration (via its binding to CXCL8), protect cartilage in models of inflammatory arthritis and has been implicated in the regulation of bone turnover (e.g. inhibiting osteoclast-mediated bone resorption). Thus, TSG-6 is likely an endogenous protector of joint and bone function during inflammation making it an attractive target for the development of novel treatments for musculoskeletal disease. Another key area of interest is the investigation of the role of complement factor H (CFH) in Age-related Macular Degeneration (AMD), which is the predominant cause of blindness in the industrialised world; the Y402H polymorphism in the CFH gene (first described by Tony in 1988) has been implicated as a major risk factor for developing AMD. We have shown that this Tyr to His coding change has a large effect on the binding of CFH to sulphated GAGs, e.g. HS and DS present in the Bruch’s membrane of the human retina, which is the site of AMD pathology. In addition, we have recently found that this is a large reduction in the amount of HS present in the Bruch's membrane as a consequence of normal ageing. The poorer binding of the disease-associated 402H variant could lead to chronic local inflammation (due to complement dysregulation), contributing directly to the development and/or progression of AMD.

For further details see http://www.wellcome-matrix.org/research_groups/tony-day.html

Projects

Research and projects

No current projects are available for public display