Peta Bradbury
@curie.fr
Postdoctoral Researcher
Institut Curue
EDUCATION
2012 - 2016 Ph.D. University of Sydney
Primary Supervisor: A/Prof. Geraldine O’Neill (University of Sydney; Australia)
Auxiliary Supervisor: Prof. Ben Fabry (Friedrich-Alexander Universität, Germany)
Thesis Title: Structural homology and functional similarity: Cas family proteins, NEDD9 and p130Cas, are functionally distinct focal adhesion molecules.
2008 Bachelor of Science (Honours). University of Wollongong
Supervisor: Dr Jason McArthur
2004 - 2007 Bachelor of Science. University of Wollongong
Scopus Publications
Scopus Publications
Diane Pelzer, Ludmilla de Plater, Peta Bradbury, Adrien Eichmuller, Anne Bourdais, Guillaume Halet, and Jean‐Léon Maître
Springer Science and Business Media LLC
AbstractCell fragmentation is commonly observed in human preimplantation embryos and is associated with poor prognosis during assisted reproductive technology (ART) procedures. However, the mechanisms leading to cell fragmentation remain largely unknown. Here, light sheet microscopy imaging of mouse embryos reveals that inefficient chromosome separation due to spindle defects, caused by dysfunctional molecular motors Myo1c or dynein, leads to fragmentation during mitosis. Extended exposure of the cell cortex to chromosomes locally triggers actomyosin contractility and pinches off cell fragments. This process is reminiscent of meiosis, during which small GTPase‐mediated signals from chromosomes coordinate polar body extrusion (PBE) by actomyosin contraction. By interfering with the signals driving PBE, we find that this meiotic signaling pathway remains active during cleavage stages and is both required and sufficient to trigger fragmentation. Together, we find that fragmentation happens in mitosis after ectopic activation of actomyosin contractility by signals emanating from DNA, similar to those observed during meiosis. Our study uncovers the mechanisms underlying fragmentation in preimplantation embryos and, more generally, offers insight into the regulation of mitosis during the maternal‐zygotic transition.
Hadi Mahmodi, Peta Bradbury, Aylin Cidem, H. X. Ong, Daniela Traini, and Irina V. Kabakova
SPIE
Brillouin microscopy has emerged as a non-invasive and label-free technique to map micro-mechanical properties of cells. Here we apply Brillouin microscopy to probe reorganization of F-actin network in respiratory cells treated with Timothy grass pollen protein extracts. The results of our measurements in conjunction with clustering data analysis confirm spatial cellular reorganization of F-actin proteins and compromised junctional integrity in treated cells as compared to controls.
Ipek Karacan, Besim Ben‐Nissan, Jerran Santos, Stanley Yiu, Peta Bradbury, Stella M. Valenzuela, and Joshua Chou
Hindawi Limited
Biofilm formation on an implant surface is most commonly caused by the human pathogenic bacteria Staphylococcus aureus, which can lead to implant related infections and failure. It is a major problem for both implantable orthopedic and maxillofacial devices. The current antibiotic treatments are typically delivered orally or in an injectable form. They are not highly effective in preventing or removing biofilms, and they increase the risk of antibiotic resistance of bacteria and have a dose‐dependent negative biological effect on human cells. Our aim was to improve current treatments via a localized and controlled antibiotic delivery‐based implant coating system to deliver the antibiotic, gentamicin (Gm). The coating contains coral skeleton derived hydroxyapatite powders (HAp) that act as antibiotic carrier particles and have a biodegradable poly‐lactic acid (PLA) thin film matrix. The system is designed to prevent implant related infections while avoiding the deleterious effects of high concentration antibiotics in implants on local cells including primary human adipose derived stem cells (ADSCs). Testing undertaken in this study measured the rate of S. aureus biofilm formation and determined the growth rate and proliferation of ADSCs. After 24 h, S. aureus biofilm formation and the percentage of live cells found on the surfaces of all 5%–30% (w/w) PLA‐Gm‐(HAp‐Gm) coated Ti6Al4V implants was lower than the control samples. Furthermore, Ti6Al4V implants coated with up to 10% (w/w) PLA‐Gm‐(HAp‐Gm) did not have noticeable Gm related adverse effect on ADSCs, as assessed by morphological and surface attachment analyses. These results support the use and application of the antibacterial PLA‐Gm‐(HAp‐Gm) thin film coating design for implants, as an antibiotic release control mechanism to prevent implant‐related infections.
