Projects per year
I completed my PhD at the University of Bristol under the supervision of Prof. Andrew Newby, studying the molecular mechanisms regulating the expression of matrix metalloproteinase (MMP) genes in vascular smooth muscle cells by inflammatory cytokines and growth factor. This research was the first to establish the essential role played by the pro-inflammatory cytokine Nuclear Factor Kappa-B (NF-kB) in the regulation of several MMP genes and provided a mechanistic link between inflammation and extracellular matrix remodelling. We also demonstrated the importance of mitogens for expression of many of these MMP genes, showing that inflammatory cytokines act in synergy with mitogens to upregulate expression of MMPs genes, linking tissue injury (a potent stimulus for mitogen production), inflammation and ECM remodelling. The publications arising from this work have now been cited almost 1000 times.
After completing my PhD, I joined Prof. Andrew Baker’s group and worked on the mechanisms underlying the pro-apoptotic properties of the MMP inhibitor, TIMP-3. TIMP3 is a secreted ECM-bind protein that is able to induce death of vascular smooth muscle cells. These properties are currently being developed by Prof Bakers groups as a novel gene therapy approach to treat late vein graft failure. I characterised how the TIMP-3 protein induces apoptotic cell death of smooth muscle cells and established that this is dependent on the protease inhibitory function of TIMP3. I also showed that TIMP induces death via a FADD-dependent type II pathway. This work has now been cited over 200 times.
After completing my first post-doctoral research post, I turned my attention to the mechanisms regulating the proliferation of vascular smooth muscle cells. These cells are normally quiescent in health blood vessels but their proliferation rate can be dramatically increase in response to vessel injury or insult, where it promotes neointima formation after angioplasty and contributes towards late vein graft failure. I focused on the second messenger, 3’, 5’-cyclic adenosine monophosphate (cAMP). At this point, cAMP had been recognised to have numerous vascular protective properties and had been shown to inhibit VSMC proliferation, although the underlying mechanisms were not known. My research established that the growth inhibitory properties of cAMP signalling in VSMC are mediated via two central cAMP-sensitive proteins, namely, Protein Kinase-A (PKA) and Exchange Protein Activated by cAMP (EPAC). The two pathways act together to inhibit the activity of members of the Rho GTPases, which control actin cytoskeleton polymerisation and organisation. We demonstrated that this disruption of actin polymerisation was a key step in cAMP-mediated growth arrest. We went on to link these changes in the actin cytoskeleton to transcription of genes needed for cell proliferation. We showed that two key transcription factors, MKL and TEAD play a central role in this.
Our work on cAMP highlighted the central role of the actin cytoskeleton in integrating multiple upstream signals and regulating appropriate cellular responses. Our current research is focussing on how these mechanisms are involved in regulating cell behaviour during a number of pathological processes that underly cardiovascular disease. These include sensing changes in cardiac tissue stiffness and regulating cardiac fibrosis and how actin can translocate into the nucleus and control expression of genes that promote vascular calcification.
- 1 Similar Profiles
Collaborations and top research areas from the last five years
Dive into details
Select a country/territory to view shared publications and projects
- 3 Finished
29/01/18 → 18/03/22
24/10/16 → 23/10/19
HARNESSING THE VASCULAR PROTECTIVE EFFECTS OF CREB: The SIK-CRTC-CREB pathway as a therapeutic target
6/02/15 → 5/10/18
Combined role for YAP-TEAD and YAP-RUNX2 signalling in substrate-stiffness regulation of cardiac fibroblast proliferationEbrahimighaei, R., Sala-Newby, G. B., Hudson, C. A., Kimura-Wozniak, T., Hathway, T. P., Hawkins, J. W., McNeill, M. C., Richardson, R., Newby, A. C. & Bond, M., 12 Aug 2022, In: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1869, 11, 45 p., 119329.
Research output: Contribution to journal › Article (Academic Journal) › peer-reviewOpen AccessFile8 Citations (Scopus)25 Downloads (Pure)
Cyclic-AMP Increases Nuclear Actin Monomer Which Promotes Proteasomal Degradation of RelA/p65 Leading to Anti-Inflammatory EffectsHawkins, J. W., McNeill, M. C., Ebrahimighaei, R., Mellor, H. H., Newby, A. C. & Bond, M., 21 Apr 2022, In: Cells. 11, 9, 20 p., 1414.
Research output: Contribution to journal › Article (Academic Journal) › peer-reviewOpen AccessFile1 Citation (Scopus)40 Downloads (Pure)
Corbin, L. J., White, S. J., Taylor, A. E., Williams, C. M., Taylor, K., Van Den Bosch, M. T. J., Teasdale, J. E., Jones, M. L., Bond, M., Harper, M. T., Falk, L., Groom, A., Hazell, G. G. J., Paternoster, L., Munafo, M. R., Nordestgaard, B. G., Tybjaerg-Hansen, A., Bojesen, S. E., Relton, C. L., Min, J. L., & 4 others, 4 Feb 2022, In: Circulation Research. 130, 3, p. 384-400 17 p.
Research output: Contribution to journal › Article (Academic Journal) › peer-reviewOpen AccessFile4 Citations (Scopus)55 Downloads (Pure)