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Ultimately, all cell signalling originates from outside the cell, typically through intermolecular interactions between cell membrane biomolecules and those in the surrounding extracellular environment.

Changes in the extracellular environment, including the structure and dynamics of the extracellular matrix, lead to altered cellular processes.  Changes in extracellular matrix structure are particularly relevant in degenerative and metabolic diseases and in cancer where they are an inherent component of disease progression.

A central paradigm in our research is that restoring normal extracellular matrix structure will restore normal cell behaviour.  Thus, a significant part of our research effort is defining drug targets to achieve this in a range of diseases.

Current work focusses on therapeutics for vascular calcification (hardening of the arteries) and cancer.

Vascular calcification

Vascular calcification is a serious and widespread clinical problem manifesting in the vessel intima as a result of atherosclerosis and in the media in chronic kidney disease (CKD), diabetes and ageing. It is an independent risk factor for cardiovascular mortality in all disease contexts and calcification is directly causal in the induction of CV events. There are currently no treatments in the clinic for this condition.

Our work in collaboration with Prof. Cathy Shanahan (Kings College London) has identified that vascular calcification is a poly(ADP ribose) polymerase (PARP)-driven process, with particular involvement of PARP2.  We have shown that PARP2 inhibitor, minocycline, inhibits vascular calcification in vitro and in vivo (see Calcification). An ongoing clinical trial in Cambridge is examining the potential of minocycline to relieve vascular calcification in patients.

Figure: (top) Two-dimensional 13C-13C correlation NMR spectra of vascular smooth muscle cell (VSMC) extracellular matrix sample grown in vitro showing poly(ADP ribose) signals; (bottom) structure of poly(ADP ribose)

Patents:

M. Duer, D. Reid, C. Shanahan, Vascular Calcification - Patent US 10159685 B2 

The patent covering the use of PARP inhibitors to treat atherosclerotic or medial vascular calcification is licensed by Cycle Pharmaceuticals.

Cancer

In 2018, Duer founded a company, Cambridge Oncology Ltd to develop new therapeutics to inhibit cancer cell invasion.  More news will be available soon!

Related Publications 

Poly(ADP-Ribose) Links the DNA Damage Response and Biomineralization
K Mueller – Cell Reports (2019) 27, 3124