Giulia Silvani, Peta Bradbury, Carin Basirun, Christine Mehner, Detina Zalli, Kate Poole, and Joshua Chou
Springer Science and Business Media LLC
AbstractThe advancement of microgravity simulators is helping many researchers better understanding the impact of the mechanically unloaded space environment on cellular function and disfunction. However, performing microgravity experiments on Earth, using simulators such as the Random Positioning Machine, introduces some unique practical challenges, including air bubble formation and leakage of growth medium from tissue culture flask and plates, all of which limit research progress. Here, we developed an easy-to-use hybrid biological platform designed with the precision of 3D printing technologies combined with PDMS microfluidic fabrication processes to facilitate reliable and reproducible microgravity cellular experiments. The system has been characterized for applications in the contest of brain cancer research by exposing glioblastoma and endothelial cells to 24 h of simulated microgravity condition to investigate the triggered mechanosensing pathways involved in cellular adaptation to the new environment. The platform demonstrated compatibility with different biological assays, i.e., proliferation, viability, morphology, protein expression and imaging of molecular structures, showing advantages over the conventional usage of culture flask. Our results indicated that both cell types are susceptible when the gravitational vector is disrupted, confirming the impact that microgravity has on both cancer and healthy cells functionality. In particular, we observed deactivation of Yap-1 molecule in glioblastoma cells and the remodeling of VE-Cadherin junctional protein in endothelial cells. The study provides support for the application of the proposed biological platform for advancing space mechanobiology research, also highlighting perspectives and strategies for developing next generation of brain cancer molecular therapies, including targeted drug delivery strategies.
Peta Bradbury, Aylin Cidem, Hadi Mahmodi, Janet M. Davies, Patrick T. Spicer, Stuart W. Prescott, Irina Kabakova, Hui Xin Ong, and Daniela Traini
Springer Science and Business Media LLC
Peta Bradbury, Cassandra P. Nader, Aylin Cidem, Sandra Rutting, Dianne Sylvester, Patrick He, Maria C. Rezcallah, Geraldine M. O’Neill, and Alaina J. Ammit
Springer Science and Business Media LLC
AbstractMany lung diseases are characterized by fibrosis, leading to impaired tissue patency and reduced lung function. Development of fibrotic tissue depends on two-way interaction between the cells and the extra-cellular matrix (ECM). Concentration-dependent increased stiffening of the ECM is sensed by the cells, which in turn increases intracellular contraction and pulling on the matrix causing matrix reorganization and further stiffening. It is generally accepted that the inflammatory cytokine growth factor β1 (TGF-β1) is a major driver of lung fibrosis through the stimulation of ECM production. However, TGF-β1 also regulates the expression of members of the tropomyosin (Tm) family of actin associating proteins that mediate ECM reorganization through intracellular-generated forces. Thus, TGF-β1 may mediate the bi-directional signaling between cells and the ECM that promotes tissue fibrosis. Using combinations of cytokine stimulation, mRNA, protein profiling and cellular contractility assays with human lung fibroblasts, we show that concomitant induction of key Tm isoforms and ECM by TGF-β1, significantly accelerates fibrotic phenotypes. Knocking down Tpm2.1 reduces fibroblast-mediated collagen gel contraction. Collectively, the data suggest combined ECM secretion and actin cytoskeleton contractility primes the tissue for enhanced fibrosis. Our study suggests that Tms are at the nexus of inflammation and tissue stiffening. Small molecules targeting specific Tm isoforms have recently been designed; thus targeting Tpm2.1 may represent a novel therapeutic target in lung fibrosis.
Giulia Silvani, Carin Basirun, Hanjie Wu, Christine Mehner, Kate Poole, Peta Bradbury, and Joshua Chou
Wiley
AbstractGlioblastoma multiforme (GBM) is one of the most aggressive malignant brain tumors and urgently requires the development of new therapeutic strategies. In this study, an innovative hybrid in vitro vascularized GBM‐on‐a‐chip model is presented as a strategic integration of microfluidics and 3D bioprinting technologies. The system can recreate the compartmentalized brain tumor microenvironment, comprising the functional blood brain barrier (BBB) and the adjacent 3D perivascular tumor niche, by selectively mimicking physiological shear stress and cell–cell, cell–matrix mechanical interaction. The GBM‐on‐a‐chip model was evaluated under simulated microgravity (µG) condition as a form of mechanical unloading showing a significant cell morphological and mechanotransduction response thereby indicating that gravitational forces play an important role in glioblastoma mechanical regulation. The proposed GBM‐on‐a‐chip represents a meaningful biological tool for further research in cancer mechanobiology and pre‐clinical approach in brain tumor therapy.
