Dr Peta Bradbury is a cell and molecular biologist within the School of Life Sciences, Faculty of Science. Peta is research intensive Honorary Visiting Research Fellow, a position that is held in collaboration with the Woolcock Institute of Medical Research, where she is the Woolcock Emphysema Centre Postdoctoral Research Fellow.
Graduating with BSc(Hons) from the University of Wollongong, Peta went on to begin her research career as a Research Assistant in the Children’s Cancer Research Unit at The Children’s Hospital at Westmead. Peta then completed her PhD (University of Sydney, 2016) in cancer cell biology, focusing specifically on the role environmental stiffness played in regulating cell migration and invasion. As a result, Peta has a keen interest in mechanobiology, a new field of scientific research that investigates how the physical and mechanical properties of an environment influence cellular behaviour.
My research focuses on identifying the molecular mechanisms that regulate the mechanotransduction and mechanosensing properties of cells. I have a particular interest in exploring the signalling pathways that govern focal adhesion dynamics and therefore, cell migration. My postdoctoral research now concentrates on elucidating the role inflammation and lung mechanics play in perpetuating emphysematous progression.
My research interests includes:
- Understanding how the mechanical properties of organs influence cell behaviour.
- Investigating the role inflammation plays in regulating cellular mechanotransduction
- Developing in-vitro models to better recapitulate the in-vivo environment.
Bradbury, P, Rumzhum, NN & Ammit, AJ 2019, 'EP2 and EP4 receptor antagonists: Impact on cytokine production and β2 -adrenergic receptor desensitization in human airway smooth muscle.', Journal of cellular physiology.View/Download from: UTS OPUS or Publisher's site
Prostaglandin E2 (PGE2 ) is a key prostanoid known to have both proinflammatory and anti-inflammatory impact in the context of chronic respiratory diseases. We hypothesize that these opposing effects may be the result of different prostanoid E (EP) receptor-mediated signaling pathways. In this study, we focus on two of the four EP receptors, EP2 and EP4 , as they are known to induce cyclic adenosine monophosphate (cAMP)-dependent signaling pathways. Using primary human airway smooth muscle (ASM) cells, we first focussed on the PGE2 -induced production of two cAMP-dependent proinflammatory mediators: interleukin 6 (IL-6) and cyclo-oxygenase 2 production. We show that PGE2 -induced IL-6 protein secretion occurs via an EP2 -mediated pathway, in a manner independent of receptor-mediated effects on messenger RNA (mRNA) expression and temporal activation kinetics of the transcription factor cAMP response element binding. Moreover, stimulation of ASM with PGE2 did not establish a positive, receptor-mediated, feedback loop, as mRNA expression for EP2 and EP4 receptors were not upregulated and receptor antagonists were without effect. Our studies revealed that the EP2 , but not the EP4 , receptor is responsible for β2 -adrenergic desensitization induced by PGE2 . We demonstrate that PGE2 -induced heterologous receptor desensitization responsible for tachyphylaxis to short- (salbutamol) or long- (formoterol) β2 -agonists (measured by cAMP release) can be reversed by the EP2 receptor antagonist PF-04418948. Importantly, this study highlights that inhibiting the EP2 receptor restores β2 -adrenergic receptor function in vitro and offers an attractive novel therapeutic target for treating infectious exacerbations in people suffering from chronic respiratory diseases in the future.
Bradbury, P, Traini, D, Ammit, AJ, Young, PM & Ong, HX 2018, 'Repurposing of statins via inhalation to treat lung inflammatory conditions', Advanced Drug Delivery Reviews, vol. 133, pp. 93-106.View/Download from: UTS OPUS or Publisher's site
© 2018 Elsevier B.V. Despite many therapeutic advancements over the past decade, the continued rise in chronic inflammatory lung diseases incidence has driven the need to identify and develop new therapeutic strategies, with superior efficacy to treat these diseases. Statins are one class of drug that could potentially be repurposed as an alternative treatment for chronic lung diseases. They are currently used to treat hypercholesterolemia by inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, that catalyses the rate limiting step in the mevalonate biosynthesis pathway, a key intermediate in cholesterol metabolism. Recent research has identified statins to have other protective pleiotropic properties including anti-inflammatory, anti-oxidant, muco-inhibitory effects that may be beneficial for the treatment of chronic inflammatory lung diseases. However, clinical studies have yielded conflicting results. This review will summarise some of the current evidences for statins pleiotropic effects that could be applied for the treatment of chronic inflammatory lung diseases, their mechanisms of actions, and the potential to repurpose statins as an inhaled therapy, including a detailed discussion on their different physical-chemical properties and how these characteristics could ultimately affect treatment efficacies. The repurposing of statins from conventional anti-cholesterol oral therapy to inhaled anti-inflammatory formulation is promising, as it provides direct delivery to the airways, reduced risk of side effects, increased bioavailability and tailored physical-chemical properties for enhanced efficacy.
