• Room Bob Champion Res

Accepting PhD Students

PhD projects

Funded PhD studentship available now to investigate molecular pathogenesis of age-related macular degeneration.

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Personal profile

Academic Background

Our research programme focuses on understanding the molecular pathogenesis of chronic degenerative diseases such as osteoarthritis, with the goal of developing novel therapies to treat these conditions. We focus specifically on defining how the activity and availability of anabolic growth factors and metalloprotease inhibitors is regulated by their trafficking between pericellular heparan sulfate proteoglycans and the cell surface endocytic receptor LRP1. 

 

(i) Defining molecular pathways that drive cartilage loss in osteoarthritis. Osteoarthritis is characterised by an increase in the activity of metalloproteases that degrade cartilage extracellular matrix components, and so impair the structural integrity of the tissue. This is caused by increased expression of these metalloproteases and decreased levels of their endogenous inhibitor, tissue inhibitor of metalloproteinases 3 (TIMP-3). Our group established that levels of TIMP-3 in cartilage are regulated by the equilibrium between its binding to heparan sulfate (HS) glycans in the extracellular matrix and its cellular endocytosis by the scavenger receptor, LDL receptor-related protein 1 (LRP1). Current projects focus on defining how HS sulfation patterns change tissue repair in OA, and designing small molecule inhibitors to target TIMP-3 loss as a therapy for osteoarthritis. 

(ii) LRP1/HS axis also regulates macrophage behaviour. We found that LRP1 also dynamically regulates TIMP-3 levels in macrophages, where TIMP-3 is the primary inhibitor of TNF release by the metalloproteinase ADAM17. This enables LRP1 to control termination of TNF release during the inflammatory response. As in chondrocytes, macrophage HS protects TIMP-3 and other ligands from uptake by LRP1. We are examining changes in expression of HS biosynthesis enzymes and core proteins upon macrophage phenotype and activation, and looking at how this alters retention and biological activity of HS-binding cytokines, chemokines and growth factors during inflammation.

 

(iii) LRP1/HS in age-related macular degeneration (AMD).  The LRP1/HS axis also regulates extracellular matrix turnover in the retina. Mutations in TIMP-3 cause Sorsby Fundus Dystrophy (SFD), a rare genetic form of macular degeneration that can serve as a model for the more common age-related macular degeneration. To better understand the molecular pathogenesis of AMD, we are investigating how retinal levels of wild-type and SFD mutants of TIMP-3 are regulated by LRP1 and HS. Funded PhD studentship available now - email for details. 

External Activities

2019-              Senior Fellow of Advance HE

2019-              Member of Versus Arthritis Musculoskeletal Disorders Research Advisory Group

2016-              Editorial board member, Journal of Biological Chemistry

2019               Research Topic Editor, Frontiers in Immunology 

2014-2017      Elected committee member of British Society for Matrix Biology

External positions

University Research Lecturer, University of Oxford

20122018

Career Development Fellow - Arthritis Research UK, University of Oxford

20112016

Post-doctoral researcher, Imperial College London

Network

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