Mathew N. Leslie, Joshua Chou, Paul M. Young, Daniela Traini, Peta Bradbury, and Hui Xin Ong
MDPI AG
The emphysema death toll has steadily risen over recent decades, causing the disease to become the third most common cause of death worldwide in 2019. Emphysema is currently incurable and could be due to a genetic condition (Alpha-1 antitrypsin deficiency) or exposure to pollutants/irritants, such as cigarette smoke or poorly ventilated cooking fires. Despite the growing burden of emphysema, the mechanisms behind emphysematous pathogenesis and progression are not fully understood by the scientific literature. A key aspect of emphysematous progression is the destruction of the lung parenchyma extracellular matrix (ECM), causing a drastic shift in the mechanical properties of the lung (known as mechanobiology). The mechanical properties of the lung such as the stiffness of the parenchyma (measured as the elastic modulus) and the stretch forces required for inhalation and exhalation are both reduced in emphysema. Fibroblasts function to maintain the structural and mechanical integrity of the lung parenchyma, yet, in the context of emphysema, these fibroblasts appear incapable of repairing the ECM, allowing emphysema to progress. This relationship between the disturbances in the mechanical cues experienced by an emphysematous lung and fibroblast behaviour is constantly overlooked and consequently understudied, thus warranting further research. Interestingly, the failure of current research models to integrate the altered mechanical environment of an emphysematous lung may be limiting our understanding of emphysematous pathogenesis and progression, potentially disrupting the development of novel treatments. This review will focus on the significance of emphysematous lung mechanobiology to fibroblast activity and current research limitations by examining: (1) the impact of mechanical cues on fibroblast activity and the cell cycle, (2) the potential role of mechanical cues in the diminished activity of emphysematous fibroblasts and, finally, (3) the limitations of current emphysematous lung research models and treatments as a result of the overlooked emphysematous mechanical environment.
Zara Sheikh, Peta Bradbury, Tristan A. Reekie, Michele Pozzoli, Paul D. Robinson, Michael Kassiou, Paul M. Young, Hui Xin Ong, and Daniela Traini
Elsevier BV
Zara Sheikh, Larissa Gomes Dos Reis, Peta Bradbury, Giulio Meneguzzo, Santo Scalia, Paul M. Young, Hui Xin Ong, and Daniela Traini
Elsevier BV
Hanieh Gholizadeh, Hui Xin Ong, Peta Bradbury, Agisilaos Kourmatzis, Daniela Traini, Paul Young, Ming Li, and Shaokoon Cheng
Informa UK Limited
ABSTRACT Objectives A human nasal epithelial mucosa (NEM) on-a-chip is developed integrated with a novel carbon nanofibers-modified carbon electrode for real-time quantitative monitoring of in vitro nasal drug delivery. The integration of platinum electrodes in the chip also enables real-time measurement of transepithelial electrical resistance (TEER). Methods The air-liquid interface culture of nasal epithelial RPMI 2650 cells in the NEM-on-a-chip was optimized to mimic the key functional characteristics of the human nasal mucosa. The epithelial transport of ibuprofen in the NEM-on-a-chip was electrochemically monitored in real-time under static and physiologically realistic dynamic flow conditions. Results The NEM-on-a-chip mimics the mucus production and nasal epithelial barrier function of the human nasal mucosa. The real-time drug quantification by the NEM-on-a-chip was validated versus the high-performance liquid chromatography method. The drug transport rate monitored in the NEM-on-a-chip was influenced by the flow in the bottom compartment of the chip, highlighting the importance of emulating the dynamic in vivo condition for nasal drug transport studies. Conclusion This novel NEM-on-a-chip can be a low-cost and time-efficient alternative to the costly laborious conventional techniques for in vitro nasal drug transport assays. Importantly, its dynamic microenvironment enables conducting nasal drug transport tests under physiologically relevant dynamic conditions.