Bradbury, PM, Turner, K, Mitchell, C, Griffin, KR, Middlemiss, S, Lau, L, Dagg, R, Taran, E, Cooper-White, J, Fabry, B & O'Neill, GM 2017, 'The focal adhesion targeting domain of p130Cas confers a mechanosensing function.', Journal of Cell Science, vol. 130, no. 7, pp. 1263-1273.View/Download from: UTS OPUS or Publisher's site
Members of the Cas family of focal adhesion proteins contain a highly conserved C-terminal focal adhesion targeting (FAT) domain. To determine the role of the FAT domain in these proteins, we compared wild-type exogenous NEDD9 with a hybrid construct in which the NEDD9 FAT domain had been exchanged for the p130Cas (also known as BCAR1) FAT domain. Fluorescence recovery after photobleaching (FRAP) revealed significantly slowed exchange of the fusion protein at focal adhesions and significantly slower two-dimensional migration. No differences were detected in cell stiffness as measured using atomic force microscopy (AFM) and in cell adhesion forces measured with a magnetic tweezer device. Thus, the slowed migration was not due to changes in cell stiffness or adhesion strength. Analysis of cell migration on surfaces of increasing rigidity revealed a striking reduction of cell motility in cells expressing the p130Cas FAT domain. The p130Cas FAT domain induced rigidity-dependent phosphorylation of tyrosine residues within NEDD9. This in turn reduced post-translational cleavage of NEDD9, which we show inhibits NEDD9-induced migration. Collectively, our data therefore suggest that the p130Cas FAT domain uniquely confers a mechanosensing function.
Bradbury, P, Bach, CT, Paul, A & O'Neill, GM 2014, 'Src Kinase Determines the Dynamic Exchange of the Docking Protein NEDD9 (Neural Precursor Cell Expressed Developmentally Down-regulated Gene 9) at Focal Adhesions', JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 289, no. 36, pp. 24792-24800.View/Download from: Publisher's site
Baquiran, JB, Bradbury, P & O'Neill, GM 2013, 'Tyrosine Y189 in the Substrate Domain of the Adhesion Docking Protein NEDD9 Is Conserved with p130Cas Y253 and Regulates NEDD9-Mediated Migration and Focal Adhesion Dynamics', PLOS ONE, vol. 8, no. 7.View/Download from: UTS OPUS or Publisher's site
Bradbury, P, Mahmassani, M, Zhong, J, Turner, K, Paul, A, Verrills, NM & O'Neill, GM 2012, 'PP2A phosphatase suppresses function of the mesenchymal invasion regulator NEDD9.', Biochimica et biophysica acta, vol. 1823, no. 2, pp. 290-297.View/Download from: UTS OPUS or Publisher's site
The mesenchymal mode of cancer cell invasion characterized by active adhesion turnover and a polarized actin cytoskeleton, is critically regulated by the adaptor protein NEDD9/HEF1/Cas-L. While it is known that NEDD9 is subject to extensive phosphorylation modification, the molecules that determine NEDD9 phosphorylation to stimulate adhesion turnover and mesenchymal cell morphologies are currently unknown. Earlier studies have suggested that the serine/threonine phosphatase PP2A regulates interconversion between a low molecular mass NEDD9 phosphoform and higher molecular mass phosphoforms. However, previous studies have used chemical inhibitors to block PP2A activity. In the present study we therefore aimed to specifically inhibit PP2A activity via siRNA and dominant negative approaches to investigate the effect of PP2A on interconversion between 115 kDa and 105 kDa NEDD9 and determine the functional consequence of PP2A activity for NEDD9 function. Strikingly, we find that while the phosphatase inhibitor Calyculin A indeed abrogates detachment-induced dephosphorylation of the 115 kDa NEDD9 phosphoform, PP2A depletion does not inhibit 115 kDa to 105 kDa interconversion. Our data suggest instead that PP2A targets discrete NEDD9 phosphorylation modifications separate to the events that mediate interconversion between the two forms. Functionally, PP2A depletion increases NEDD9 mediated cell spreading and mutation of S369 in the serine-rich region of NEDD9 to aspartate mimics this effect. Importantly, mutation of S369 to alanine abrogates the ability of dominant negative PP2A to increase NEDD9-mediated cell spreading. Collectively, our data reveal that the tumour suppressor PP2A may act via S369 to regulated NEDD9-mediated cell spreading.
Lees, JG, Bach, CTT, Bradbury, P, Paul, A, Gunning, PW & O'Neill, GM 2011, 'The actin-associating protein Tm5NM1 blocks mesenchymal motility without transition to amoeboid motility', ONCOGENE, vol. 30, no. 10, pp. 1241-1251.View/Download from: UTS OPUS or Publisher's site
Bradshaw, LN, Zhong, J, Bradbury, P, Mahmassani, M, Smith, JL, Ammit, AJ & O'Neill, GM 2011, 'Estradiol stabilizes the 105-kDa phospho-form of the adhesion docking protein NEDD9 and suppresses NEDD9-dependent cell spreading in breast cancer cells', BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, vol. 1813, no. 2, pp. 340-345.View/Download from: UTS OPUS or Publisher's site