Zara Sheikh, Peta Bradbury, Michele Pozzoli, Paul M. Young, Hui Xin Ong, and Daniela Traini
Elsevier BV
Aylin Cidem, Peta Bradbury, Daniela Traini, and Hui Xin Ong
Frontiers Media SA
For the past 50 years, the route of inhalation has been utilized to administer therapies to treat a variety of respiratory and pulmonary diseases. When compared with other drug administration routes, inhalation offers a targeted, non-invasive approach to deliver rapid onset of drug action to the lung, minimizing systemic drug exposure and subsequent side effects. However, despite advances in inhaled therapies, there is still a need to improve the preclinical screening and the efficacy of inhaled therapeutics. Innovative in vitro models of respiratory physiology to determine therapeutic efficacy of inhaled compounds have included the use of organoids, micro-engineered lung-on-chip systems and sophisticated bench-top platforms to enable a better understanding of pulmonary mechanisms at the molecular level, rapidly progressing inhaled therapeutic candidates to the clinic. Furthermore, the integration of complementary ex vivo models, such as precision-cut lung slices (PCLS) and isolated perfused lung platforms have further advanced preclinical drug screening approaches by providing in vivo relevance. In this review, we address the challenges and advances of in vitro models and discuss the implementation of ex vivo inhaled drug screening models. Specifically, we address the importance of understanding human in vivo pulmonary mechanisms in assessing strategies of the preclinical screening of drug efficacy, toxicity and delivery of inhaled therapeutics.
Emelie Landh, Lyn M Moir, Peta Bradbury, Daniela Traini, Paul M Young, and Hui Xin Ong
Future Medicine Ltd
Background: Lymphangioleiomyomatosis (LAM) is characterized by growth of smooth muscle-like cells in the lungs that spread to other organs via lymphatic vessels. Current oral rapamycin treatment is limited by low bioavailability of approximately 15%. Aim: The effect of inhaled rapamycin solid lipid nanoparticles (Rapa-SLNs) size on its penetration through the lymphatics. Method: Three Rapa-SLN formulations (200–1000 nm) were produced and assessed for particle characteristics and further for toxicity and performance in vitro. Results: Rapa-SLNs of 200 nm inhibited proliferation in TSC2-negative mouse embryonic fibroblast cells and penetrated the respiratory epithelium and lymphatic endothelium significantly faster compared with free rapamycin and larger Rapa-SLNs. Conclusion: Rapa-SLN approximately 200 nm allows efficient entry of rapamycin into the lymphatic system and is therefore a promising treatment for LAM patients.
Chun-Te Wu, Hsiao-Tzu Chang, Chien-Yu Wu, Shi-Wei Chen, Sih-Ying Huang, Mingxin Huang, Yeong-Tsuen Pan, Peta Bradbury, Joshua Chou, and Hung-Wei Yen
Elsevier BV
Peta Bradbury, Hanjie Wu, Jung Un Choi, Alan E. Rowan, Hongyu Zhang, Kate Poole, Jan Lauko, and Joshua Chou
Frontiers Media SA
A lack of gravity experienced during space flight has been shown to have profound effects on human physiology including muscle atrophy, reductions in bone density and immune function, and endocrine disorders. At present, these physiological changes present major obstacles to long-term space missions. What is not clear is which pathophysiological disruptions reflect changes at the cellular level versus changes that occur due to the impact of weightlessness on the entire body. This review focuses on current research investigating the impact of microgravity at the cellular level including cellular morphology, proliferation, and adhesion. As direct research in space is currently cost prohibitive, we describe here the use of microgravity simulators for studies at the cellular level. Such instruments provide valuable tools for cost-effective research to better discern the impact of weightlessness on cellular function. Despite recent advances in understanding the relationship between extracellular forces and cell behavior, very little is understood about cellular biology and mechanotransduction under microgravity conditions. This review will examine recent insights into the impact of simulated microgravity on cell biology and how this technology may provide new insight into advancing our understanding of mechanically driven biology and disease.
Peta Bradbury, Nowshin N. Rumzhum, and Alaina J. Ammit
Wiley
AbstractProstaglandin 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.
Peta Bradbury, Brijeshkumar S. Patel, Aylin Cidem, Cassandra P. Nader, Brian G. Oliver, and Alaina J. Ammit
Springer Science and Business Media LLC
Peta Bradbury, Daniela Traini, Alaina J. Ammit, Paul M. Young, and Hui Xin Ong
Elsevier BV
Peta M. Bradbury, Kylie Turner, Camilla Mitchell, Kaitlyn R. Griffin, Shiloh Middlemiss, Loretta Lau, Rebecca Dagg, Elena Taran, Justin Cooper-White, Ben Fabry,et al.
The Company of Biologists
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 we compared wildtype exogenous NEDD9 with a hybrid construct in which the NEDD9 FAT domain is exchanged for the p130Cas FAT domain. Fluorescence recovery after photobleaching (FRAP) revealed significantly slowed exchange of the fusion protein at focal adhesions and significantly slower 2D migration. No differences were detected in cell stiffness measured with Atomic Force Microscopy (AFM) and 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 tyrosine phosphorylation of the NEDD9 substrate domain. 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 mechanosensing function.
Peta Bradbury, Cuc T. Bach, Andre Paul, and Geraldine M. O'Neill
Elsevier BV
Background: Dynamic exchange provides a mechanism for rapidly reorganizing macromolecular structures. Results: Exchange of the focal adhesion-targeted protein NEDD9 between the cytoplasm and focal adhesions is faster in the absence of Src kinase activity. Conclusion: Src kinase modulates the transit time of NEDD9 at focal adhesion sites. Significance: This is a new function for Src kinase in cell migration. Dynamic exchange of molecules between the cytoplasm and integrin-based focal adhesions provides a rapid response system for modulating cell adhesion. Increased residency time of molecules that regulate adhesion turnover contributes to adhesion stability, ultimately determining migration speed across two-dimensional surfaces. In the present study we test the role of Src kinase in regulating dynamic exchange of the focal adhesion protein NEDD9/HEF1/Cas-L. Using either chemical inhibition or fibroblasts genetically null for Src together with fluorescence recovery after photobleaching (FRAP), we find that Src significantly reduces NEDD9 exchange at focal adhesions. Analysis of NEDD9 mutant constructs with the two major Src-interacting domains disabled revealed the greatest effects were due to the NEDD9 SH2 binding domain. This correlated with a significant change in two-dimensional migratory speed. Given the emerging role of NEDD9 as a regulator of focal adhesion stability, the time of NEDD9 association at the focal adhesions is key in modulating rates of migration and invasion. Our study suggests that Src kinase activity determines NEDD9 exchange at focal adhesions and may similarly modulate other focal adhesion-targeted Src substrates to regulate cell migration.
Jaime B. Baquiran, Peta Bradbury, and Geraldine M. O'Neill
Public Library of Science (PLoS)
The focal adhesion docking protein NEDD9/HEF1/Cas-L regulates cell migration and cancer invasion. NEDD9 is a member of the Cas family of proteins that share conserved overall protein-protein interaction domain structure, including a substrate domain that is characterized by extensive tyrosine (Y) phosphorylation. Previous studies have suggested that phosphorylation of Y253 in the substrate domain of the Cas family protein p130Cas is specifically required for p130Cas function in cell migration. While it is clear that tyrosine phosphorylation of the NEDD9 substrate domain is similarly required for the regulation of cell motility, whether individual NEDD9 tyrosine residues have discrete function in regulating motility has not previously been reported. In the present study we have used a global sequence alignment of Cas family proteins to identify a putative NEDD9 equivalent of p130Cas Y253. We find that NEDD9 Y189 aligns with p130Cas Y253 and that it is conserved among NEDD9 vertebrate orthologues. Expression of NEDD9 in which Y189 is mutated to phenylalanine results in increased rates of cell migration and is correlated with increased disassembly of GFP.NEDD9 focal adhesions. Conversely, mutation to Y189D significantly inhibits cell migration. Our previous data has suggested that NEDD9 stabilizes focal adhesions and the present data therefore suggests that phosphorylation of Y189 NEDD9 is required for this function. These findings indicate that the individual tyrosine residues of the NEDD9 substrate domain may serve discrete functional roles. Given the important role of this protein in promoting cancer invasion, greater understanding of the function of the individual tyrosine residues is important for the future design of approaches to target NEDD9 to arrest cancer cell invasion.
Peta Bradbury, Maha Mahmassani, Jessie Zhong, Kylie Turner, Andre Paul, Nicole M. Verrills, and Geraldine M. O'Neill
Elsevier BV
Peta Bradbury, Ben Fabry, and Geraldine M. O'Neill
Informa UK Limited
The critical role of migration and invasion in cancer metastasis warrants new therapeutic approaches targeting the machinery regulating cell migration and invasion. While 2-dimensional (2D) models have helped identify a range of adhesion molecules, cytoskeletal components and regulators that are potentially important for cell migration, the use of models that better mimic the 3-dimensional (3D) environment has yielded new insights into the physiology of cell movement. For example, studying cells in 3D models has revealed that invading cancer cells may switch between heterogeneous invasion modes and thus evade pharmacological inhibition of invasion. Here we summarize published data in which the role of cell adhesion molecules in 2D vs. 3D migration have been directly compared and discuss mechanisms that regulate migration speed and persistence in 2D and 3D. Finally we discuss limits of 3D culture models to recapitulate the in vivo „situation.
J G Lees, C T T Bach, P Bradbury, A Paul, P W Gunning, and G M O'Neill
Springer Science and Business Media LLC